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.

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.

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.

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.

[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.

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.

[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.

[Macroamylasaemia in paediatrics]. / Macroamilasemia en pediatría.

Macroamylasaemia should be considered in any patient with high plasma amylase, no clinical signs and negative additional investigations for pancreatic or parotid diseases. It is characterised by an increase in serum amylase due to circulating high molecular mass macrocomplexes, most often formed due the binding of the amylase to an immunoglobulin. With a normal renal function, a hyperamylasaemia without an increase in urine amylase suggests the diagnosis, and is confirmed by identifying the macromolecular components. It is an uncommon entity in paediatrics. It has been described as a casual finding associated to abdominal pain and to celiac disease. We report two paediatric cases of macroamylasaemia, and a review of the tests needed for its diagnosis. The better understanding of this biochemical anomaly allows us to differentiate it from other situations associated to hyperamylasaemia, in order to avoid additional invasive explorations and unnecessary treatments.

Osteoporosis and multiple fractures in an antiretroviral-naive, HIV-positive child.

As a result of the increased incidence of osteopenia and osteoporosis in HIV-infected patients, numerous publications have suggested that there may be a link between bone metabolism alterations and HIV infection. The early bone loss seen in these patients was initially attributed to the use of highly active antiretroviral treatment (HAART) that included protease inhibitors. Recent studies, however, have suggested that it may be a direct consequence of the viral infection on bone metabolism, persistent activation of pro-inflammatory cytokines (TNFa), or altered vitamin D metabolism secondary to the virus, combined with subsequent factors (e.g., antiretroviral treatment) that aggravate the bone demineralization. We present an antiretroviral-naive 6-year-old girl with vertically transmitted HIV infection who presented with severe osteoporosis and multiple pathological fractures of the vertebrae, ribs, and upper and lower limbs. The child was treated with HAART, appropriate nutritional support for her age, physiotherapy and rehabilitation, calcium and vitamin D supplements, and alendronate therapy. After 6 weeks of treatment, the intense pain and muscle atrophy had disappeared and she was able to walk unassisted. At 6 months, bone mass had increased by 72%. The interest of this case lies in the presence of severe osteoporosis and multiple pathological fractures in an HIVinfected naive child. To date, this condition has only been described in patients treated with antiretrovirals. Moreover, this is the first reported HIV-positive pediatric patient treated with bisphosphonates, which proved to be highly successful.

[Pneumococcal endocarditis in a previously healthy 17-month-old boy]. / Endocarditis neumocócica en niño de 17 meses previamente sano.

Invasive pneumococcal infection is a severe disease and its incidence may be increasing. Endocarditis due to Streptococcus pneumoniae is uncommon, particularly in children without risk factors. Etiologic diagnosis is difficult when cultures are negative. We report the case of a previously healthy, 17-month-old boy not vaccinated against pneumococcus who, during the course of pneumonia treated with beta-lactam antibiotics, developed cardiorespiratory deterioration and heart murmur. Mitral valve vegetation was identified by transthoracic echocardiography. Endocarditis was diagnosed and new antibiotics were given for 6 weeks (cefotaxime, gentamycin and vancomycin). Cultures were negative. Because of lack of improvement, prosthetic mitral replacement was indicated. S. pneumoniae was identified by polymerase chain reaction (PCR) in the pathological specimen. Outcome was favorable, and the patient remained symptom-free after 6 months of follow-up. The possibility of endocarditis as an invasive pneumococcal infection should be considered in children without risk factors. PCR is a useful technique to establish the etiology when cultures are negative.

[D-lactic acidosis in an 11-year-old patient with short bowel syndrome]. / Acidosis D-láctica en un paciente de 11 años con síndrome de intestino corto.

The short bowel syndrome is the result of a congenital or acquired loss of a large part of the small intestine. The most frequent causes of surgical resection of the intestine in infants are arterial or venous thrombosis, intestinal volvulus, necrotizing enterocolitis, and Crohn's disease. Symptoms include nutrient and electrolyte malabsorption, steatorrhea and diarrhea, which can result in failure to thrive. The consequences of extensive small bowel resections consist of nutritional deficiencies, gastric acid hypersecretion, nephrolithiasis, cholelithiasis and lactic acidosis. Of these, D-lactic acidosis is an infrequent but important complication because of the symptoms that it can produce. D-lactic acid in the human organism is generated by intestinal bacteria, D-lactate ingestion, or endogenous production in the methyl glycoxylase pathway. Neurological symptoms such as somnolence, ataxia or altered behavior in a patient with short bowel syndrome should make us think of D-lactic acidosis caused by bacterial overgrowth. We present the case of an 11-year-old boy with short bowel syndrome secondary to multiple resections during the postnatal period who was admitted to hospital for episodes of confusion and altered behavior. The diagnosis was lactic acidosis. Outcome was favorable due to prompt instauration of treatment.

[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.

[Group B Streptococcus late-onset disease presenting as cellulitis-adenitis syndrome]. / Síndrome de celulitis-adenitis por estreptococo del grupo B como presentación de sepsis neonatal tardía.

Cellulitis-adenitis syndrome is a rare clinical manifestation of group B Streptococcus (GBS) late-onset disease. Its significance lies in the fact that local infection may be the only initial sign of systemic infection that is often concurrent with meningitis. Soft tissue involvement (cellulitis-adenitis) can sometimes be the only initial manifestation of GBS infection. We report four cases of GBS cellulitis-adenitis syndrome from different hospitals in Barcelona and Tarragona. We emphasize that early diagnosis and treatment may improve the potentially poor prognosis of these patients, and stress the need to rule out central nervous system involvement by studying cerebrospinal fluid.

[Glycogen storage disease type IX presenting as abdominal distention, hepatomegaly and hypoglycemia during infancy]. / Hepatomegalia, distensión abdominal e hipoglucemia en un lactante: expresión clínica de la glucogenosis tipo IX.

Glycogen storage diseases are a rare group of disorders in daily pediatric practice but must be taken into account when a patient presents with poor physical growth, hepatomegaly, hypoglycemia, hypotonia and/or other metabolic disturbances. Early diagnosis allows treatment that might improve the patient's outcome to be started or, at the very least, genetic counseling to be given to the parents. We present a 10-month-old boy who presented with growth retardation, abdominal distention and hepatomegaly and who was finally diagnosed with glycogenosis type IX. Definitive diagnosis was obtained by demonstrating the enzyme defect (phosphorylase beta-kinase) in affected tissues. Enteral nutrition was started using a diurnal high-carbohydrate diet with frequent feedings and nocturnal nasogastric continuous feeding, achieving optimal growth parameters and clinical response.

[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.

[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.