RESUMEN
Severe combined immunodeficiency (SCID) is characterized by a severe deficiency in T cell numbers. We analyzed data collected (n = 307) for PHA-based T cell proliferation from the PIDTC SCID protocol 6901, using either a radioactive or flow cytometry method. In comparing the two groups, a smaller number of the patients tested by flow cytometry had <10% of the lower limit of normal proliferation as compared to the radioactive method (p = 0.02). Further, in patients with CD3+ T cell counts between 51 and 300 cells/µL, there was a higher proliferative response with the PHA flow assay compared to the 3H-T assay (p < 0.0001), suggesting that the method of analysis influences the resolution and interpretation of PHA results. Importantly, we observed many SCID patients with profound T cell lymphopenia having normal T cell proliferation when assessed by flow cytometry. We recommend this test be considered only as supportive in the diagnosis of typical SCID.
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Linfopenia , Inmunodeficiencia Combinada Grave , Recién Nacido , Humanos , Inmunodeficiencia Combinada Grave/diagnóstico , Linfopenia/diagnóstico , Tamizaje Neonatal/métodos , Linfocitos T , Proliferación CelularRESUMEN
BACKGROUND: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. OBJECTIVE: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. METHODS: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. RESULTS: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). CONCLUSIONS: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.
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Inmunodeficiencia Combinada Grave , Recién Nacido , Humanos , Lactante , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Estudios Retrospectivos , Estudios Prospectivos , Proteínas de Homeodominio/genéticaRESUMEN
BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.
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Enfermedades Raras , Enfermedades no Diagnosticadas , Estados Unidos , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Enfermedades Raras/terapia , Atención Terciaria de Salud , Medicina Genómica , Pruebas Genéticas , Asesoramiento GenéticoRESUMEN
BACKGROUND: Myocarditis following coronavirus disease 2019 (COVID-19) mRNA vaccines (Pfizer-BioNTech and Moderna) has been increasingly reported. Incidence rates in the general population are lacking, with pericarditis rather than myocarditis diagnostic codes being used to estimate background rates. This comparison is critical for balancing the risk of vaccination with the risk of no vaccination. METHODS: A retrospective case series was performed using the Mayo Clinic COVID-19 Vaccine Registry. We measured the incidence rate ratio (IRR) for myocarditis temporally related to COVID-19 mRNA vaccination compared with myocarditis in a comparable population from 2016 through 2020. Clinical characteristics and outcomes of the affected patients were collected. A total of 21 individuals were identified, but ultimately 7 patients met the inclusion criteria for vaccine-associated myocarditis. RESULTS: The overall IRR of COVID-19-related myocarditis was 4.18 (95% confidence interval [CI], 1.63-8.98), which was entirely attributable to an increased IRR among adult males (IRR, 6.69; 95% CI, 2.35-15.52) compared with females (IRR 1.41; 95% CI, .03-8.45). All cases occurred within 2 weeks of a dose of the COVID-19 mRNA vaccine, with the majority occurring within 3 days (range, 1-13) following the second dose (6 of 7 patients, 86%). Overall, cases were mild, and all patients survived. CONCLUSIONS: Myocarditis is a rare adverse event associated with COVID-19 mRNA vaccines. It occurs in adult males with significantly higher incidence than in the background population. Recurrence of myocarditis after a subsequent mRNA vaccine dose is not known at this time.
