COVID-19 in children and young adults with moderate/severe inborn errors of immunity in a high burden area in pre-vaccine era.

BACKGROUND: Information regarding inborn error of immunity (IEI) as a risk factor for severe COVID-19 is scarce. We aimed to determine if paediatric patients with moderate/severe IEI got COVID-19 at the same level as the general population, and to describe COVID-19 expression. MATERIAL AND METHODS: We included patients with moderate/severe IEI aged 0-21 years old: cross-sectional study (June2020) to determine the prevalence of COVID-19; prospective study (January2020-January2021) including IEI patients with COVID-19. Assays used: nasopharyngeal swab SARS-CoV-2 PCR and SARS-CoV-2-specific immunoglobulins. RESULTS: Seven from sixty-five patients tested positive (prevalence: 10.7% (7%-13%)) after the first SARS-COV-2 wave and 13/15 patients diagnosed with COVID-19 had an asymptomatic/mild course. CONCLUSIONS: In our area, prevalence of COVID-19 in moderate/severe IEI paediatric patients after the first wave was slightly higher than in the general population. The majority of patients presented a benign course, suggesting a possible protective factor related with age despite IEI.

Cardiomyopathy in Patients With Hereditary Bullous Epidermolysis. / Miocardiopatía en pacientes con epidermólisis ampollosa hereditaria.

INTRODUCTION AND OBJECTIVE: In recent decades, an association has been reported between epidermolysis bullosa (EB) and dilated cardiomyopathy (DC). DC is typically in an advanced phase when detected, leading to a poorer prognosis. Our objective was to determine the prevalence of DC in patients with EB seen in Hospital San Joan de Déu in Barcelona, Spain, between May 1986 and April 2015. METHODS: This was a descriptive, cross-sectional chart-review study in which we recorded the type and main subtypes of EB and the presence or absence of DC. RESULTS: Fifty-seven patients with EB were found, 19 with EB simplex, 10 with junctional EB, 27 with dystrophic EB (14 dominant dystrophic and 13 recessive dystrophic), and just 1 with Kindler syndrome. DC was detected in only 2 patients with recessive dystrophic EB. Twenty-three patients had presented factors that could have had a causal relationship with the potential onset of DC. CONCLUSION: DC is a possible complication of EB, particularly in recessive dystrophic EB. Periodic follow-up should be performed to make an early diagnosis and start treatment.

Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells in the Rs1h-/- mouse.

X-linked retinoschisis, a disease characterized by splitting of the retina, is caused by mutations in the retinoschisin gene, which encodes a putative secreted cell adhesion protein. Currently, there is no effective treatment for retinoschisis, though viral vector-mediated gene replacement therapies offer promise. We used intravitreal delivery of three different AAV vectors to target delivery of the RS1 gene to Müller glia, photoreceptors or multiple cell types throughout the retina. Müller glia radially span the entire retina, are accessible from the vitreous, and remain intact throughout progression of the disease. However, photoreceptors, not glia, normally secrete retinoschisin. We compared the efficacy of rescue mediated by retinoschisin secretion from these specific subtypes of retinal cells in the Rs1h-/- mouse model of retinoschisis. Our results indicate that all three vectors deliver the RS1 gene, and that several cell types can secrete retinoschisin, leading to transport of the protein across the retina. The greatest long-term rescue was observed when photoreceptors produce retinoschisin. Similar rescue was observed with photoreceptor-specific or generalized expression, although photoreceptor secretion may contribute to rescue in the latter case. These results collectively point to the importance of cell targeting and appropriate vector choice in the success of retinal gene therapies.

Two novel recessive mutations in KRT14 identified in a cohort of 21 Spanish families with epidermolysis bullosa simplex.

