Inmunodeficiencia combinada grave: Presentación de un caso / Severe Combined Immunodeficiency: Case presentation

Introducción: Las inmunodeficiencias primarias son un grupo heterogéneo de trastornos hereditarios ocasionados por defectos del desarrollo o función del sistema inmunológico. Las inmunodeficiencias combinadas graves constituyen el 15 por ciento de las inmunodeficiencias primarias, son graves y los pacientes rara vez sobreviven sin tratamiento después del primer año de vida, lo que obliga a un diagnóstico y tratamiento oportuno. Objetivo: Presentar un caso con inmunodeficiencia combinada grave, condición reportada con poca frecuencia y evolución desfavorable. Presentación de caso: Lactante masculino de seis meses con antecedentes de cuatro ingresos en Unidad de Terapia Intensiva por infecciones, el último por bronconeumonía bilateral. Fue valorado por Inmunología y se diagnosticó una inmunodeficiencia combinada grave por la clínica (infecciones por gérmenes oportunistas: Candida albicans y Pneumocistys jirovecii) y estudios inmunológicos (con disminución de los anticuerpos IgG: 0,02 g/L, IgM: 0.1 g/L e IgA: 0 g/L), subpoblaciones linfocitarias disminuidas (CD3/CD4: 9,3 por ciento, CD3/CD8: 5,6 por ciento, CD19: 0 por ciento, CD 16: 0,73 por ciento), además hipoplasia tímica severa (120 mm2). Se inició tratamiento con antimicrobianos de amplio espectro e inmunoestimulantes (Hebertrans y Biomodulina T). Evolucionó desfavorablemente y falleció por shock séptico. Conclusiones: La inmunodeficiencia combinada grave es una emergencia pediátrica que debe tenerse en cuenta en pacientes con antecedentes de infecciones recurrentes, es vital conocer las manifestaciones clínicas tempranas que permitan la sospecha diagnóstica, haciendo uso de todas las herramientas disponibles para su confirmación. El diagnóstico precoz es el elemento clave para la reducción de la morbilidad y mortalidad relacionada con estas enfermedades(AU)

Introduction: Primary Immunodeficiencies are a heterogeneous group of inherited disorders caused by defects in development or function of the immune system. Severe Combined Immunodeficiencies constitute 15% of the primary immunodeficiencies, they are acute and patients rarely survive without treatment after the first year of life, requiring a quick diagnosis and treatment. Objective: To present a case on Severe Combined Immunodeficiency, a condition infrequently reported and with unfavorable evolution. Case presentation: Six-month-old male infant with a history of four admissions to the Intensive Care Unit due to infections, in the latter one due to bilateral bronchopneumonia. He was evaluated by Immunology and a Severe Combined Immunodeficiency was diagnosed by the clinic (infections by opportunistic germs: Candida albicans and Pneumocistys jirovecii) and immunological studies (with a decrease in IgG antibodies: 0.02 g/L, IgM: 0.1 g/L and IgA: 0 g/L), decreased lymphocyte subpopulations (CD3/CD4: 9.3 percent, CD3/CD8: 5.6 percent, CD19: 0 percent, CD 16: 0.73 percent), in addition to severe thymic hypoplasia (120 mm2). Treatment with broad spectrum antimicrobials and immunostimulants (Hebertrans and Biomodulin T) was started. He evolved unfavorably and died of septic shock. Conclusions: Severe Combined Immunodeficiency is a pediatric emergency that must be taken into account in patients with a history of recurrent infections, it is vital to know the early clinical manifestations that allow a suspected diagnosis, making use of all the available tools for its confirmation. Early diagnosis is the key element in reducing morbidity and mortality related to these diseases(AU)

Severe combined immunodeficiency: From its discovery to the perspective.

Severe combined immunodeficiency (SCID) is impaired in lymphocyte development and function. Affected children have extreme susceptibility to infections, which are fatal in the first year of life without treatment. The estimate of incidence is one in approximately 50,000 live birth. The first series of diseases were described in 1950s, and all patients died in infancy. The first transplant for SCID was carried out in 1968, and it has been described that SCID patients could be treated by hematopoietic stem cell transplantation (HSCT) since then. Adenosine deaminase and common gamma chain were identified to be causative genes for SCID in 1972 and 1993, respectively. SCID arises from a variety of genetic defects. The early intervention of healthy SCID infants without infections affords higher survival rate, and newborn screening (NBS) was suggested. T-cell receptor (TCR) exicision circles (TRECs) are circular DNA formed from the leftover fragment generated from the TCR rearrangement. TRECs can be measured from a small aliquot of DNA such as Guthrie card by quantitative PCR. SCID patients lack TRECs, and TRECs quantification is useful for NBS for SCID. NBS for SCID have been already carried out in most of the Unite States, and the early introduction is desired in Japan to save SCID children.

