Purpose
X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of ...autoimmune and inflammatory complications in X-linked agammaglobulinemia (XLA), the spectrum of gastrointestinal manifestations has not previously been fully explored.
Methods
We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the United States Immunodeficiency Network, a national registry of primary immunodeficiencies.
Results
In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide ranging, and management strategies were diverse and mainly experimental.
Conclusions
Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.
Common variable immunodeficiency (CVID) is increasingly recognized for its association with autoimmune and inflammatory complications. Despite recent advances in immunophenotypic and genetic ...discovery, clinical care of CVID remains limited by our inability to accurately model risk for non-infectious disease development. Herein, we demonstrate the utility of unbiased network clustering as a novel method to analyze inter-relationships between non-infectious disease outcomes in CVID using databases at the United States Immunodeficiency Network (USIDNET), the centralized immunodeficiency registry of the United States, and Partners, a tertiary care network in Boston, MA, USA, with a shared electronic medical record amenable to natural language processing. Immunophenotypes were comparable in terms of native antibody deficiencies, low titer response to pneumococcus, and B cell maturation arrest. However, recorded non-infectious disease outcomes were more substantial in the Partners cohort across the spectrum of lymphoproliferation, cytopenias, autoimmunity, atopy, and malignancy. Using unbiased network clustering to analyze 34 non-infectious disease outcomes in the Partners cohort, we further identified unique patterns of lymphoproliferative (two clusters), autoimmune (two clusters), and atopic (one cluster) disease that were defined as CVID non-infectious endotypes according to discrete and non-overlapping immunophenotypes. Markers were both previously described {high serum IgE in the atopic cluster odds ratio (OR) 6.5 and low class-switched memory B cells in the total lymphoproliferative cluster (OR 9.2)} and novel low serum C3 in the total lymphoproliferative cluster (OR 5.1). Mortality risk in the Partners cohort was significantly associated with individual non-infectious disease outcomes as well as lymphoproliferative cluster 2, specifically (OR 5.9). In contrast, unbiased network clustering failed to associate known comorbidities in the adult USIDNET cohort. Together, these data suggest that unbiased network clustering can be used in CVID to redefine non-infectious disease inter-relationships; however, applicability may be limited to datasets well annotated through mechanisms such as natural language processing. The lymphoproliferative, autoimmune, and atopic Partners CVID endotypes herein described can be used moving forward to streamline genetic and biomarker discovery and to facilitate early screening and intervention in CVID patients at highest risk for autoimmune and inflammatory progression.
Background Cartilage-hair hypoplasia (CHH) is characterized by metaphyseal dysplasia, bone marrow failure, increased risk of malignancies, and a variable degree of immunodeficiency. CHH is caused by ...mutations in the RNA component of the mitochondrial RNA processing (RMRP) endoribonuclease gene, which is involved in ribosomal assembly, telomere function, and cell cycle control. Objectives We aimed to define thymic output and characterize immune function in a cohort of patients with molecularly defined CHH with and without associated clinical immunodeficiency. Methods We studied the distribution of B and T lymphocytes (including recent thymic emigrants), in vitro lymphocyte proliferation, cell cycle, and apoptosis in 18 patients with CHH compared with controls. Results Patients with CHH have a markedly reduced number of recent thymic emigrants, and their peripheral T cells show defects in cell cycle control and display increased apoptosis, resulting in poor proliferation on activation. Conclusion These data confirm that RMRP mutations result in significant defects of cell-mediated immunity and provide a link between the cellular phenotype and the immunodeficiency in CHH.
Massachusetts began newborn screening (NBS) for severe combined immunodeficiency (SCID) using measurement of T-cell receptor excision circles (TRECs) from dried blood spots.
We describe developments ...and outcomes from the first 10 years of this program (February 1, 2009, to January 31, 2019).
TREC values, diagnostic, and outcome data from all patients screened for SCID were evaluated.
NBS of 720,038 infants prompted immunologic evaluation of 237 (0.03%). Of 237, 9 were diagnosed with SCID/leaky SCID (4% of referrals vs 0.001% general population). Another 7 were diagnosed with other combined immunodeficiencies, and 3 with athymia. SCID/leaky SCID incidence was approximately 1 in 80,000, whereas approximately 1 in 51,000 had severe T-cell lymphopenia for which definitive treatment was indicated. All patients with SCID/leaky SCID underwent hematopoietic cell transplant or gene therapy with 100% survival. One patient with athymia underwent successful thymus transplant. No known cases of SCID were missed. Compared with outcomes from the 10 years before SCID NBS, survival trended higher (9 of 9 vs 4 of 7), likely due to a lower rate of infection before treatment.
Our data support a single NBS testing-and-referral algorithm for all gestational ages. Despite lower median TREC values in premature infants, the majority for all ages are well above the TREC cutoff and the algorithm, which selects urgent (undetectable TREC) and repeatedly abnormal TREC values, minimizes referral. We also found that low naïve T-cell percentage is associated with a higher risk of SCID/CID, demonstrating the utility of memory/naïve T-cell phenotyping as part of follow-up flow cytometry.
