The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype.

In addition to their detection in typical X-linked severe combined immunodeficiency, hypomorphic mutations in the interleukin (IL)-2 receptor common gamma chain gene (IL2RG) have been described in patients with atypical clinical and immunological phenotypes. In this leaky clinical phenotype the diagnosis is often delayed, limiting prompt therapy in these patients. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in two siblings: a 4-year-old boy with lethal Epstein-Barr virus-related lymphoma and his asymptomatic 8-month-old brother with a Tlow B+ natural killer (NK)+ immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation and reduced levels of T cell receptor excision circles. After confirming normal IL-2RG expression (CD132) on T lymphocytes, signal transducer and activator of transcription-1 (STAT-5) phosphorylation was examined to evaluate the functionality of the common gamma chain (γc ), which showed partially preserved function. Co-immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with Janus kinase (JAK)3, concluding that R328X impairs JAK3 binding to γc . Here, we describe how the R328X mutation in IL-2RG may allow partial phosphorylation of STAT-5 through a JAK3-independent pathway. We identified a region of three amino acids in the γc intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable clearer understanding of partial defects leading to leaky phenotypes.

Clinical practice update of antifungal prophylaxis in immunocompromised children.

Due to the rise in the number and types of immunosuppressed patients, invasive fungal infections (IFI) are an increasing and major cause of morbidity and mortality in immunocompromised adults and children. There is a broad group of pediatric patients at risk for IFI in whom primary and/or secondary antifungal prophylaxis (AFP) should be considered despite scant evidence. Pediatric groups at risk for IFI includes extremely premature infants in some settings, while in high-risk children with cancer receiving chemotherapy or undergoing haematopoietic stem cell transplantation (HCT), AFP against yeast and moulds is usually recommended. For solid organ transplanted, children, prophylaxis depends on the type of transplant and associated risk factors. In children with primary or acquired immunodeficiency such as HIV or long-term immunosuppressive treatment, AFP depends on the type of immunodeficiency and the degree of immunosuppression. Chronic granulomatous disease is associated with a particular high-risk of IFI and anti-mould prophylaxis is always indicated. In contrast, AFP is not generally recommended in children with long stay in intensive care units. The choice of AFP is limited by the approval of antifungal agents in different age groups and by their pharmacokinetics characteristics. This document aims to review current available information on AFP in children and to provide a comprehensive proposal for each type of patient.

Screening protocols to monitor respiratory status in primary immunodeficiency disease: findings from a European survey and subclinical infection working group.

Many patients with primary immunodeficiency (PID) who have antibody deficiency develop progressive lung disease due to underlying subclinical infection and inflammation. To understand how these patients are monitored we conducted a retrospective survey based on patient records of 13 PID centres across Europe, regarding the care of 1061 adult and 178 paediatric patients with PID on immunoglobulin (Ig) G replacement. The most common diagnosis was common variable immunodeficiency in adults (75%) and hypogammaglobulinaemia in children (39%). The frequency of clinic visits varied both within and between centres: every 1-12 months for adult patients and every 3-6 months for paediatric patients. Patients diagnosed with lung diseases were more likely to receive pharmaceutical therapies and received a wider range of therapies than patients without lung disease. Variation existed between centres in the frequency with which some clinical and laboratory monitoring tests are performed, including exercise tests, laboratory testing for IgG subclass levels and specific antibodies, and lung function tests such as spirometry. Some tests were carried out more frequently in adults than in children, probably due to difficulties conducting these tests in younger children. The percentage of patients seen regularly by a chest physician, or who had microbiology tests performed following chest and sinus exacerbations, also varied widely between centres. Our survey revealed a great deal of variation across Europe in how frequently patients with PID visit the clinic and how frequently some monitoring tests are carried out. These results highlight the urgent need for consensus guidelines on how to monitor lung complications in PID patients.

[Is familial screening useful in selective immunoglobulin A deficiency?]. / ¿Es útil el cribado familiar en el déficit selectivo de inmunoglobulina A?