Expanded newborn screening by mass spectrometry: New tests, future perspectives.

Tandem mass spectrometry (MS/MS) has become a leading technology used in clinical chemistry and has shown to be particularly sensitive and specific when used in newborn screening (NBS) tests. The success of tandem mass spectrometry is due to important advances in hardware, software and clinical applications during the last 25 years. MS/MS permits a very rapid measurement of many metabolites in different biological specimens by using filter paper spots or directly on biological fluids. Its use in NBS give us the chance to identify possible treatable metabolic disorders even when asymptomatic and the benefits gained by this type of screening is now recognized worldwide. Today the use of MS/MS for second-tier tests and confirmatory testing is promising especially in the early detection of new disorders such as some lysosomal storage disorders, ADA and PNP SCIDs, X-adrenoleucodistrophy (X-ALD), Wilson disease, guanidinoacetate methyltransferase deficiency (GAMT), and Duchenne muscular dystrophy. The new challenge for the future will be reducing the false positive rate by using second-tier tests, avoiding false negative results by using new specific biomarkers and introducing new treatable disorders in NBS programs.

Different clinical phenotypes in 2 siblings with X-linked severe combined immunodeficiency

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Diagnostic Criteria and Evaluation of Severe Combined Immunodeficiency in the Neonate.

Severe combined immunodeficiency disorders (SCID) are a group of primary immunodeficiencies resulting from any one of a diverse group of mutations impacting T-cell development. SCID is diagnosed and classified through assessment of the lymphocyte subset(s) affected and by the mechanisms responsible for the primary immune defect. Regardless of the genetics involved, patients invariably succumb to an early death without medical intervention. In the past, patients were primarily identified either by previous family history, physical manifestations, or after the onset of symptoms. However, the introduction of newborn screening for SCID has allowed the pediatrician to identify these patients at a much earlier age, greatly improving their survival. Currently, 23 states include SCID testing for T-cell deficiencies in their newborn screening platform. Protocols for confirmatory testing and medical intervention after a positive screen vary slightly from state-to-state. However, the standard curative treatment remains stem cell transplantation, although depending on the genetic cause of the disease, enzyme replacement and gene therapy may also be considered.

Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency.

One of the severe combined immunodeficiencies (SCIDs), which is caused by a genetic defect in the signal transduction pathways involved in T-cell activation, is the ZAP70 deficiency. Mutations in ZAP70 lead to both abnormal thymic development and defective T-cell receptor (TCR) signaling of peripheral T-cells. In contrast to the lymphopenia in most SCID patients, ZAP70-deficient patients have lymphocytosis, despite the selective absence of CD8+ T-cells. The clinical presentation is usually before 2 years of age with typical findings of SCID. Here, we present three new ZAP70-deficient patients who vary in their clinical presentation. One of the ZAP70-deficient patients presented as a classical SCID, the second patient presented as a healthy looking wheezy infant, whereas the third patient came to clinical attention for the eczematous skin lesions simulating atopic dermatitis with eosinophilia and elevated immunoglobulin E (IgE), similar to the Omenn syndrome. This study illustrates that awareness of the clinical heterogeneity of ZAP70 deficiency is of utmost importance for making a fast and accurate diagnosis, which will contribute to the improvement of the adequate treatment of this severe immunodeficiency.

Severe combined immunodeficiency: a cohort of 40 patients.

Severe Combined Immunodeficiency (SCID) consists of a heterogeneous group of genetic disorders characterized by an arrest in T lymphocyte development which is variably associated with an abnormal differentiation of B and NK cells. In order to depict the clinical state of Iranian patients with SCID, records of forty patients were reviewed. Patients were classified based on the flow cytometry data in two groups of B- and B+. In thirty two families (80%) parents were consanguine and in 17 families (50%) there were affected members other than proband. We showed that autosomal forms of SCID might be more frequent due to higher rate of consanguineous marriages. Alongside several infective complications, complicated Bacillus Calmette-Guérin (BCG) vaccination was documented in 18 cases (45%) following the routine vaccination at birth. BCG immunization is still a part of standard vaccination for newborns in developing countries; whereas in communities with a better health condition it could be held for a few months and performed for kids whose immune system sounds intact. We discuss where consanguine mating is common, a test of screening should be run timely. A complete blood count of cord blood could reveal lymphocytopenia at birth; this helps early diagnosis. Genetic consultation would help the families with affected members preventing new SCID offspring.