BACKGROUND: Basal epidermolysis bullosa simplex (EBS) is a group of blistering genodermatoses mostly caused by mutations in the keratin genes, KRT5 and KRT14. Recessive mutations represent about 5% of all EBS mutations, being common and specific in populations with high consanguinity, where affected patients show severe phenotypes. OBJECTIVES: To accomplish the first mutational analysis in patients of Spanish origin with EBS and to delineate a comprehensive genotype-phenotype correlation. METHODS: Twenty-one EBS families were analysed. Immunofluorescence mapping at the dermoepidermal junction level was performed on skin biopsies from patients. Mutation screening of the entire coding sequences of KRT5 and KRT14 in genomic DNA was assessed by polymerase chain reaction and direct sequencing. RESULTS: KRT5 or KRT14 causative mutations were identified in 18 of the 21 EBS families. A total of 14 different mutations were disclosed, of which 12 were dominant missense mutations and two truncating recessive mutations. Five of the 14 mutations were novel including three dominant in KRT5 (p.V186E, p.T321P and p.A428T) and two recessive in KRT14 (p.K116X and p.K250RfsX8). The two patients with EBS carrying homozygous recessive mutations were affected by severe phenotypes and belonged to consanguineous families. All five families with the EBS Dowling-Meara subtype carried recurrent mutations affecting the highly conserved ends of the α-helical rod domain of K5 and K14. The seven mutations associated with the localized EBS subtype were widely distributed along the KRT5 and KRT14 genes. Two families with mottled pigmentation carried the P25L mutation in KRT5, commonly associated with this subtype. CONCLUSIONS: This study further confirms the genotype-phenotype correlation established for EBS in other ethnic groups, and is the first in a Mediterranean country (excluding Israel). This study adds two novel recessive mutations to the worldwide record to date, which includes a total of 14 mutations. As in previous reports, the recessive mutations resulted in a lack of keratin K14, giving rise to a generalized and severe presentation.

Outbreak of brainstem encephalitis associated with enterovirus-A71 in Catalonia, Spain (2016): a clinical observational study in a children's reference centre in Catalonia.

OBJECTIVES: To describe the characteristics of an outbreak of brainstem encephalitis and encephalomyelitis related to enterovirus (EV) infection in Catalonia (Spain), a setting in which these manifestations were uncommon. METHODS: Clinical and microbiological data were analysed from patients with neurological symptoms associated with EV detection admitted to a reference paediatric hospital between April and June 2016. RESULTS: Fifty-seven patients were included. Median age was 27.7 months (p25-p75 17.1-37.6). Forty-one (72%) were diagnosed with brainstem encephalitis, seven (12%) with aseptic meningitis, six (11%) with encephalitis, and three (5%) with encephalomyelitis (two out of three with cardiopulmonary failure). Fever, lethargy, and myoclonic jerks were the most common symptoms. Age younger than 12 months, higher white-blood-cell count, and higher procalcitonin levels were associated with cardiopulmonary failure. Using a PAN-EV real-time PCR, EV was detected in faeces and/or nasopharyngeal aspirate in all the patients, but it was found in cerebrospinal fluid only in patients with aseptic meningitis. EV was genotyped in 47 out of 57 and EV-A71 was identified in 40 out of 47, being the only EV type found in patients with brainstem symptoms. Most of the detected EV-A71 strains were subgenogroup C1. Intravenous immunoglobulins were used in 34 patients. Eight cases (14%) were admitted to the intensive care unit. All the patients but three, those with encephalomyelitis, showed a good clinical course and had no significant sequelae. No deaths occurred. CONCLUSIONS: The 2016 outbreak of brainstem encephalitis in Catalonia was associated with EV-A71 subgenogroup C1. Despite the clinical manifestations of serious disease, a favourable outcome was observed in the majority of patients.

Diagnosis by (18)F-FDG PET/CT of infective endocarditis, staging and monitoring of antibiotic treatment after transposition of surgically corrected great arteries.

Infective endocarditis is one of the leading causes of fever of unknown origin in those patients with intravascular catheters, prosthetic valves or cardiovascular implantable electronic devices. The diagnosis of infective endocarditis is made according to modified Duke criteria, which are based on blood culture and echocardiographic findings. Demonstration of vegetation with the transoesophageal echocardiography may be difficult in these cases with previous anatomical changes, especially in early phases. Positron emission tomography with (18)F-fluorodeoxyglucose ((18)F-FDG PET/CT) is well known to show an increased glucidic metabolism in malignant, inflammatory, and infectious processes. Thus, it provides useful functional imaging that enables the disease causing the fever of unknown origin to be detected well before structural changes are evident. Moreover, (18)F-FDG PET/CT helps to detect infectious extra-cardiac involvement, since the whole body is imaged with this technique. (18)F-FDG PET/CT may have an additional promising role for the monitoring of response to antimicrobial therapy in patients with established infective endocarditis, thus evaluating standard treatment outcome, as well as evaluating the need for alternative/intensified treatment options.

