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[Discriminant analysis to predict the clinical diagnosis of primary immunodeficiencies: a preliminary report].

Rev Alerg Mex. 2015 Apr-Jun;62(2):125-133

Authors: Murata C, Ramírez AB, Ramírez G, Cruz A, Morales JL, Lugo-Reyes SO

Abstract
BACKGROUND: The features in a clinical history from a patient with suspected primary immunodeficiency (PID) direct the differential diagnosis through pattern recognition. PIDs are a heterogeneous group of more than 250 congenital diseases with increased susceptibility to infection, inflammation, autoimmunity, allergy and malignancy. Linear discriminant analysis (LDA) is a multivariate supervised classification method to sort objects of study into groups by finding linear combinations of a number of variables.
OBJECTIVE: To identify the features that best explain membership of pediatric PID patients to a group of defect or disease.
MATERIAL AND METHOD: An analytic cross-sectional study was done with a pre-existing database with clinical and laboratory records from 168 patients with PID, followed at the National Institute of Pediatrics during 1991-2012, it was used to build linear discriminant models that would explain membership of each patient to the different group defects and to the most prevalent PIDs in our registry. After a preliminary run only 30 features were included (4 demographic, 10 clinical, 10 laboratory, 6 germs), with which the training models were developed through a stepwise regression algorithm. We compared the automatic feature selection with a selection made by a human expert, and then assessed the diagnostic usefulness of the resulting models (sensitivity, specificity, prediction accuracy and kappa coefficient), with 95% confidence intervals.
RESULTS: The models incorporated 6 to 14 features to explain membership of PID patients to the five most abundant defect groups (combined, antibody, well-defined, dysregulation and phagocytosis), and to the four most prevalent PID diseases (X-linked agammaglobulinemia, chronic granulomatous disease, common variable immunodeficiency and ataxiatelangiectasia). In practically all cases of feature selection the machine outperformed the human expert. Diagnosis prediction using the equations created had a global accuracy of 83 to 94%, with sensitivity of 60 to 100%, specificity of 83 to 95% and kappa coefficient of 0.37 to 0.76.
CONCLUSIONS: In general, the selection of features has clinical plausibility, and the practical advantage of utilizing only clinical attributes, infecting germs and routine lab results (blood cell counts and serum immunoglobulins). The performance of the model as a diagnostic tool was acceptable. The study’s main limitations are a limited sample size and a lack of cross validation. This is only the first step in the construction of a machine learning system, with a wider approach that includes a larger database and different methodologies, to assist the clinical diagnosis of primary immunodeficiencies.

PMID: 25958376 [PubMed – as supplied by publisher]

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[Orofacial clinical manifestations in adult patients with variable common immunodeficiency].

Rev Alerg Mex. 2015 Apr-Jun;62(2):107-111

Authors: Chávez-García AA, Moreno-Alba MÁ, Elizalde-Monroy M, Segura-Méndez NH, Romero-Flores J, Cambray-Gutiérrez JC, López-Pérez P, Del Rivero-Hernández LG

Abstract
BACKGROUND: Common variable immunodeficiency is the primary immunodeficiency (CVID) frequently found in adults. Its prevalence is estimated from 1:25,000 to 75,000 alive newborns; there are variations by ethnic groups, it is estimated about 50-70% in Caucasian patients. Oral cavity lesions are rarely found in adult patients with CVID, there are reports about lesions on pediatric patients mostly caused by infections.
OBJECTIVE: To describe the orofacial lesions (oral, maxillofacial and neck area) affecting adults with CVID.
MATERIAL AND METHOD: A transversal, prospective study was done in patients with CVID attended at Specialties Hospital, CMN SXXI, Mexico City. Patients where examined by the oral and maxillofacial surgeon and clinical findings were reported, then the descriptive analysis of the lesions was done.
RESULTS: We evaluated 26 patients, 16 female and 10 males, average age of 38.6 years. In 18/26 patients we found oral lesions on 7 different types. The most frequent was minor salivary glands hiperplasia (19/26),petechiae (12/26) and herpetic ulcers (7/26). In head and neck, we found 4 different lesions, the most common was lymphadenopathy <2cm (4/26).
CONCLUSIONS: The immunologic alterations associated to CVID favors the development of lesions mainly of infectious and probably autoinmune origin that affects the oral cavity and head and neck area.

PMID: 25958373 [PubMed – as supplied by publisher]

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[Structural and functional heart diseases in adult patients with common variable immunodeficiency].