Purified hematopoietic stem cell engraftment of rare niches corrects severe lymphoid deficiencies without host conditioning.

In the absence of irradiation or other cytoreductive conditioning, endogenous hematopoietic stem cells (HSCs) are thought to fill the unique niches within the bone marrow that allow maintenance of full hematopoietic potential and thus prevent productive engraftment of transplanted donor HSCs. By transplantation of purified exogenous HSCs into unconditioned congenic histocompatible strains of mice, we show that approximately 0.1-1.0% of these HSC niches are available for engraftment at any given point and find no evidence that endogenous HSCs can be displaced from the niches they occupy. We demonstrate that productive engraftment of HSCs within these empty niches is inhibited by host CD4+ T cells that recognize very subtle minor histocompatibility differences. Strikingly, transplantation of purified HSCs into a panel of severe combined immunodeficient (SCID) mice leads to a rapid and complete rescue of lymphoid deficiencies through engraftment of these very rare niches and expansion of donor lymphoid progenitors. We further demonstrate that transient antibody-mediated depletion of CD4+ T cells allows short-term HSC engraftment and regeneration of B cells in a mouse model of B(-) non-SCID. These experiments provide a general mechanism by which transplanted HSCs can correct hematopoietic deficiencies without any host conditioning or with only highly specific and transient lymphoablation.

Potential costs and benefits of newborn screening for severe combined immunodeficiency.

OBJECTIVE: Severe combined immunodeficiency (SCID) is a rare, treatable disorder of the immune system. The incidence is unknown but may be more common than published estimates because infants frequently die of infection before diagnosis. SCID is a candidate for universal newborn screening, so there is a need to determine under which circumstances screening would be cost-effective. STUDY DESIGN: We assumed a screening program for SCID would use T-cell lymphopenia as the screening criterion and performed a cost-utility analysis comparing universal screening with screening only those with a family history of SCID. RESULTS: Assuming society is willing to pay $50,000 for every quality-adjusted life-year saved, a SCID screening test that cost less than $5 with a false-negative rate of 0.9% and a false-positive rate of 0.4% would be considered cost-effective. A nationwide screening program would cost an additional $23.9 million per year for screening costs but would result in 760 years of life saved per year of screening. The cost to detect 1 case of SCID would be $485,000. CONCLUSION: SCID screening could result in a large benefit to detected individuals, making screening relatively cost-effective in spite of the low incidence of the disease. However, an adequate test is critical to cost-effectiveness.

Applying public health strategies to primary immunodeficiency diseases: a potential approach to genetic disorders.

Primary immunodeficiency (PI) diseases are a group of primarily single-gene disorders of the immune system. Approximately 100 separate PI diseases have been described, but <20 probably account for >90% of cases. Although diverse, PI diseases share the common feature of susceptibility to infection and result in substantial morbidity and shortened life spans. Most important, prompt diagnosis and treatment can now lead to life-saving treatment and result in marked improvements in the quality and length of life for persons with PI diseases. In November 2001, a workshop was convened by CDC in Atlanta, Georgia, to discuss ways to improve health outcomes among persons with PI disease. A multidisciplinary panel of persons knowledgeable in PI diseases and public health met to identify and discuss public health strategies that can be applied to PI diseases and possibly for other genetic disorders. A systematic assessment based on the established public health framework was applied to the growing group of PI diseases, whose diverse genetic mutations span multiple components of the immune system but all lead to increased incidence and severity of infections. During the meeting, specialists in clinical immunology, public health, genetics, pediatrics, health communication, and ethics from state and federal agencies, academic centers, professional organizations, and advocacy foundations discussed the four components of the public health framework as they relate to PI diseases. These four components include 1) public health assessment (application of traditional public health methods to assess the occurrence and impact of PI diseases on communities); 2) population-based interventions (development, implementation, and evaluation of screening tests administered to newborns and clinical algorithms for early recognition of symptomatic persons to facilitate the earliest possible diagnosis and treatment for PI diseases); 3) evaluation of screening and diagnostic tools (to ensure their quality and appropriateness for identification of patients with PI diseases); and 4) communication (communication with and information dissemination to health-care providers and the public to facilitate prompt and appropriate diagnosis and intervention). The working group's deliberations focused on challenges and opportunities, priority research questions, and recommendations for future action for these four components. These recommendations, developed by workshop participants, will be useful to medical and public health professionals who are evaluating methods to increase recognition of PI diseases and other genetic disorders.