INTRODUCTION: Selective immunoglobulin A deficiency (SIgAD), the most common primary immunodeficiency, is often asymptomatic. High rates of familial clustering have been described in SIgAD, but the causative genetic defect and mechanism of inheritance are unknown. OBJECTIVES: To determine whether familial SIgAD cases show more severe clinical and immunological characteristics than sporadic ones; to investigate the utility of screening first-degree relatives (FDRs) of these patients, and to determine whether symptoms in affected family members are important enough to justify screening. PATIENTS AND METHODS: Descriptive, cross-sectional study (October 2010-September 2011) of all patients with SIgAD and followed up in our center. Demographic, clinical, and analytical data were reviewed. A familial case was defined as an SIgAD patient with at least one affected FDR. RESULTS: Of the 130 participants, 42 were SIgAD patients and 88 FDR. There were 13 (31%) familial cases and and 14 (16%) affected FDRs. Six family members had to be analyzed in order to detect one affected one. There were no clinical differences between familial and sporadic SIgAD cases. The percentages of intestinal disease (p=001, OR=9.57, 95%CI 2.59-35.3), hospitalizations (p=045, OR=4.01; 95%CI 1.10-14.67], and need for chronic treatment (p=006, OR=5.5; 95%CI 1.57-19.54) were higher in affected FDRs than in unaffected ones. CONCLUSIONS: The symptoms were not more severe in familial than sporadic SIgAD cases. Nonetheless, the elevated prevalence of affected FDRs with significant morbidity may justify routine screening of close family members of these patients.

[Recurrent meningitis due to anatomical defects: The bacteria indicates its origin]. / Meningitis recurrente por defectos anatómicos: la bacteria indica su origen.

INTRODUCTION: Recurrent meningitis is a rare disease. Anatomical abnormalities and immunodeficiency states are predisposing factors. Four cases, in which immunodeficiency was excluded, are presented. The causal microorganism led to the detection of the anatomical defect responsible for the recurrences. PATIENTS AND METHODS: Retrospective review of 4 cases with clinical diagnosis of recurrent bacterial meningitis. RESULTS: Case 1: a thirty month-old boy with unilateral hearing loss, diagnosed with Mondini abnormality by magnetic resonance imaging (MRI) after 2 episodes of Haemophilus influenzae meningitis. Surgical repair after third recurrence. Case 2: fourteen year-old girl diagnosed by MRI with cribriform plate defect after 3 episodes of meningitis due to Streptococcus pneumoniae. Ventriculoperitoneal shunt was placed. Case 3: girl with meningitis due to Staphylococcus aureus at 2 and 7 months. MRI shows occipital dermal sinus requiring excision. Complication with cerebellar abscesses because of a coexisting dermoid cyst. Case 4: child with meningitis due to Streptococcus bovis at 9 days and Enterococcus faecium, Klebsiella pneumoniae and Escherichia coli at 7 months, with positive cultures to Citrobacter freundii and E. faecium later on. Spinal MRI led to the diagnosis of Currarino syndrome with CSF fistula, which was surgically repaired. The 4 patients had undergone image studies reported as normal during the first episodes. CONCLUSIONS: In patients with recurrent meningitis the possibility of an anatomical defect should be considered. The isolated microorganism should help to locate it. It is essential to know the normal flora of the different anatomical sites. The definitive treatment is usually surgical.

[The use of polymerase chain reaction in the diagnosis of invasive meningococcal disease]. / La reacción en cadena de la polimerasa en el diagnóstico de la enfermedad meningocócica invasiva.

INTRODUCTION AND OBJECTIVES AND AIMS: Invasive meningococcal disease (IMD) remains a serious public health problem. Although culture is the gold standard, previous antibiotic therapy reduces its sensibility. The aim of this study is the epidemiological analysis of IMD in our area, to assess the usefulness of polymerase chain reaction (PCR) to increase its diagnostic accuracy,and to show the association of antibiotic administration with the negative result of the culture. PATIENTS AND METHODS: A retrospective study was conducted on all children younger than 16 years with microbiologically (positive culture and/or PCR) confirmed IMD, admitted to our hospital between 2004-2012. RESULTS: Seventy-five patients were included, of whom 52% had sepsis, 30.7% meningitis, and 17.3% with both of them. PCR was positive in all samples, whereas a positive was seen 50.7% of the cultures. Previously administered antibiotic was documented in 40 patients (53.3%), and 40% of them were confirmed by PCR only. CONCLUSIONS: PCR was the only test providing evidence for IMD diagnosis and serogroup determination in almost 39% of cases.

[Imported infectious diseases in tertiary hospital]. / Patología infecciosa importada en hospitales terciarios.