Rev Alerg Mex. 2015 Apr-Jun;62(2):91-97

Authors: Cambray-Gutiérrez JC, Fernández-Muñoz MJ, Del Rivero-Hernández LG, López-Pérez P, Chávez-García AA, Segura-Méndez NH

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the primary immunodeficiency with the largest number of comorbidities in adulthood. It has been associated with bronchiectasis between 17%-76%, and these with the presence of cardiovascular complications such as pulmonary hypertension and heart failure. The new image methods of diagnosis, to assess the cardiovascular structural and functional conformation of adult patients with bronchiectasis, help to establish more efficient and timely diagnoses.
OBJECTIVE: To define the presence of structural and functional heart disease in CVID patients by transthoracic echocardiography.
MATERIAL AND METHOD: A cross-sectional study was done in a cohort of 26 adult patients diagnosed with CVID and replacement therapy with intravenous immunoglobulin (IVIG), belonging to the Immunodeficiency Clinic. All patients underwent transthoracic echocardiography and tissue ECO doopler; the results were evaluated by a echocardiographer physician.
RESULTS: We evaluated 26 patients, of whom 10 patients were male, with a mean age of 35.7 ± 13.7 years. The results of thoracic echocardiography of the left cardiac cavities found the following functional changes: 17 patients presented with mitral insufficiency and only 2 had aortic insufficiency, none symptoms. Regarding the structural alterations of the right cavities: 8 adults with CVID had right cavities growth and 5 of them, hypermobile atrial septum was reported; respect to functional alterations, 24 patients had tricuspid insufficiency; in 20 it was mild and only in 3 is was moderate. Up to 12 had pulmonary valve insufficiency, and 8 had pulmonary arterial hypertension (PAH); of which, in 2 it was mild and in one it was moderate; and 4 patients had PSAP in high limit values.
CONCLUSIONS: Patients with CVID, despite having a high incidence of bronchiectasis, had low incidence of PAH, but a significant number of patients had PSAP in high cutoff level, so, these patients should be monitored annually, because probably they will evolve to PAH in the future. Also, they have a high incidence of mild valvular regurgitation due to mild degenerative changes with valvular sclerosis, therefore, they also require regular monitoring.

PMID: 25958371 [PubMed – as supplied by publisher]

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An open, prospective trial investigating the pharmacokinetics and safety, and the tolerability of escalating infusion rates of a 10% human normal immunoglobulin for intravenous infusion (IVIg), BT090, in patients with primary immunodeficiency disease.

Vox Sang. 2015 May 7;

Authors: Kriván G, Königs C, Bernatowska E, Salama A, Wartenberg-Demand A, Sonnenburg C, Linde R

Abstract
BACKGROUND AND OBJECTIVES: Pharmacokinetics, safety and tolerability of escalating infusion rates of BT090, a 10% intravenous immunoglobulin (IVIg), were studied in patients with primary immunodeficiency disease.
MATERIALS AND METHODS: In Part A, patients (n = 30) received 3 infusions of BT090 at their pretrial dose and dosing interval; the infusion rate of BT090 was increased from 0·3 to 1·4 to 2·0 ml/kg/h for each infusion in each patient initially at 30-min intervals. Pharmacokinetics was evaluated at the 3rd infusion (n = 24). At the 4th infusion, infusion rates were to be gradually escalated from 0·3 to 1·4 to 4·0 to a maximum of 8·0 ml/kg/h initially at 30-min intervals to establish the maximum tolerated infusion rate per patient.
RESULTS: The pharmacokinetic characteristics and safety profile of BT090 were comparable with those of other IVIgs, including Intratect(®) . Escalation of infusion rates was well tolerated, allowing identification of individual patient’s maximum tolerated infusion rate. At subsequent infusions, all patients tolerated their individually defined maximum infusion rate: 17 patients (68·0%) tolerated infusion rates of 6·0 or 8·0 ml/kg/h and four patients (16%) had maximum tolerated infusion rates of <4·0 ml/kg/h at subsequent infusions. Escalation of infusion rates shortened infusion time from a median of around 2·5 h to around 1·6 h. SAEs were reported in three patients, but none was related to BT090 treatment.
CONCLUSIONS: Shortening infusion time may reduce overall healthcare spending, for example nursing time needed, and also minimize disruption of patients’ daily routine, especially for those patients in work or school settings.

PMID: 25953213 [PubMed – as supplied by publisher]

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The importance of vaccination and immunoglobulin treatment for patients with primary immunodeficiency diseases (PIDs) – World PI Week April 22-29, 2015.

Eur J Immunol. 2015 May;45(5):1285-6

Authors: Reda SM, Cant AJ

PMID: 25952627 [PubMed – in process]

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[Pulmonary complications in pediatric patients with primary immunodeficiency].