Factors associated with severity in invasive community-acquired Staphylococcus aureus infections in children: a prospective European multicentre study.

Staphylococcus aureus is the main pathogen responsible for bone and joint infections worldwide and is also capable of causing pneumonia and other invasive severe diseases. Panton-Valentine leukocidin (PVL) and methicillin-resistant S. aureus (MRSA) have been studied as factors related with severity in these infections. The aims of this study were to describe invasive community-acquired S. aureus (CA-SA) infections and to analyse factors related to severity of disease. Paediatric patients (aged 0-16 years) who had a CA-SA invasive infection were prospectively recruited from 13 centres in 7 European countries. Demographic, clinical and microbiological data were collected. Severe infection was defined as invasive infection leading to death or admission to intensive care due to haemodynamic instability or respiratory failure. A total of 152 children (88 boys) were included. The median age was 7.2 years (interquartile range, 1.3-11.9). Twenty-six (17%) of the 152 patients had a severe infection, including 3 deaths (2%). Prevalence of PVL-positive CA-SA infections was 18.6%, and 7.8% of the isolates were MRSA. The multivariate analysis identified pneumonia (adjusted odds ratio (aOR) 13.39 (95% confidence interval (CI) 4.11-43.56); p 0.008), leukopenia at admission (<3000/mm(3)) (aOR 18.3 (95% CI 1.3-259.9); p 0.03) and PVL-positive infections (aOR 4.69 (95% CI 1.39-15.81); p 0.01) as the only factors independently associated with severe outcome. There were no differences in MRSA prevalence between severe and nonsevere cases (aOR 4.30 (95% CI 0.68- 28.95); p 0.13). Our results show that in European children, PVL is associated with more severe infections, regardless of methicillin resistance.

Potential risk factors for vertical HIV-1 transmission in Catalonia, Spain: the protective role of cesarean section. The Working Group on HIV-1 Vertical Transmission in Catalonia.

OBJECTIVE: To evaluate the roles of certain potential risk factors on the vertical transmission of HIV-1. DESIGN: Prospective registry of infants born to HIV-1-infected women in Catalonia (north-east Spain) from 1987 to 1992. METHODS: A total of 599 infants, born in Catalan hospitals to 520 women who were identified as being HIV-1-infected during gestation or at delivery, were included. Data on mode of delivery, birth weight, gestational age and breast-feeding as well as the mother's age, her route of HIV-1 infection, clinical stage and p24 antigenaemia, were recorded. HIV-1 infection status of 489 (82%) of the infants was determined according to the criteria of the US Centers for Disease Control and Prevention. Risk estimates and odds ratio (OR) were calculated and logistic regression was performed. RESULTS: The overall rate of vertical transmission was 18.6% (95% confidence interval, 15.2-22.0%). Multivariate analyses revealed that Cesarean section was associated with a lower rate of vertical transmission (OR = 0.3; P = 0.001), as was maternal HIV-1 infection via injecting drug use (OR = 0.44; P = 0.02). Breast-feeding (OR = 6.9; P = 0.001), very low birth weight (< 1500 g; OR = 6.3; P = 0.001) and p24 antigenaemia (OR = 4.6; P = 0.04) were all related to increased risk. The crude rate of HIV-1 transmission was 6% among Cesarean births compared with 21% for infants born via vaginal deliveries. The population-attributable risk for vaginal deliveries was 61.7%. CONCLUSIONS: The results show a protective effect of Cesarean section in the absence of zidovudine prophylaxis. However, current research should be directed towards the individual and combined effects that antiretroviral agents and Cesarean section may have on mother-to-child HIV-1 infection.

Low serum carnitine in HIV-infected children on antiretroviral treatment.

