Development of cancer surveillance guidelines in ataxia telangiectasia: A Delphi-based consensus survey of international experts.

BACKGROUND/OBJECTIVES: Ataxia telangiectasia (A-T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A-T. We aimed to understand the current international practice regarding cancer surveillance in A-T and agreed-upon approaches to develop cancer surveillance in A-T. DESIGN/METHODS: We used a consensus development method, the e-Delphi technique, comprising three rounds. Round 1 consisted of a Delphi questionnaire and a survey that collected the details of respondents' professional background, experience, and current practice of cancer surveillance in A-T. Rounds 2 and 3 were designed based on previous rounds and modified according to the comments made by the panellists. The pre-specified consensus threshold was ≥75% agreement. RESULTS: Thirty-five expert panellists from 13 countries completed the study. The survey indicated that the current practice of cancer surveillance varies widely between experts and centres'. Consensus was reached that evidence-based guidelines are needed for cancer surveillance in people with A-T, with separate recommendations for adults and children. Statements relating to the tests that should be included, the age for starting and stopping cancer surveillance and the optimal surveillance interval were also agreed upon, although in some areas, the consensus was that further research is needed. CONCLUSION: The international expert consensus statement confirms the need for evidence-based cancer surveillance guidelines in A-T, highlights key features that the guidelines should include, and identifies areas of uncertainty in the expert community. This elucidates current knowledge gaps and will inform the design of future clinical trials.

New diagnosis of mother-to-child transmission of HIV in 8 Latin-American countries during 2018.

BACKGROUND: Important prevention efforts have led to a reduction in mother-to-child transmission of HIV (MTCT) globally. However, new cases of paediatric HIV infections still occur. Early diagnosis of new HIV infections is essential to start an appropriate antiretroviral treatment to avoid childhood morbidity and mortality related to infection. The aim of this study was to describe the new cases of MTCT in Latin-American referral hospitals. METHODS: A retrospective, multicentre and descriptive study of the new cases of MTCT diagnosed during 2018 in 13 referral hospitals from 8 Latin-American countries (Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Panama) belonging to PLANTAIDS (Paediatric Network for Prevention, Early Detection and Treatment of HIV in Children), was conducted. PLANTAIDS is included in CYTED (Ibero-American Programme of Science and Technology for Development). RESULTS: Eighty-one children (40.7% males) were included, median age at diagnosis of 2.33 years (IQR:0.7-4.7). Less than 3% of women knew their HIV diagnosis before pregnancy. More than 80% of them were diagnosed after delivery, 8.7% during pregnancy, and 2.9% at delivery. Only one patient underwent antiretroviral therapy (ART) prior to pregnancy. At diagnosis, 50.0% of the children presented with an advanced stage of disease (stage C following the current CDC classification for HIV infection), and 34.4% had less than 15% CD4+ cells/mm3. The time elapsed between delivery and the maternal diagnosis was correlated with the age of children at diagnosis, ρ = 0.760, p < 0.001. Younger age at diagnosis (p = 0.03), a smaller number of previous hospitalizations (p < 0.01), and better immunovirological status (p < 0.01) were found in children whose mothers knew their HIV status at delivery, compared to mothers who were not aware of it. CONCLUSIONS: Although MTCT in Latin America has declined in recent years, our series shows there are still cases that indicate some failures in prevention, being a critical point to improve an earlier diagnosis of pregnant women. Half of the children were diagnosed in an advanced stage of disease and the delay in maternal diagnosis entailed a worse clinical and immunological child' prognosis.

CD40 Ligand Deficiency in Latin America: Clinical, Immunological, and Genetic Characteristics.

CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.