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Vacunas contra la COVID-19 , COVID-19 , Miocarditis , Adulto , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Femenino , Humanos , Incidencia , Masculino , Miocarditis/diagnóstico , Miocarditis/epidemiología , Miocarditis/etiología , ARN Mensajero/genética , Estudios Retrospectivos , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
PURPOSE: This is a functional characterization of a novel CYBA variant associated with normal DHR flow cytometry. Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by recurrent bacterial and fungal infections and dysregulated inflammatory responses due to defective phagocytic cell function leading to the formation of granulomas. CGD patients have pathogenic variants in any of the five components of the phagocytic NADPH oxidase, which transfers electrons through the phagosomal membrane and produces superoxide upon bacterial uptake. Here, we report a pediatric female patient with a novel homozygous missense variant (c.293C > T, p.(Ser98Leu)) in CYBA, encoding the p22phox protein, associated with autosomal recessive CGD. METHODS AND RESULTS: The patient presented with severe recurrent pneumonia. Specific pathogens identified included Burkholderia and Serratia species suggesting neutrophil functional abnormalities; however, the dihydrorhodamine-1,2,3 (DHR) flow cytometric and cytochrome c reduction assays for neutrophil respiratory burst fell within the low side of the normal range. Western blot and flow cytometric analysis of individual NADPH oxidase components revealed reduced levels of p22phox and gp91phoxphox proteins. The pathological consequence of the p.Ser98Leu variant was further evaluated in heterologous expression systems, which confirmed reduced p22phox protein stability and oxidase activity. CONCLUSIONS: Although this patient did not exhibit all the classic features of CGD, such as granulomas and skin infections, she had recurrent pneumonias with oxidant-sensitive pathognomonic organisms, resulting in appropriate targeted CGD testing. This case emphasizes the need to contextually interpret laboratory data, especially using clinical findings to direct additional assessments including genetic analysis.
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Enfermedad Granulomatosa Crónica , Niño , Femenino , Citometría de Flujo , Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/genética , Humanos , Mutación/genética , NADPH Oxidasa 2/genética , NADPH Oxidasas/genética , FagocitosRESUMEN
BACKGROUND: The mechanism of coronavirus disease 2019 (COVID-19) vaccine hypersensitivity reactions is unknown. COVID-19 vaccine excipient skin testing has been used in evaluation of these reactions, but its utility in predicting subsequent COVID-19 vaccine tolerance is also unknown. OBJECTIVE: To evaluate the utility of COVID-19 vaccine and vaccine excipient skin testing in both patients with an allergic reaction to their first messenger RNA COVID-19 vaccine dose and patients with a history of polyethylene glycol allergy who have not yet received a COVID-19 vaccine dose. METHODS: In this multicenter, retrospective review, COVID-19 vaccine and vaccine excipient skin testing was performed in patients referred to 1 of 3 large tertiary academic institutions. Patient medical records were reviewed after skin testing to determine subsequent COVID-19 vaccine tolerance. RESULTS: A total of 129 patients underwent skin testing, in whom 12 patients (9.3%) had positive results. There were 101 patients who received a COVID-19 vaccine after the skin testing, which was tolerated in 90 patients (89.1%) with no allergic symptoms, including 5 of 6 patients with positive skin testing results who received a COVID-19 vaccine after the skin testing. The remaining 11 patients experienced minor allergic symptoms after COVID-19 vaccination, none of whom required treatment beyond antihistamines. CONCLUSION: The low positivity rate of COVID-19 vaccine excipient skin testing and high rate of subsequent COVID-19 vaccine tolerance suggest a low utility of this method in evaluation of COVID-19 vaccine hypersensitivity reactions. Focus should shift to the use of existing vaccine allergy practice parameters, with consideration of graded dosing when necessary. On the basis of these results, strict avoidance of subsequent COVID-19 vaccination should be discouraged.
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Vacunas contra la COVID-19/efectos adversos , COVID-19 , Hipersensibilidad , Pruebas Cutáneas , COVID-19/prevención & control , Humanos , Hipersensibilidad/etiología , Inutilidad Médica , Estudios Retrospectivos , Excipientes de Vacunas/efectos adversos , Vacunas Sintéticas/efectos adversos , Vacunas de ARNm/efectos adversosRESUMEN
BACKGROUND: Vaccine nonresponse during the coronavirus disease 2019 (COVID-19) pandemic has considerable individual and societal risks. OBJECTIVE: To investigate the clinical characteristics of patients with lack of seroconversion after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Demographic and clinical data were collected from 805 patients who had validated antibody assays against the SARS-CoV-2 spike protein at least 14 days after completion of their COVID-19 vaccination. Clinical characteristics from patients with a negative (< 0.4 U/mL) antibody response were assessed and summarized. RESULTS: A total of 622 (77.3%) patients attained seroconversion as defined by a titer of greater than or equal to 0.4 U/mL, whereas 183 out of 805 (22.7%) patients exhibited no seroconversion after vaccination against SARS-CoV-2. Univariately, older age (P = .02) and male sex were associated with a lower likelihood of seroconversion (P = .003). Therapy with immunosuppressive drugs was noted in 93 (50.8%) of seronegative patients with most (n = 83/93, 89.2%) receiving ongoing immunosuppressive therapy at the time of vaccination. Among the 134 (73.2%) seronegative patients with immunodeficiency, 110 (82.1%) had primary immunodeficiency. Cancer (n = 128, 69.9%), B cell depletion therapy (n = 90/115, 78.3%), and immunosuppressant steroid use (n = 71/93 on immunosuppressants, 76.3%) were the other common characteristics among the vaccine nonresponders. More importantly, our study did not evaluate the actual efficacy of COVID-19 vaccination. CONCLUSION: Vaccine responses vary by age and sex, with men showing lower rates of seroconversion as compared with women. Primary immunodeficiency along with active malignancy and ongoing immunosuppression with steroids or B cell depletion therapy appeared to be the most common characteristics for those with a lack of vaccine seroconversion after COVID-19 vaccination.