INTRODUCTION: An Imported Diseases Clinic was created in the hospital in 2009. The aim of this study was to asses its contribution in terms of capacity, quality of care and teaching offered. PATIENTS AND METHODS: A retrospective study was conducted from 2009 to 2011, analyzing: A) development of knowledge by means of protocols and publications created, and subject taught; B) capacity and quality of care offered by the analysis of patients seen, the adequacy of the protocols and accessibility. The patients were classified into 3 groups. Group 1: immigrant patient screening, group 2: patient consultation after tropical or sub-tropical travel, group 3: screening of vertical transmission of imported disease. RESULTS: Six protocols have been developed and disseminated on the unit website, as well as 5 scientific publications. A total of 316 patients were evaluated: 191 included in group 1 (29 Adopted and 162 Immigrants), 57 in group 2 (94.7% Visiting Friends and Relatives and 81.5% without a pre-travel consultation). They consulted due to, gastrointestinal symptoms (52.6%) and fever (43.8%), with 68 included in group 3 at risk of imported disease by vertical transmission (62 Trypanosoma cruzi, 1 Human T Lymphotropic Virus and 5 Plasmodium spp.). The overall adherence to the protocols was about 77.1%. DISCUSSION: Infectious Diseases Units must adapt to the reality of the population and be flexible in its structure. Periodic assessment of the quality of care offered is essential, as well as an evaluation on the need for additional studies.

Increase in gonorrhoea among very young adolescents, Catalonia, Spain, January 2012 to June 2013.

Between January 2012 and June 2013, 27 sexually transmitted infections were reported in adolescents aged 13-15 years in Catalonia, Spain. In the first half of 2013, there were nine cases of gonorrhoea, while in the same period of 2012, there was one. In June 2013, two gonorrhoea cases aged 13-14 years, linked to a common source through a social network, were reported. The public health response should be adapted to this vulnerable population.

The incidence of AIDS-defining illnesses at a current CD4 count ≥ 200 cells/µL in the post-combination antiretroviral therapy era.

BACKGROUND: Few studies consider the incidence of individual AIDS-defining illnesses (ADIs) at higher CD4 counts, relevant on a population level for monitoring and resource allocation. METHODS: Individuals from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) aged ≥14 years with ≥1 CD4 count of ≥200 µL between 1998 and 2010 were included. Incidence rates (per 1000 person-years of follow-up [PYFU]) were calculated for each ADI within different CD4 strata; Poisson regression, using generalized estimating equations and robust standard errors, was used to model rates of ADIs with current CD4 ≥500/µL. RESULTS: A total of 12 135 ADIs occurred at a CD4 count of ≥200 cells/µL among 207 539 persons with 1 154 803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0-21.1 per 1000 PYFU) with current CD4 200-349 cells/µL to 4.1 per 1000 PYFU (95% CI, 3.6-4.6 per 1000 PYFU) with current CD4 ≥ 1000 cells/µL. Persons with a current CD4 of 500-749 cells/µL had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10-1.32), whereas those with a current CD4 of ≥1000 cells/µL had a similar rate (aIRR, 0.92; 95% CI, .79-1.07), compared to a current CD4 of 750-999 cells/µL. Results were consistent in persons with high or low viral load. Findings were stronger for malignant ADIs (aIRR, 1.52; 95% CI, 1.25-1.86) than for nonmalignant ADIs (aIRR, 1.12; 95% CI, 1.01-1.25), comparing persons with a current CD4 of 500-749 cells/µL to 750-999 cells/µL. DISCUSSION: The incidence of ADIs was higher in individuals with a current CD4 count of 500-749 cells/µL compared to those with a CD4 count of 750-999 cells/µL, but did not decrease further at higher CD4 counts. Results were similar in patients virologically suppressed on combination antiretroviral therapy, suggesting that immune reconstitution is not complete until the CD4 increases to >750 cells/µL.

[Antibiotic prophylaxis for surgical wound infection in cardiac surgery: results of a Spanish survey]. / Encuesta nacional sobre profilaxis antibiótica de infección de herida quirúrgica en cirugía cardíaca.

INTRODUCTION: No Spanish guidelines for the prevention of surgical wound infection in paediatric cardiac surgery are currently available. The aim of this study was to analyse the nationwide variability in antibiotic prophylaxis use. MATERIAL AND METHODS: An online questionnaire was distributed to all members of the Cardiology Group of the Spanish Society of Paediatric Intensive Care. Fifteen centres participated in the study. RESULTS: In heart surgery with no delayed sternal closure, all 15 centres used a 1st or 2nd generation cephalosporin in paediatric patients, while 3 hospitals used a broader-spectrum antibiotic therapy in neonates. Prophylaxis was maintained for 12-72h in 11 centres and until drainage removal in four. Thirteen centres used delayed sternal closure, eight of which followed the same protocol for these patients as for standard procedures. Prophylaxis was maintained for 12-72h in 6 centres, and until sternal closure at the rest. Five out of 10 centres performing extracorporeal membrane oxygenation (ECMO) maintained the same antibiotic protocol as in standard surgery. CONCLUSIONS: A wide variability was observed in antibiotic prophylaxis use in high-risk patients. Thus, national protocols need to be standardised.