Artritis crónica en una paciente pediátrica posterior a Chikungunya / Chronic arthritis in a pediatric patient following Chikungunya

Resumen El virus Chikungunya produce una enfermedad de reciente aparición y creciente incidencia en Costa Rica. Las manifestaciones crónicas de la enfermedad se consideran de importancia en el área de la reumatología. La paciente presentó factores de riesgo para cronicidad como el sexo, la duración y severidad de la fase aguda, el número de articulaciones comprometidas y la asociación con el síndrome de activación macrofágica. En una artritis idiopática juvenil, que es el principal diagnóstico diferencial, se esperaría un inicio más insidioso y no agudo como en este caso; además, la paciente no presentó hepatomegalia o serositis e inicialmente no tuvo trombocitosis, pero manifestó un síndrome de activación macrofágica, que es una complicación inflamatoria descrita en artritis idiopática juvenil. La remisión del cuadro de artritis crónica con el uso de metotrexate, no ayuda al diagnóstico diferencial, porque se ha reportado que este es el tratamiento crónico de elección en ambas patologías. En este reporte se presenta el caso de una paciente pediátrica que ingresó con un cuadro agudo de Chikungunya confirmado serológicamente, y que evolucionó con criterios de una artritis idiopática juvenil sistémica y un síndrome de activación macrofágica secundario.

Abstract Chikungunya virus produce a disease of recent emergence and increasing incidence in Costa Rica. Chronicmanifestations of the disease are considered of importance in the rheumatology area. The patient presented risk factors for chronicity such as sex, the duration and severity of the acute phase, the number of joints involved, and the association with macrophage activation syndrome. In juvenile idiopathic arthritis, which is the main differential diagnosis, a more insidious and non-acute onset would be expected, as in this case, in addition, the patient did not present hepatomegaly or serositis and initially did not have thrombocytosis, but had a macrophage activation syndrome, which is an inflammatory complication described in juvenile idiopathic arthritis. Remission of the chronic arthritis condition with the use of methotrexate does not help the differential diagnosis, because it has been reported that this is the chronic treatment of choice in both pathologies. This report presents the case of a pediatric patient who was admitted with an acute episode of Chikungunya confirmed serologically and who evolved with systemic juvenile idiopathic arthritis criteria and secondary macrophage activation syndrome.

Latin American consensus on the supportive management of patients with severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 "agreed" and 38 "nonagreed" statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID.

Determinantes de la inercia en el tratamiento hipolipidemiante de pacientes con diabetes mellitus tipo 2 / Determinants of inertia with lipid-lowering treatment in patients with type 2 diabetes mellitus

Objetivo: Valorar el control del cLDL de pacientes con diabetes, medir la influencia en este control de la inercia con los hipolipidemiantes y explorar sus factores predictores. Métodos: Estudio de cohortes históricas de pacientes con diabetes. Se midió el porcentaje que alcanzó un cLDL dentro de objetivo. Se consideró inercia terapéutica cuando no se ajustó la dosis de los hipolipidemiantes, ni se cambió ni añadió ningún nuevo hipolipidemiante en los pacientes con cLDL inicial fuera de objetivo. Se estudiaron el cambio experimentado en el cLDL entre la primera y la última visita y la inercia con los hipolipidemiantes en función de las comorbilidades, factores de riesgo cardiovascular asociados y tratamientos utilizados. Resultados: Se incluyó a 639 pacientes (tiempo medio de seguimiento 11,1±11,2 meses). El 27,5% alcanzó un cLDL dentro de objetivo. Se produjo inercia en el 43,6% de los pacientes con un cLDL inicial fuera de objetivo. Resultaron predictores independientes de la inercia el cLDL inicial (p<0,001), la polineuropatía (p=0,014), el ajuste de los antihipertensivos (p=0,002), la adecuación de los hipolipidemiantes (p<0,001), el uso de ezetimiba (p=0,001) y la adherencia a los hipolipidemiantes (p=0,015). Conclusiones: La inercia en el tratamiento hipolipidemiante de un paciente con diabetes es menos frecuente ante valores iniciales de cLDL más altos, en los casos de polineuropatía, cuando se ajustan o cambian los antihipertensivos y cuando se detecta falta de adherencia. La prescripción inicial adecuada de estatinas y la asociación con ezetimiba disminuyen la probabilidad de caer en la inercia