IMPORTANCE: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the ...national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100 000 births. OBJECTIVES: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. DESIGN: Epidemiological and retrospective observational study. SETTING: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3 030 083 newborns screened with a TREC test. MAIN OUTCOMES AND MEASURES: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. RESULTS: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58 000 infants (95% CI, 1/46 000-1/80 000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. CONCLUSIONS AND RELEVANCE: Newborn screening in 11 programs in the United States identified SCID in 1 in 58 000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.
Humoral immune deficiencies have been associated with noninfectious disease complications including autoimmune cytopenias and pulmonary disease. Herein we present a patient who underwent splenectomy ...for autoimmune cytopenias and subsequently was diagnosed with humoral immune deficiency in the context of recurrent infections. Immunoglobulin analysis prior to initiation of intravenous immunoglobulin (IVIG) therapy was notable for low age-matched serum levels of IgA (11 mg/dL), IgG2 (14 mg/L), and IgG4 (5 mg/L) with a preserved total level of IgG. Flow cytometry was remarkable for B cell maturation arrest at the IgM+/IgD+ stage. Selective screening for known primary immune deficiency-causing genetic defects was negative. The disease course was uniquely complicated by the development of pulmonary arteriovenous malformations (AVMs), ultimately requiring bilateral lung transplantation in 2012. This is a patient with humoral immune deficiency that became apparent only after splenectomy, which argues for routine immunologic evaluation prior to vaccination and splenectomy. Lung transplantation is a rare therapeutic endpoint and to our knowledge has never before been described in a patient with humoral immune deficiency for the indication of pulmonary AVMs.
The article presents a combined analysis of more than 3 million infants screened for severe combined immunodeficiency (SCID) and other conditions with T-cell lymphopenia, and document early ...institution of effective treatments in 10 US states and Navajo Nation. Newborn screening in 11 programs in US were bale to identify SCID in 1 in 58?000 infants, with high survival.
Following the largest Ebola virus disease outbreak from 2013 to 2016, viral RNA has been detected in survivors from semen and breast milk long after disease recovery. However, as there have been few ...cases of sexual transmission, it is unclear whether every RNA positive fluid sample contains infectious virus. Virus isolation, typically using cell culture or animal models, can serve as a tool to determine the infectivity of patient samples. However, the sensitivity of these methods has not been assessed for the Ebola virus isolate, Makona. Described here is an efficiency comparison of Ebola virus Makona isolation using Vero E6, Huh-7, monocyte-derived macrophage cells, and suckling laboratory mice. Isolation sensitivity was similar in all methods tested. Laboratory mice and Huh-7 cells were less affected by toxicity from breast milk than Vero E6 and MDM cells. However, the advantages associated with isolation in Huh-7 cells over laboratory mice, including cost effectiveness, sample volume preservation, and a reduction in animal use, make Huh-7 cells the preferred substrate tested for Ebola virus Makona isolation.
El dictamen pericial se erige como un medio de prueba especial y único, ya que a través de conocimientos científicos, técnicos o artísticos las partes y/o el Juez logran probar hechos que por sí ...mismos o través de otro medio de prueba no se pueden esclarecer. En el caso de la Jurisdicción Contencioso Administrativa en los distintos medios de control, cada vez más ha adquirido importancia este medio probatorio, sin embargo, frente a la práctica y contradicción del dictamen pericial de la regulación prevista en la en la Ley 1437 de 2011, con la reforma introducida por la Ley 2080 de 2021, no es dable determinar si en efecto estas normas ostentan el carácter de especial y/o propio o simplemente son la reproducción o complementariedad del Código General del Proceso. Es a raíz de dicho aspecto que surgen una serie de interrogantes, especialmente porque no es clara la forma en que debe proceder el juzgador ante un problema de interpretación y/o vacío al momento de aplicar la regulación prevista para la práctica y contradicción de este medio probatorio. Así entonces, a través del presente artículo se pretende abordar el estudio de las normas que rigen la práctica y contradicción del dictamen pericial tanto en el Código de Procedimiento Administrativo y de lo Contencioso Administrativo como en el Código General del Proceso y, de igual manera, la función del principio de integración normativa previsto en el artículo 306 de la Ley 1437 de 2011. Ello, con el fin de determinar la forma en que se debe adelantar su aplicación en los eventos en que se susciten problemas de interpretación y aplicación de las normas modificadas por la Ley 2080 de 2021.
Romero, exiliado antitrujillista desde 1937 hasta 1961, narra la pérdida dolorosa y traumática de su espacio geográfico, las dificultades emocionales y económicas de la adaptación a un nuevo ...territorio y las angustias personales de volver a su país. A través de Del duro exilio el autor revela las profundas huellas o heridas de un destierro político que constituye las características más sentidas y repetidas de su memoria.
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