[Evaluation of a program for assessing adherence to antiretroviral treatment]. / Evaluación de un programa de valoración de adherencia al tratamiento antirretroviral.

INTRODUCTION: Poor adherence to antiretroviral treatment (ART) is the commonest cause of treatment failure in children and adults living with HIV, and this is especially important during adolescence. Therefore, any analysis of ART effectiveness in children should include an evaluation of adherence to ART. The aim of this study is to assess the usefulness of an ART adherence monitoring program in an HIV-infected paediatric population. PATIENTS AND METHODS: An observational and cross-sectional study was performed, within the framework of the "Health Education Program for Optimising Adherence in Paediatric Patients with HIV", which is part of the "I am not alone" project. Adherence was assessed simultaneously by different methods: personal interview, therapeutic drug monitoring, pharmacy dispensing records and evolution of viral load and T CD4+ lymphocyte count. RESULTS: Twenty patients were included (50% female, median age 14.5 years). Percentage of self-reported full adherence was 90% (95% CI: 70-97.2%); however, the median adherence percentage according to pharmacy dispensing records was significantly lower (83.3%, SD=32.88). The average of drugs and dosage forms per day were 3.5 (SD=0.83) and 5.5 (SD=2.72), respectively. There was an inverse relationship between the number of dosage forms per day and adherence scores (F=13.8; P=.002). No single method was statistically related to adherence, although therapeutic drug monitoring showed a trend towards significance. CONCLUSIONS: Global adherence to ART was high and was easier with simpler regimens. Self-reported adherence overestimated real adherence to ART in our cohort. The simultaneous use of different methods to assess adherence is recommended in HIV-infected children.

[Spectrum of primary immunodeficiencies in a tertiary hospital over a period of 10 years]. / Espectro de las inmunodeficiencias primarias en un hospital de tercer nivel en un periodo de 10 años.

INTRODUCTION: More than 200 primary immunodeficiencies (PID) have been described and about 60% present during childhood. Early diagnosis and treatment have been shown to improve patient outcome. AIM: Analysis of patients with a PID diagnosed in a paediatric tertiary care hospital-referral centre over a period of 10 years. PATIENTS AND METHODS: Medical records of all paediatric patients followed up in our unit were retrospectively reviewed. Clinical and epidemiological features, laboratory tests, therapy and outcome were analysed. RESULTS: One hundred and eighty nine patients were followed up in this period of time. Antibody disorders were the most common diagnosis. In our series, clinical presentation at diagnosis were: recurrent respiratory infections in selective IgA deficiency and common variable immunodeficiency (CVID) patients, failure to thrive and opportunistic infections (mainly viral infections) in patients with severe combined immunodeficiency (SCID), skin abscesses (Staphylococcus aureus, Serratia spp.) and complicated pneumonia (Aspergillus spp., Rhodococcus equi) in chronic granulomatous disease, congenital heart disease and consistent phenotype in 22q11 deletion syndrome, skin abscesses and ecthyma gangrenosum in severe congenital neutropenia and opportunistic infections and sepsis (Pseudomonas aeruginosa) in children with X-linked agammaglobulinaemia (XLA). Lymphoproliferative disorders were common in CVID. No malignancies were observed during this period. One patient with XLA developed chronic encephalitis. All patients with CVID and XLA were receiving immunoglobulin replacement therapy (8 intravenous and 14 (since 2006) subcutaneous route) and in all but two SCID patients, stem cell transplantation was performed. Outcome was good in most of them except 8 SCID (2 prior and 6 after transplantation), 3 Wiskott-Aldrich syndrome, 1 complete DiGeorge, 1 chronic granulomatous disease and 1 ataxia-telangiectasia patients who died during follow-up. CONCLUSION: The vast majority of patients included in this series presented with typical clinical features; therefore, basic knowledge of these entities in primary care and collaboration with hospital referral centres should allow a large number of PID in children to be diagnosed at an early stage, leading to proper treatment and monitoring, and therefore improvement of patient prognosis.

[Consensus Document on the differential diagnosis and therapeutic approach to recurrent fever by the Paediatric Infectology Society and the Paediatric Rheumatology Society]. / Documento de Consenso de la Sociedad de Infectología Pediatrica y la Sociedad de Reumatología Pediatrica sobre el diagnóstico diferencial y el abordaje terapéutico de la fiebre recurrente.