Objective: To assess the control of cLDL in diabetic patients, to measure the impact on such control of inertia with lipid-lowering agents and to explore factors that allow for predicting this inertia. Methods: Study of historical cohorts of diabetic patients. The proportion of patients who achieved the target cLDL levels was estimated. Therapeutic inertia was considered when the dose of the lipid-lowering agents was not adjusted, or a lipid-lowering agent was not changed or added in patients with initial cLDL outside the target. Change in cLDL from the first to the last visit and inertia with lipid-lowering drugs were analyzed according to comorbidities, cardiovascular risk factors and treatments used. Results: The study simple consisted of 639 patients (mean follow-up time 11.1±11.2 months), of whom 27.5% achieved target cLDL levels. Inertia occurred in 43,6% of patients with initial cLDL outside the target. Independent predictors of inertia were the initial cLDL (P<0.001), polyneuropathy (P=0.014), adjustment of antihypertensive agents (P=0.002), adequacy of lipid-lowering agents (P<0.001), use of ezetimibe (P=0.001) and adherence to lipid-lowering drugs (P=0.015). Conclusions: Inertia with lipid-lowering agents in a diabetic patient is less frequent in the presence of higher cLDL values, in cases of polyneuropathy, when antihypertensive agents are adjusted or changed, and when non-adherence is detected. The adequate initial prescription of statins and the association with ezetimibe decrease the likelihood of committing inertia

Determinants of inertia with lipid-lowering treatment in patients with type 2 diabetes mellitus. / Determinantes de la inercia en el tratamiento hipolipidemiante de pacientes con diabetes mellitus tipo 2.

OBJECTIVE: To assess the control of cLDL in diabetic patients, to measure the impact on such control of inertia with lipid-lowering agents and to explore factors that allow for predicting this inertia. METHODS: Study of historical cohorts of diabetic patients. The proportion of patients who achieved the target cLDL levels was estimated. Therapeutic inertia was considered when the dose of the lipid-lowering agents was not adjusted, or a lipid-lowering agent was not changed or added in patients with initial cLDL outside the target. Change in cLDL from the first to the last visit and inertia with lipid-lowering drugs were analyzed according to comorbidities, cardiovascular risk factors and treatments used. RESULTS: The study simple consisted of 639 patients (mean follow-up time 11.1±11.2 months), of whom 27.5% achieved target cLDL levels. Inertia occurred in 43,6% of patients with initial cLDL outside the target. Independent predictors of inertia were the initial cLDL (P<0.001), polyneuropathy (P=0.014), adjustment of antihypertensive agents (P=0.002), adequacy of lipid-lowering agents (P<0.001), use of ezetimibe (P=0.001) and adherence to lipid-lowering drugs (P=0.015). CONCLUSIONS: Inertia with lipid-lowering agents in a diabetic patient is less frequent in the presence of higher cLDL values, in cases of polyneuropathy, when antihypertensive agents are adjusted or changed, and when non-adherence is detected. The adequate initial prescription of statins and the association with ezetimibe decrease the likelihood of committing inertia.

Determinantes de la adherencia a los hipoglucemiantes y a las visitas médicas en pacientes con diabetes mellitus tipo 2 / Determinants of adherence to hypoglycemic agents and medical visits in patients with type 2 diabetes mellitus