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Vacunas contra la COVID-19 , COVID-19 , Seroconversión , Anticuerpos Antivirales , COVID-19/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Femenino , Humanos , Masculino , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/inmunología , VacunaciónRESUMEN
Background: There is growing concern about the rising incidence and prevalence of food allergy globally. We previously reported the incidence of food allergy in Olmsted County, Minnesota, between 2002 and 2011. We sought to update the incidence and temporal trends of food allergies in our region through 2018. Methods: By using the Rochester Epidemiology Project, all Olmsted County residents, with an incident diagnosis of food allergy between January 2, 2012, and December 31, 2018, were identified and their medical records were reviewed. These cases were combined with the previously collected incidence cases from January 2, 2002, and December 31, 2011, to understand longitudinal trends in food allergy incidence rates. Results: Over the 17-year study period, 1076 patients (58.0% male patients, 72.1% white) were diagnosed with an incident food allergy. The median (interquartile range) age at first diagnosis was 2.0 years (1.1-8.4 years). The overall annual incidence rate for all ages was 3.9 (95% confidence interval [CI], 3.6-4.1) per 10,000 person-years and was significantly higher in male than in female patients (4.4 [95% CI, 4.0-4.7] and 3.3 [95% CI, 3.0-3.6], respectively; p < 0.001). The most common food allergen was egg in infancy (57.7%), peanuts in ages 1-4 years (58.3%), tree nuts in ages 5-18 years (57.4%), and seafood in adults (≥19 years) (45.3%). Conclusion: The incidence of food allergy in Olmsted County steadily increased from 2002 to 2008, then remained relatively stable between the years 2008 and 2013, and again presented a rising trend over the next 5 years until 2018. This warrants further investigations into the effects of changes in guidelines for early introductions of allergenic foods and other factors that affect causality.
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Hipersensibilidad a los Alimentos , Adolescente , Adulto , Arachis , Niño , Preescolar , Femenino , Hipersensibilidad a los Alimentos/epidemiología , Humanos , Incidencia , Lactante , Masculino , Minnesota/epidemiología , PrevalenciaRESUMEN
Background: As the vaccination campaign in response to the coronavirus disease 2019 (COVID-19) pandemic continues, concerns with regard to adverse reactions to the vaccine remain. Although immediate hypersensitivity reactions have received much attention, delayed systemic urticarial reactions after vaccination can occur. Objective: To describe the clinical presentation, vaccine excipient skin testing results, and outcomes of subsequent COVID-19 vaccination in patients who experienced delayed systemic urticarial reactions after messenger RNA (mRNA) COVID-19 vaccination. Methods: This was a retrospective case series of 12 patients referred to the Mayo Clinics in Rochester, Minnesota, and Jacksonville, Florida, between January 19, 2021, and April 30, 2021, for evaluation of delayed systemic urticarial reactions after mRNA COVID-19 vaccination. Demographics, medical and allergic history, reaction details, vaccine excipient skin testing results (when performed), and the outcome after subsequent vaccination were collected for each patient. Results: The mean age of the patients was 52 years, all were white, and 9 (75%) were women. Half of the patients had a history of drug allergy, and one had a history of chronic spontaneous urticaria. Seven patients reacted to the Pfizer-BioNTech vaccine and five reacted to the Moderna vaccine. Seven patients developed symptoms between 8 and 24 hours after vaccination. Nine patients required antihistamines for treatment. The median time to symptom resolution was 4 days. Nine patients underwent allergist-directed COVID-19 vaccine excipient skin testing, all of which were negative. Ten patients chose to receive their next mRNA COVID-19 vaccine dose, and four patients experienced recurrent delayed urticaria. Conclusion: Delayed systemic urticarial reactions after mRNA COVID-19 vaccination were not life-threatening, could be treated with antihistamines, and were not predicted with vaccine excipient skin testing. They were not a contraindication to subsequent vaccination, although patients should be counseled with regard to the possibility of recurrence.