Gac Med Mex. 2015 Mar-Apr;151(2):157-163

Authors: Membrila-Mondragón J, Staines-Boone AT, Sánchez-Sánchez LM, Ruiz-Pedraza MD

Abstract
Introducción: Las IDP son enfermedades que comprenden alteraciones del sistema inmunitario. Las manifestaciones clínicas se caracterizan por presentar infecciones respiratorias de repetición, las cuales pueden complicarse con bronquiectasias, engrosamiento peribronquial, abscesos, bulas y fibrosis pulmonar. El objetivo de este estudio fue determinar las complicaciones pulmonares en pacientes pediátricos según su tipo de IDP. Resultados: Se incluyeron 65 pacientes: 28 con inmunodeficiencias humorales, 4 con inmunodeficiencias celulares, 13 con síndromes bien definidos y 20 con defectos fagocíticos. Los pacientes con inmunodeficiencias celulares iniciaron la sintomatología a edades tempranas: se diagnosticaron antes del año de edad (p = 0.01). Los pacientes con inmunodeficiencias humorales tuvieron cuadros respiratorios más frecuentes y tempranos (p = 0.01). Las enfermedades respiratorias más frecuentes fueron otitis media aguda supurada (OMAS), sinusitis y neumonías, más frecuentes en las inmunodeficiencias humorales y los defectos fagocíticos. Las complicaciones pulmonares más frecuentes fueron bronquiectasias, daño intersticial y fibrosis pulmonar, sin diferencia estadística entre el tipo de IDP. Las pruebas de función pulmonar (PFP) mostraron mayor alteración en los pacientes con defectos fagocíticos, pero sin diferencia estadística (p = 0.28). La presencia de complicaciones pulmonares no mostró diferencias al comparar según el tipo de inmunodeficiencia, excepto la agammaglobulinemia (p = 0.02). Conclusiones: Las inmunodeficiencias celulares se diagnostican de forma más temprana, ya que el inicio de los síntomas ocurre antes del año de edad. Las inmunodeficiencias humorales presentan mayor número de infecciones respiratorias altas y bajas, así como mayor riesgo de complicaciones pulmonares, especialmente de agammaglobulinemia.

PMID: 25946525 [PubMed – as supplied by publisher]

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STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function.

J Exp Med. 2015 May 4;

Authors: Wilson RP, Ives ML, Rao G, Lau A, Payne K, Kobayashi M, Arkwright PD, Peake J, Wong M, Adelstein S, Smart JM, French MA, Fulcher DA, Picard C, Bustamante J, Boisson-Dupuis S, Gray P, Stepensky P, Warnatz K, Freeman AF, Rossjohn J, McCluskey J, Holland SM, Casanova JL, Uzel G, Ma CS, Tangye SG, Deenick EK

Abstract
Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.

PMID: 25941256 [PubMed – as supplied by publisher]

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Altrered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype.

Clin Immunol. 2015 May 1;

Authors: Lougaris V, Faletra F, Lanzi G, Vozzi D, Marcuzzi A, Valencic E, Piscianz E, Bianco A, Girardelli M, Baronio M, Loganes C, Fasth A, Salvini F, Trizzino A, Moratto D, Facchetti F, Giliani S, Plebani A, Tommasini A

Abstract
PIK3R1 monoallelic mutations were recently reported in eight patients to be responsible for the APDS-like syndrome, a rare form of primary immunodeficiency presenting with a Hyper-IgM like phenotype. This study reports on four novel patients carrying PIK3R1 mutations with early, not previously reported, alterations in peripheral B cell maturation and describes the novel findings of the tonsillar architecture in PIK3R1 mutated disorder, that resembles AID deficiency, offering novel insight on the role of PIK3R1 in the human germinal center reaction. Furthermore, this study offers insight on the prevalence of the PIK3R1 mutation among HIGM-like patients. Finally, the comparison of the available clinical features from the reported patients to date shows that poor growth is an underestimated frequent feature of this disorder.

PMID: 25939554 [PubMed – as supplied by publisher]

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Related Articles

History and current status of newborn screening for severe combined immunodeficiency.

Semin Perinatol. 2015 Apr 30;

Authors: Kwan A, Puck JM

Abstract
The development of a T-cell receptor excision circle (TREC) assay utilizing dried blood spots in universal newborn screening has allowed the early detection of T-cell lymphopenia in newborns. Diagnosis of severe combined immunodeficiency (SCID) in affected infants in the neonatal period, while asymptomatic, permits early treatment and restoration of a functional immune system. SCID was the first immunodeficiency disease to be added to the Recommended Uniform Screening Panel of Core Conditions in the United States in 2010, and it is now implemented in 26 states in the U.S. This review covers the development of newborn screening for SCID, the biology of the TREC test, its current implementation in the U.S., new findings for SCID in the newborn screening era, and future directions.

PMID: 25937517 [PubMed – as supplied by publisher]

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Corrigendum: Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome.

Front Pediatr. 2015;3:28

Authors: Rider NL, Boisson B, Jyonouchi S, Hanson EP, Rosenzweig SD, Casanova JL, Orange JS

Abstract
[This corrects the article on p. 2 in vol. 3, PMID: 25688341.].

PMID: 25932458 [PubMed – as supplied by publisher]

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