OBJECTIVE: HIV-infection and antiretroviral therapies are associated with energy dysfunction and lipid metabolism in adults. Our aim was to detect a possible carnitine deficiency in HIV-infected children on antiretroviral treatments. We analysed the relation among serum carnitine, its amino-acid precursors (methionine and lysine), clinical evaluation and antiretroviral therapy. DESIGN AND SETTING: Cross-sectional study performed in a tertiary care hospital. SUBJECTS: A total of 79 HIV-infected children on antiretroviral therapy, monitored prospectively in our hospital. INTERVENTIONS: Antiretroviral therapy included nucleoside analogues plus protease inhibitors and/or non-nucleoside analogues. Carnitine was analysed by an enzymatic-spectrometric procedure, and amino acids by ion exchange chromatography. Reference values of carnitine and amino acids were established in apparently healthy children who underwent presurgical analysis for minor surgery. RESULTS: Serum free and total carnitine, acylcarnitines, methionine and lysine were significantly lower in HIV-infected children compared with our reference values for similar ages (P<0.0001; Student's t-test). Low carnitine values were observed in 37% of our HIV-infected children. A significantly positive correlation was observed between serum total carnitine and methionine or lysine (P<0.0001 and P=0.005, respectively; Pearson test). No relation was observed between serum carnitine and clinical stage of HIV infection, immunological or nutritional status or lipodystrophy. Free and total carnitine were significantly lower (P=0.002 and 0.033, respectively) in HIV-infected patients on protease inhibitors (N=56) compared with those on other treatments (N=23). CONCLUSIONS: Low serum carnitine concentration was observed in 37% of our HIV-infected children on antiretroviral therapy. Malabsorption or defective synthesis may also account for the low serum carnitine values detected in these patients.

[Determinants of HIV mother-to-child transmission in Catalonia, Spain [1997-2001]: is it possible to eliminate it?]. / Determinantes de la transmisión vertical del VIH en Cataluña (1997-2001): ¿es posible su eliminación?

OBJECTIVES: To identify and describe the factors that have led to new cases of HIV infection through mother-to-child transmission since the introduction of antiretroviral therapy in HIV-seropositive pregnant women (1997-2001) in Catalonia. METHODS: Systematic review of cases identified in the pediatric services of all the hospitals in Catalonia. RESULTS: Twenty-eight cases of pediatric HIV infection were identified: 9, 9, 8, 2 and 0 per year of birth from 1997 to 2001, respectively. Of 16 mothers with a diagnosis of known HIV infection before or during pregnancy, nine underwent antiretroviral prophylaxis during pregnancy (compliance was good in five, unknown in one and poor in one) and seven did not undergo prophylaxis (six refused it and no information was available in one). Of 12 mothers diagnosed after delivery, pregnancy was not monitored in five and was little or well-monitored in the remaining seven. Of mothers with well-monitored pregnancy, a serological HIV test was not performed in six and was negative in the first trimester in one. CONCLUSIONS: Mother-to-child transmission of HIV has decreased in the last few years in Catalonia, but infections have sometimes occurred through poor implementation of preventive measures. Pregnant women should be offered an HIV diagnostic test not only in the first trimester but also at the end of pregnancy if HIV exposure is suspected. In women with unmonitored pregnancies, rapid diagnostic tests for HIV should be used in the delivery room.

[Multiple intracranial tuberculomas in infancy]. / Tuberculomas intracraneales múltiples en la infancia.

INTRODUCTION: Tuberculous involvement of the CNS is most frequent in children aged between 6 months and 6 years, although it may occur at any age. It may present as meningoencephalitis, basal arachnoiditis or intracranial tuberculomas. Whilst meningitis is typical of infancy, tuberculomas and arachnoiditis are commoner in adults. It has been estimated that tuberculomas make up 3% of the cases of neurotuberculosis. The increasing use of CAT and MR has been a great help for diagnosis of this serious complication of tuberculosis. CLINICAL CASE: A 5 month old patient presented with tuberculous meningitis which had been treated with streptomycin, isoniazid, pyrazinamide and rifampicin at the usual dosage. One month later, after good initial progress, triventricular hydrocephaly was diagnosed and a ventriculoperitoneal shunt inserted. Three months after this, there was an episode of intracranial hypertension. Cranial CAT showed considerable zones of hypodense parenchyma without ventricle dilatation. On MR there were multiple, disseminated, rounded areas which were hyperintense on T2 and compatible with intracranial tuberculomas. After fresh insertion of a ventricular shunt, the patient progressed but still had a residual right hemiparesia and retarded development. CONCLUSIONS: Although intracranial tuberculomas usually occur in adults, they may be seen in children following meningoencephalitis. Occasionally, following a good initial response to tuberculostatic drugs, tuberculomas appear, although not present before, as happened in our patient. This usually occurs within the first three months, and although the mechanism is unknown, it is believed to be due to the accumulation of lymphocytes and macrophages at preexisting microscopic foci when treatment is started.