Recurrent fever is a relatively common problem during childhood. Diagnosis is often easy and related to mild viral infections. However a small proportion of these cases originate from an underlying non-infectious process that is generally difficult to diagnose. In this paper we describe the differential diagnosis of recurrent or periodic fever versus other processes, with especial attention to autoinflammatory disorders (AD). AD are alterations of innate immunity, and they have been recently classified as an immunodeficiency. Anyhow, since infections are not present, these processes are different to the classic primary immunodeficiency. An important part of AD is of known genetic aetiology. The symptoms originate from an underlying inflammatory process and can have different clinical expressions. One of the most relevant groups is the hereditary syndromes of periodic fever. This group of diseases associates recurrent fever and several clinical symptoms with a relative periodicity, separated by intervals free or almost free of symptoms. We include the diagnostic criteria for some processes as well as the characteristics that should, eventually, lead to a genetic study. Although treatment should be individualised, we also include some general recommendations.

[Spanish Paediatric Infectious Diseases Society consensus document on the treatment of fungal infections based on the immune response]. / Documento de consenso de la Sociedad de Infectología Pediátrica sobre el tratamiento de la infección fúngica basado en la respuesta inmunológica.

Despite the emergence of new diagnostic and therapeutic methods, invasive fungal infections are still a major cause of morbidity and mortality in immunocompromised and critical patients. Therefore, adjuvant treatments to the standard antifungal therapy are being investigated, with immunity-based therapy being one of the most important. Both immunomodulatory (dendritic and T cells transfusions, colony stimulating factors, interferón-gamma, interleukin 12, fungal vaccines, transfer factors and certain drugs such as chloroquine) and immunotherapeutic modalities (granulocyte transfusions, monoclonal antibodies and intravenous immunoglobulin) have been described. This document aims to summarise currently available data on immunity-based therapy of fungal infections and to provide basic knowledge on the immune response to fungal infections. This helps to understand how, in selected cases, immunity-based therapy may improve the response to standard antifungal treatment. The potential indications of immunity-based therapy in the paediatric patient are reviewed, although there is still a lack of scientific evidence for its use in children.

[Subcutaneous gammaglobulin in common variable immunodeficiency. First experience in Spain]. / Gammaglobulina subcutánea en inmunodeficiencia común variable. Primera experiencia en España.

INTRODUCTION AND AIM: Weekly home-based subcutaneous immunoglobulin (SCIg) therapy is an alternative to intravenous immunoglobulin (IVIg) in the treatment of patients with primary antibody deficiencies. The objective of this study was to investigate the efficacy, safety, related quality of life and cost effectiveness of SCIg in our area. MATERIALS AND METHODS: Observational and descriptive study including paediatric patients with common variable immunodeficiency (CVID) receiving SCIg in our hospital (November 2006 to April 2008). Obtained data were compared with those from the last year with IVIg. RESULTS: Eleven patients with CVID were included. Median age was 15 years. The median trough serum IgG level was 622 mg/dl with IVIg. In patients in whom the SCIg dose was maintained or reduced compared to IVIg, the median trough serum IgG level was 850 mg/dl (p < 0.0005). Annual rate of infection was 2.22 per patient-year, without significant differences to IVIg (p = 0.212). There were 58 treatment-related adverse events (AE) reported with SCIg (45 local AE and 13 systemic AE). The most frequent treatment-related adverse event was infusion-site reaction. Switching to home-based subcutaneous IgG treatment led to significant improvements in quality of life and substantial cost savings. CONCLUSIONS: We conclude that subcutaneous administration of 16% SCIg is a safe and cost-effective alternative to IVIg for replacement therapy of primary antibody deficiencies. Median trough serum IgG levels were higher with SCIg. Local AE were common but mild and the incidence decreased over time. Quality of life is significantly improved.

[Invasive pneumococcal disease and hemolytic uremic syndrome]. / Enfermedad neumocócica invasiva y síndrome hemolítico urémico.

INTRODUCTION: Streptococcus pneumoniae is an infrequent casual agent of hemolytic uremic syndrome (HUS) with more severity than classic HUS. CASE REPORT: We present two patients with pneumococcal pneumonia and empyema who developed HUS. One patient the renal function returned to normal and the other needed a renal transplantation. CONCLUSION: Pneumococcal invasive disease may be a cause of severe HUS, so a high index of suspicion is mandatory to prompt appropriate diagnosis and management.