Objetivo: Valorar el control glucémico de pacientes diabéticos, medir la influencia en este control de la adherencia a los hipoglucemiantes y a las visitas médicas, y explorar factores que permitan predecir esta adherencia. Métodos: Estudio de cohortes históricas de pacientes diabéticos. Se midió el porcentaje que alcanzó una HbA1c dentro del objetivo. Se valoró la adherencia mediante la pregunta de Haynes-Sacket. Se estudiaron el cambio en la HbA1c entre la primera y la última visita, la adherencia y la asistencia a las consultas en función de las comorbilidades, los factores de riesgo cardiovascular y los tratamientos utilizados. Resultados: Se incluyeron 639 pacientes (tiempo medio de seguimiento 11,1±11,2 meses). El 66,6% alcanzó una HbA1c dentro del objetivo. El cambio en la HbA1c entre la primera y última visita se explicó en un 54,2% por la HbA1c inicial (p<0,001), en un 13% por la adherencia terapéutica (p<0,001) y en un 9,6% por la adherencia a las citas (p<0,001). La no insulinización (p=0,011) y el cese del tabaco (p=0,032) predispusieron a una mayor adherencia. La insulinización (p=0,019) y la falta de educación terapéutica (p=0,033) predispusieron a no acudir a las visitas. Conclusiones: La mejora de la HbA1c está determinada por la HbA1c inicial, la adherencia terapéutica y la asistencia a las citas. Los insulinizados tienen peor adherencia y faltan más a la consulta, los que dejan de fumar se adhieren más a los hipoglucemiantes y los que reciben educación terapéutica acuden más a la consulta (AU)

Aim: To assess glycemic control in diabetic patients, to measure the impact on such control of adherence to hypoglycemic agents and to medical visits, and to explore factors that allow for predicting adherence. Methods: Study of historical cohorts of diabetic patients. The proportion of patients who achieved the target HbA1c levels was estimated. Adherence was assessed using the Haynes-Sackett test. Change in HbA1c from the first to the last visit, adherence, and attendance to visits were analyzed according to comorbidities, cardiovascular risk factors, and treatments used. Results: The study simple consisted of 639 patients (mean follow-up time, 11.1±11.2 months), of whom 66.6% achieved target HbA1c levels. Change in HbA1c from the first to the last visit was explained in 54.2% of patients by baseline HbA1c (P<0.001), in 13% by treatment adherence (P<0.001), and in 9.6% by visit adherence (P<0.001). Non-insulinization (P=0.011) and smoking cessation (P=0.032) predisposed to greater adherence. Insulinization (P=0.019) and lack of diabetes education (P=0.033) predisposed to visit non-compliance. Conclusions: Improvement in HbA1c is determined by baseline HbA1c, treatment adherence, and attendance to visits. Patients on insulin have poorer adherence and are more likely to miss the appointments, those who stop smoking adhere more to hypoglycemic agents, and those given therapeutic education are more likely to keep the appointments (AU)

Determinants of adherence to hypoglycemic agents and medical visits in patients with type 2 diabetes mellitus. / Determinantes de la adherencia a los hipoglucemiantes y a las visitas médicas en pacientes con diabetes mellitus tipo 2.

AIM: To assess glycemic control in diabetic patients, to measure the impact on such control of adherence to hypoglycemic agents and to medical visits, and to explore factors that allow for predicting adherence. METHODS: Study of historical cohorts of diabetic patients. The proportion of patients who achieved the target HbA1c levels was estimated. Adherence was assessed using the Haynes-Sackett test. Change in HbA1c from the first to the last visit, adherence, and attendance to visits were analyzed according to comorbidities, cardiovascular risk factors, and treatments used. RESULTS: The study simple consisted of 639 patients (mean follow-up time, 11.1±11.2 months), of whom 66.6% achieved target HbA1c levels. Change in HbA1c from the first to the last visit was explained in 54.2% of patients by baseline HbA1c (P<0.001), in 13% by treatment adherence (P<0.001), and in 9.6% by visit adherence (P<0.001). Non-insulinization (P=0.011) and smoking cessation (P=0.032) predisposed to greater adherence. Insulinization (P=0.019) and lack of diabetes education (P=0.033) predisposed to visit non-compliance. CONCLUSIONS: Improvement in HbA1c is determined by baseline HbA1c, treatment adherence, and attendance to visits. Patients on insulin have poorer adherence and are more likely to miss the appointments, those who stop smoking adhere more to hypoglycemic agents, and those given therapeutic education are more likely to keep the appointments.