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Vacunas contra la COVID-19/efectos adversos , COVID-19 , Urticaria , Vacunas Sintéticas/efectos adversos , Vacunas de ARNm/efectos adversos , COVID-19/prevención & control , Femenino , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Urticaria/inducido químicamente , Urticaria/diagnóstico , Vacunación/efectos adversos , Excipientes de Vacunas/efectos adversosRESUMEN
PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913.
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Control de Infecciones , Infecciones/epidemiología , Infecciones/etiología , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/epidemiología , Edad de Inicio , Profilaxis Antibiótica , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Recién Nacido , Infecciones/diagnóstico , Masculino , Tamizaje Neonatal , Pronóstico , Vigilancia en Salud Pública , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/terapia , Encuestas y Cuestionarios , Tiempo de TratamientoRESUMEN
OBJECTIVE: To determine the trends in testing and incidence of vitamin D deficiency/insufficiency in Olmsted County, Minnesota over a 16-year period. STUDY DESIGN: The Rochester Epidemiology Project (REP) was used to identify Olmsted County, Minnesota residents aged <19 years who had 25-hydroxyvitamin D [25(OH)D] levels measured between January 2, 2002 and December 31, 2017. Using each patient's first 25(OH)D measurement during this period, patients were categorized into 3 groups: <20 ng/mL, 20-50 ng/mL, and >50 ng/mL. Vitamin D deficiency/insufficiency was defined as a total 25(OH)D level of <20 ng/mL. RESULTS: There was a 42-fold increase in the proportion of the county's pediatric population tested each year, starting at 3.7 per 10 000 persons in 2002 and increasing to 156.1 per 10 000 persons in 2017. The largest increase in testing occurred in children aged ≥10 years, specifically the females in this age group, in whom we observed a 90-fold increase from 2002 to 2017. During the 16-year period, the incidence of vitamin D deficiency/insufficiency (per 10 000 persons) increased from 1.7 in 2002-2003 to 19.9 in 2016-2017, but the proportion that were tested and had vitamin D deficiency/insufficiency remained stable, with rates of 21.9% (95% CI, 16.1%-29.1%) in 2006-2007 and 18.5% (95% CI, 16.0%-21.2%) in 2016-2017. CONCLUSIONS: The proportion of the county's pediatric population who underwent vitamin D testing increased from 2002 to 2017, in parallel to the increased incidence of vitamin D deficiency/insufficiency, but the proportion tested that had vitamin D deficiency/insufficiency remained stable over time.
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Pautas de la Práctica en Medicina/tendencias , Deficiencia de Vitamina D/diagnóstico , Deficiencia de Vitamina D/epidemiología , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Minnesota/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Vitamina D/análogos & derivados , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/etiologíaRESUMEN
Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamond Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counseling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms.
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Evolución Clonal , Neoplasias Hematológicas/genética , Adolescente , Adulto , Anciano , Anemia de Diamond-Blackfan/genética , Niño , Preescolar , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Anemia de Fanconi/genética , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Introduction: Asthma is one of the most common airway diseases that nearly all pediatricians will encounter in their clinical practice. Using spirometry to compare a patient's forced expiratory volume in one second (FEV1) both pre- and post-bronchodilator administration is the ideal way to document a paradoxical bronchodilator response.Case Study: Here, we present a patient who experienced paradoxical responses to short acting beta-2 agonists (SABAs; albuterol and levalbuterol).Results: This patient responded to an anti-cholinergic agent (ipratropium bromide) with both subjective as well as objective response.Conclusion: This case highlights the need to include paradoxical response to SABAs in the differential of a patient with poorly controlled asthma. It also provides an example of successful treatment of a pediatric patient with a class of medications previously reserved for adults with chronic obstructive pulmonary disease.