[Neurofibromatosis type 2 as a result of a de novo mutation: a case report]. / Neurofibromatosis tipo 2 por mutación de novo. A propósito de un caso.

INTRODUCTION: Neurofibromatosis type 2 is a dominant autosomic hereditary disease which courses with distinct tumours of the central nervous system and scant cutaneous manifestations. The increased knowledge of the natural history and the genetics of NF 2 acquired over the past few years has shown that clinical onset possibly occurs during the paediatric age and an early diagnosis of these patients can be decisive in the final outcome. CLINICAL CASE: A 12 year old girl who visited the clinic because of a month old presentation of cervical tumour, otalgia and dysphonia. Exploration revealed signs of cranial nerve disorder and the magnetic resonance (MR) showed bilateral schwannomas of the eighth cranial nerves. The extension study showed ocular, auditory, troncoencephalic and cervical spinal cord disorders. The patient died three months after hospital admission. The genetic study showed a de novo mutation in the NF 2 gene (chromosome 22q12). DISCUSSION: The identification of the various mutations that cause NF 2 has enabled the early diagnosis of the patient s relatives. However, there are still patients who have not been confirmed genetically. Furthermore, de novo mutations are not predictable. NF 2 diagnosis is still clinical. In the last few years, two disease phenotypes have been defined: mild and moderate/serious, which is associated with an early onset and de novo mutations. The high incidence rate of cataracts and other associated tumours, such as those affecting paraspinal and cutaneous areas together with meningiomas, which up until now could have gone unnoticed, has also been observed. Clinical onset in the paediatric age is more frequent than was expected and shows distinct and subtle symptoms.

The relation between obesity, abdominal fat deposit and the angiotensin-converting enzyme gene I/D polymorphism and its association with coronary heart disease.

OBJECTIVE: To analyse the relation between overweight, obesity and fat distribution with I/D polymorphism of the angiotensin-converting enzyme (ACE) gene and its association with coronary heart disease (CHD). DESIGN: Cross-sectional, case-control study. SUBJECTS: A total of 185 cases (141 males) who had suffered at least one episode of CHD and 182 controls (127 males). MEASUREMENTS: Body mass index, waist circumference, blood pressure, plasma total cholesterol, triglycerides, HDL cholesterol and fasting glucose were measured with standard methods, genotyping the I/D polymorphism of ACE gene. RESULTS: Obesity and abdominal fat deposit are associated with CHD in women, but not independently. We have found an association between obesity and abdominal fat deposit with the ACE gene I/D polymorphism in subjects with CHD. Subjects with CHD and DD or ID genotypes have significantly higher prevalence of obesity and abdominal fat deposit and higher values of weight and waist circumference. In addition, the DD and ID genotypes increased crude OR of obesity. The DD and ID genotypes of the ACE gene I/D polymorphism and BMI are independently associated with CHD. CONCLUSION: There is a relation between the type and grade of obesity with the genotypes of the ACE gene I/D polymorphism in subjects with CHD.

[Marginality, ethnic groups and health]. / Marginalidad, grupos étnicos y salud.

Main marginated ethnic groups in Span are to be found among gypsies and 3rd world immigrants. The first group include about 250,000 persons and the second group more tan half a million people. Their origins and their being past of the less fortunate social layers made them a group of health risk. Pediatric pathologies are those favored by socio-economic shortcomings as well as hygienic-sanitary deficiencies. Imported pediatric pathologies have a small incident.