Genetic testing and screening in pediatric populations.

It is conceivable that in the near future a family could present themselves to their health care provider and request to be tested for diseases X, Y, and Z, equipped only with a web page listing of disease-causing genes. The testing of children suggests subtle and controversial inherent conflicts, however. Decisions about whether to provide genetic testing become increasingly murky for a health care professional as the requests advance from testing a child for carrier status for an autosomal recessive disorder, to testing a girl for a sex-linked mutation, to testing an asymptomatic child for a susceptibility to a particular disorder. Although no single case can exemplify every variable and circumstance confronting health care professionals today, this case-based discussion of x-linked severe combined immune deficiency can serve as a framework to examine some of the potential dilemmas surrounding the testing of children for genetic disorders.

IL-12 protects immunocompetent and immunodeficient neonatal mice against infection with Cryptosporidium parvum.

The protozoan parasite Cryptosporidium parvum (Cp) causes diarrhea that can be acutely severe in immunocompetent persons and can become chronic and life-threatening in immunocompromised individuals. Because studies in mice have implicated IFN-gamma in protection against this parasite, and IL-12 can induce IFN-gamma production, we examined the ability of IL-12 to prevent or cure Cp infection in neonatal BALB/c and SCID mice. Treatment of both immunocompetent and immunodeficient mice with IL-12 before experimental inoculation with Cp oocysts prevented or greatly reduced the severity of infection. Intestinal epithelial cell invasion and/or early intracellular development of Cp was inhibited by exogenous IL-12. The protective effect of IL-12 was completely blocked by anti-IFN-gamma mAb. Established infections were associated with elevated IFN-gamma gene expression and were not ameliorated by IL-12 treatment, even though such treatment further enhanced IFN-gamma gene expression. The severity of Cp infection was, however, exacerbated by treatment with anti-IL-12 Ab. These observations provide the first evidence that treatment with exogenous IL-12 can prevent Cp infection through an IFN-gamma-dependent, specific immune system-independent mechanism, and that endogenous IL-12 production has a role in limiting Cp infection.

Cytotoxic T cells from a human chimera induce regression of Epstein-Barr virus-infected allogeneic host cells.

The anti-Epstein-Barr virus (EBV) T cell response was studied in a severe combined immunodeficiency patient (PS) in whom stable peripheral blood chimerism was induced by transplantation of fetal liver stem cells from two donors. PS is characterized by a complete mismatch between the T lymphocytes, derived from the transplants, and all the other cells, including EBV+ B lymphocytes, of host origin. The patient's peripheral blood mononuclear cells were incubated with EBV and cultured for 1 month. In these cultures, T lymphocytes strongly inhibited the proliferation of the host EBV-infected lymphoblastoid cell line (PS-LCL) and, after expansion under repeated stimulation with PS-LCL in the presence of IL-2, they specifically inhibited the growth of host-HLA-matched LCL. In contrast, these T lymphocytes failed to recognize and to lyse EBV-infected HLA-identical targets. Lysis of PS-LCL was reduced after incubation with W6/32 or with anti-DR antibodies, suggesting a role for host HLA class I and HLA class II determinants in the lysis of the target cells. PS-HLA class I and HLA class II-matched LCL were also killed. However, lymphocytes from the father or from the mother were not killed when not EBV-infected, indicating that host HLA antigens served as restricting determinants for the anti-viral T cells.

LP-BM5 murine retrovirus-induced immunodeficiency disease in allogeneic SCID chimeric mice. Inability to recognize a putative viral superantigen does not prevent induction of disease.

T cell recognition of viral superantigens has been postulated to contribute to the pathogenesis of the immunodeficiency disease induced in mice by infection with the LP-BM5 murine leukemia virus complex. A candidate superantigen has been identified in the B cell lymphoma line B6-1710 derived from an LP-BM5-infected C57BL/6 (H-2b) mouse. We have asked whether the stimulatory activity expressed by B6-1710 behaves as a superantigen by assessing the ability of T cells from fully allogeneic H-2b-->H-2d SCID chimeric mice to respond to the line. T cells from allochimeric mice failed to respond to B6-1710, whereas they responded normally to Staphylococcus enterotoxin B, a well characterized superantigen. Despite this finding, allochimeric mice were fully susceptible to the immune deficiency disease induced by LP-BM5 virus infection. These findings show that the role of superantigen expression in retrovirus-induced immune deficiency disease remains to be defined.