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Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Albuterol/efectos adversos , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Levalbuterol/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Albuterol/uso terapéutico , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Niño , Femenino , Humanos , Ipratropio/uso terapéutico , Levalbuterol/uso terapéuticoRESUMEN
Background: As the global COVID-19 pandemic has unfolded, there has been much debate surrounding the optimal management of patients with asthma who are at risk of or contract COVID-19, whether asthma and steroids are risk factors for severe COVID-19, and how transmissible the virus is among children. Objective: The objective of this study is to provide allergists and other clinicians with pearls pertaining to the management of patients with asthma in the setting of the COVID-19 pandemic and to provide some information regarding the risk of transmission among the pediatric population. Methods: Utilizing the case of one of our own patients with asthma who developed COVID-19 as context, we review the recent literature discussing the risk of COVID-19 in patients with asthma, the management of asthma medications in the time of the pandemic, and the risk of viral transmission. Results: Despite initial reports that asthma was a risk factor for developing severe COVID-19, subsequent investigation has shown that this is likely not true. Additionally, the use of systemic or inhaled glucocorticoids does not appear to increase the risk of severe COVID-19, but there is no evidence guiding the use of biologic therapy. There is conflicting evidence regarding the ability of children to transmit the virus. Conclusion: We provide pearls that asthma does not appear to be associated with an increased risk of COVID-19 and continued use of inhaled corticosteroids appears to be safe. While there is no evidence guiding the use of biologic therapies, a recent position paper suggests that they should be continued unless a patient contracts COVID-19, at which point they should be held until clinical recovery occurs.
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Asma/complicaciones , Asma/terapia , COVID-19/terapia , COVID-19/transmisión , SARS-CoV-2/patogenicidad , Niño , Humanos , MasculinoRESUMEN
Background: It remains unclear if asthma is a risk factor associated with worse outcomes among patients with coronavirus disease 2019 (COVID-19). Methods: We performed a comprehensive database search for studies published from January 1, 2019, to October 2, 2020. We included studies that evaluated outcomes among patients with COVID-19 and underlying asthma. Outcomes of interest included the need for hospitalization, length of hospitalization, intensive care unit (ICU) admission, and death. The meta-analysis was conducted by using random-effects methodology. Results: A total of 389 studies were identified through data base searches. After abstract and full-text screening, 16 observational studies with 92,275 patients were included in the analysis. Of the 16 studies, 15 were retrospective and 1 was a prospective cohort study. The average age was 39.6 years, with 48% female patients. Six of the studies included pediatric patients, and one of these studies only evaluated pediatric patients. One study only evaluated pregnant patients. Among patients with COVID-19, the presence of asthma was not associated with any significant increase in risk of hospitalization (odds ratio [OR] 1.46 [95% confidence interval {CI}, 0.29-7.28]), length of hospitalization (1.59 days [-0.55 to 3.74]), ICU admission (OR 1.65 [95% CI, 0.56-4.17]), or death (OR 0.73 [95% CI, 0.38-1.40]). The overall risk of bias of the included studies was high. Conclusion: Among the patients with COVID-19, asthma did not seem to significantly increase the risk of hospitalization, length of hospitalization, ICU admission, or death.