PIP: Marginalized ethnic groups in Spain consist primarily of some 250,000 gypsies and over half million immigrants from Third World countries who began to seek work in newly industrialized Spain beginning around 1970. The numbers of immigrants doubled between 1970-85 and immigration continues from Latin America, Africa south of the Sahara, North America, and the Philippines. Over 300,000 are believed to be undocumented, and around 23% are under 16 years old. This large scale immigration in a traditional country of emigration has created previously unknown problems for the health services. Health personnel still lack adequate knowledge of the cultural patterns, illnesses and needs of these groups, and frequent difficulties of communication complicate problems. Immigrants frequently initiate contact with the health services in search of treatment for their children, who are considered a population at risk. Imported diseases from the region of origin progressively lose importance as the immigrants are assimilated, typically into the least prosperous classes. Their illnesses lose specificity, and perinatal and early childhood problems emerge as the predominant concerns. Imported problems may include genetically determined illnesses such as sickle cell anemia, infectious and parasitic diseases prevalent in the region of origin, or pathologies contracted directly from indigenous medical treatments. Ailments of children acquired in Spain include the normal childhood diseases, with respiratory and gastrointestinal infections most common, dehydration caused by dietary errors, rickets, chronic lead poisoning caused by old paint in the dwelling, and accidents. Pathologies of adaptation may include other diseases but are typically psychic disorders resulting from the 2 greatest disadvantages facing immigrants: poverty and racism. Greater perinatal morbidity and mortality and more frequent and longer hospitalizations of infants and children are 2 consequences. The degree of marginalization experienced by gypsies in Spain depends somewhat on their region of residence. In recent years they have tended to cluster in periurban zones outside the large cities, where their neighbors live in similar poverty and share the same diseases of deprivation. Pediatric health problems are similar to those acquired in Spain by immigrant children. Gypsies have higher rates of fertility and infant mortality. Gypsy children are at higher risk of tuberculosis, malnutrition, accidents, dental caries, sand drug consumption, and they are less likely to be immunized. They are a recognized risk group for iron deficiency anemia and lead poisoning, and their rates of hospitalization and consultations in emergency rooms are elevated.

Cross-sectional survey of hospital paediatric HIV/AIDS care in Catalonia, 1992. Hospital Contributors.

A cross-sectional survey to assess the impact of the paediatric HIV/AIDS epidemic on the hospital-based health care system was performed in state-financed hospitals in Catalonia during 1992, raising issues of relevance today. Out of the 27 hospitals contacted, 20 responded. A considerable proportion of the health care to children with an HIV-related condition was provided by four hospitals. The average length of stay of the 176 HIV patients who were admitted was 10.8 days; these patients were admitted to the hospital twice a year on average. Nearly half of the out-patients who attended with an HIV-related condition were either seropositive without a confirmed diagnosis of an HIV infection (class P-0) or seronegative. Thirteen per cent of the overall admissions to paediatric day care hospitals were attributable to an HIV-related condition. By ownership status of the hospitals, HIV/AIDS paediatric in-patients of public hospitals generated the majority of admissions per patient per year, and had the shortest lengths of stay. Unlike the HIV/AIDS epidemic in adults, the magnitude and characteristics of the epidemic in children may not require the shift of hospital-based health care to primary health care.

Creation of a Spanish nephrological nursing accrediting course.

In 1989, the Spanish Association of Nephrological Nursing (Sociedad Espanola de Enfermeria Nefrologica--SEDEN) created a course directed to all graduates in nephrological nursing in Spain to answer a need for further training. This article details the objectives, methodology, and results of the Course for Accrediting Specialized Knowledge in Nephrological Nursing since it was created.

MHC class II alleles associated with clinical and immunological manifestations of HIV-1 infection among children in Catalonia, Spain.

Children with perinatally-acquired HIV-1 infection were studied to determine if major histocompatibility complex (MHC) genes are involved in progression to pediatric AIDS. Molecular genetic techniques were used to genotype loci in the class II region (DRB1, DQA1, DQB1, DPA1, DPB1, LMP2 and LMP7). HIV-infected children were classified by clinical manifestations and degree of immunosuppression using age-specific CD4 T-lymphocyte counts at enrollment. Alleles at the DPB1 and DQB1 loci showed independent and opposite associations; DPB1*0301 showed a trend toward protection while DQB1*0201 appeared to be a risk factor for developing severe immunosuppression and severe clinical outcomes. Presence of DQB1*0201 conferred a greater than 10-fold increased odds of having severe clinical manifestations and a 2.8-fold increased odds of severe immunosuppression. Presence of DPB1*0301 was associated with a greater than 8-fold decreased odds of severe immunosuppression and severe clinical manifestations. These results support host genetic influences on HIV-1 outcomes in children.