Polimiositis secundaria a tuberculosis en un niño de 11 años / Polymyositis secondary to tuberculosis in an 11-year-old boy

Resumen:La polimiositis es una de las miopatías inflamatorias idiopáticas. Tiene una incidencia mundial estimada en 4 casos por cada millón de habitantes al año. Es considerada un diagnóstico de exclusión y se ha establecido una asociación con la infección por micobacterias. Se reporta el caso de un niño de 11 años de edad con polimiositis secundaria a tuberculosis. La polimiositis tuvo una adecuada respuesta a los corticosteroides, pero estos no fueron necesarios después del diagnóstico de una infección pulmonar por Mycobacterium tuberculosis. El tratamiento antifímico, sin la terapia con esteroides, permitió una resolución de ambas patologías y la evolución favorable del paciente.

Abstract:Polymyositis is one of the idiopathic inflammatory myopathies. It has an estimated worldwide incidence of 4 cases per million population per year. It is considered an exclusion diagnosis and a relationship with mycobacterial infection has been established. This article reports the case of an 11-year-old boy with polymyositis secondary to tuberculosis. Polymyositis had an adequate response to corticosteroids, but these were not needed after the diagnosis of a Mycobacterium tuberculosis lung infection. Anti-tuberculosis treatment without steroid therapy, allowed a resolution of both conditions and the favorable outcome of the patient.

Clinical and Genotypic Spectrum of Chronic Granulomatous Disease in 71 Latin American Patients: First Report from the LASID Registry.

AIM: We analyzed data from 71 patients with chronic granulomatous disease (CGD) with a confirmed genetic diagnosis, registered in the online Latin American Society of Primary Immunodeficiencies (LASID) database. RESULTS: Latin American CGD patients presented with recurrent and severe infections caused by several organisms. The mean age at disease onset was 23.9 months, and the mean age at CGD diagnosis was 52.7 months. Recurrent pneumonia was the most frequent clinical condition (76.8%), followed by lymphadenopathy (59.4%), granulomata (49.3%), skin infections (42%), chronic diarrhea (41.9%), otitis (29%), sepsis (23.2%), abscesses (21.7%), recurrent urinary tract infection (20.3%), and osteomyelitis (15.9%). Adverse reactions to bacillus Calmette-Guérin (BCG) vaccination were identified in 30% of the studied Latin American CGD cases. The genetic diagnoses of the 71 patients revealed 53 patients from 47 families with heterogeneous mutations in the CYBB gene (five novel mutations: p.W361G, p.C282X, p.W483R, p.R226X, and p.Q93X), 16 patients with the common deletion c.75_76 del.GT in exon 2 of NCF1 gene, and two patients with mutations in the CYBA gene. CONCLUSION: The majority of Latin American CGD patients carry a hemizygous mutation in the CYBB gene. They also presented a wide range of clinical manifestations most frequently bacterial and fungal infections of the respiratory tract, skin, and lymph nodes. Thirty percent of the Latin American CGD patients presented adverse reactions to BCG, indicating that this vaccine should be avoided in these patients.

DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients.

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies.