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Asma/terapia , COVID-19/terapia , Hospitalización , Adulto , Anciano , Asma/diagnóstico , Asma/mortalidad , COVID-19/diagnóstico , COVID-19/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Admisión del Paciente , Pronóstico , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
Underlying lung disease, especially asthma, has recently been found to be associated with a higher risk of hospitalization with coronavirus disease 2019 (COVID-19) infection. Inhaled corticosteroids (ICS) are the most commonly used controller medications in patients with asthma. It is unclear whether ICS use increases the risk for severe COVID-19 infection. At the current time, asthma organizations are still recommending the continued use of ICS and other asthma medications to minimize the risk of uncontrolled asthma. However, for patients with asthma and who have recovered from COVID-19 infection, the timing of resumption of asthma therapy is equally uncertain. Pulmonary function testing and exhaled oral nitric oxide testing are aerosol-generating procedures and are currently being severely restricted at most health-care facilities. We presented a case of a patient with cough-variant asthma who developed severe COVID-19 associated acute respiratory distress syndrome with the need for intubation and prolonged mechanical ventilation. We highlighted the potential utility of using COVID-19 RNA detection as well as immunoglobulin G antibody testing to help guide the timing of resumption of asthma therapy.
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Corticoesteroides/uso terapéutico , Asma/complicaciones , Asma/tratamiento farmacológico , Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Corticoesteroides/administración & dosificación , Corticoesteroides/efectos adversos , Adulto , Algoritmos , Asma/diagnóstico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/genética , Biomarcadores , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Manejo de la Enfermedad , Humanos , Masculino , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/terapia , Neumonía Viral/virología , Pruebas de Función Respiratoria , SARS-CoV-2 , Resultado del TratamientoRESUMEN
BACKGROUND: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8+ T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4+ T cells in disease pathogenesis. OBJECTIVE: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4+ T-cell function. METHODS: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4+ T cells and a novel murine disease model caused by overactive PI3K signaling. RESULTS: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (TFH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human TFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH cell function were cell intrinsic. CONCLUSION: Our studies reveal that CD4+ T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations.
Asunto(s)
Linfocitos T CD4-Positivos , Diferenciación Celular , Fosfatidilinositol 3-Quinasas/genética , Animales , Linfocitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Mutación con Ganancia de Función , Humanos , Ratones , FenotipoRESUMEN
Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation.
Asunto(s)
Agammaglobulinemia/inmunología , Autoinmunidad/inmunología , Linfocitos B/inmunología , Diabetes Mellitus Tipo 1/congénito , Diarrea/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades del Sistema Inmune/congénito , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Agammaglobulinemia/terapia , Anemia Hemolítica Autoinmune/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/terapia , Diarrea/genética , Diarrea/terapia , Eccema/inmunología , Familia , Femenino , Factores de Transcripción Forkhead/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Heterocigoto , Humanos , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/terapia , Cambio de Clase de Inmunoglobulina/inmunología , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Enfermedades Intestinales/inmunología , Masculino , Persona de Mediana Edad , Linaje , Neumonía/inmunología , Recurrencia , Sinusitis/inmunología , Adulto JovenRESUMEN
PURPOSE: We report a female infant identified by newborn screening for severe combined immunodeficiencies (NBS SCID) with T cell lymphopenia (TCL). The patient had persistently elevated alpha-fetoprotein (AFP) with IgA deficiency, and elevated IgM. Gene sequencing for a SCID panel was uninformative. We sought to determine the cause of the immunodeficiency in this infant. METHODS: We performed whole-exome sequencing (WES) on the patient and parents to identify a genetic diagnosis. Based on the WES result, we developed a novel flow cytometric panel for rapid assessment of DNA repair defects using blood samples. We also performed whole transcriptome sequencing (WTS) on fibroblast RNA from the patient and father for abnormal transcript analysis. RESULTS: WES revealed a pathogenic paternally inherited indel in ATM. We used the flow panel to assess several proteins in the DNA repair pathway in lymphocyte subsets. The patient had absent phosphorylation of ATM, resulting in absent or aberrant phosphorylation of downstream proteins, including γH2AX. However, ataxia-telangiectasia (AT) is an autosomal recessive condition, and the abnormal functional data did not correspond with a single ATM variant. WTS revealed in-frame reciprocal fusion transcripts involving ATM and SLC35F2 indicating a chromosome 11 inversion within 11q22.3, of maternal origin. Inversion breakpoints were identified within ATM intron 16 and SLC35F2 intron 7. CONCLUSIONS: We identified a novel ATM-breaking chromosome 11 inversion in trans with a pathogenic indel (compound heterozygote) resulting in non-functional ATM protein, consistent with a diagnosis of AT. Utilization of several molecular and functional assays allowed successful resolution of this case.