BACKGROUND: Severe combined immunodeficiency (SCID) is a syndrome characterized by profound T-cell deficiency. BCG vaccine is contraindicated in patients with SCID. Because most countries encourage BCG vaccination at birth, a high percentage of patients with SCID are vaccinated before their immune defect is detected. OBJECTIVES: We sought to describe the complications and risks associated with BCG vaccination in patients with SCID. METHODS: An extensive standardized questionnaire evaluating complications, therapeutics, and outcomes regarding BCG vaccination in patients given a diagnosis of SCID was widely distributed. Summary statistics and association analysis was performed. RESULTS: Data on 349 BCG-vaccinated patients with SCID from 28 centers in 17 countries were analyzed. Fifty-one percent of the patients had BCG-associated complications, 34% disseminated and 17% localized (a 33,000- and 400-fold increase, respectively, over the general population). Patients receiving early vaccination (≤1 month) showed an increased prevalence of complications (P = .006) and death caused by BCG-associated complications (P < .0001). The odds of experiencing complications among patients with T-cell numbers of 250/µL or less at diagnosis was 2.1 times higher (95% CI, 1.4-3.4 times higher; P = .001) than among those with T-cell numbers of greater than 250/µL. BCG-associated complications were reported in 2 of 78 patients who received antimycobacterial therapy while asymptomatic, and no deaths caused by BCG-associated complications occurred in this group. In contrast, 46 BCG-associated deaths were reported among 160 patients treated with antimycobacterial therapy for a symptomatic BCG infection (P < .0001). CONCLUSIONS: BCG vaccine has a very high rate of complications in patients with SCID, which increase morbidity and mortality rates. Until safer and more efficient antituberculosis vaccines become available, delay in BCG vaccination should be considered to protect highly vulnerable populations from preventable complications.

First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes.

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.

Attending to warning signs of primary immunodeficiency diseases across the range of clinical practice.

PURPOSE: Patients with primary immunodeficiency diseases (PIDD) may present with recurrent infections affecting different organs, organ-specific inflammation/autoimmunity, and also increased cancer risk, particularly hematopoietic malignancies. The diversity of PIDD and the wide age range over which these clinical occurrences become apparent often make the identification of patients difficult for physicians other than immunologists. The aim of this report is to develop a tool for educative programs targeted to specialists and applied by clinical immunologists. METHODS: Considering the data from national surveys and clinical reports of experiences with specific PIDD patients, an evidence-based list of symptoms, signs, and corresponding laboratory tests were elaborated to help physicians other than immunologists look for PIDD. RESULTS: Tables including main clinical manifestations, restricted immunological evaluation, and possible related diagnosis were organized for general practitioners and 5 specialties. Tables include information on specific warning signs of PIDD for pulmonologists, gastroenterologists, dermatologists, hematologists, and infectious disease specialists. CONCLUSIONS: This report provides clinical immunologists with an instrument they can use to introduce specialists in other areas of medicine to the warning signs of PIDD and increase early diagnosis. Educational programs should be developed attending the needs of each specialty.

Lentiviral gene transfer of TCIRG1 into peripheral blood CD34(+) cells restores osteoclast function in infantile malignant osteopetrosis.

Infantile malignant osteopetrosis (IMO) is a rare, lethal, autosomal recessive disorder characterized by non-functional osteoclasts. More than 50% of the patients have mutations in the TCIRG1 gene, encoding for a subunit of the osteoclast proton pump. The aim of this study was to restore the resorptive function of IMO osteoclasts by lentiviral mediated gene transfer of the TCIRG1 cDNA. CD34(+) cells from peripheral blood of five IMO patients and from normal cord blood were transduced with lentiviral vectors expressing TCIRG1 and GFP under a SFFV promoter, expanded in culture and differentiated on bone slices to mature osteoclasts. qPCR analysis and western blot revealed increased mRNA and protein levels of TCIRG1, comparable to controls. Vector corrected IMO osteoclasts generated increased release of Ca(2+) and bone degradation product CTX-I into the media as well as increased formation of resorption pits in the bone slices, while non-corrected IMO osteoclasts failed to resorb bone. Resorption was approximately 70-80% of that of osteoclasts generated from cord blood. Furthermore, transduced CD34(+) cells successfully engrafted in NSG-mice. In conclusion we provide the first evidence of lentiviral-mediated correction of a human genetic disease affecting the osteoclastic lineage.