Belimumab in refractory organizing pneumonia associated with systemic lupus erythematosus: a case report.

Organizing pneumonia is an inflammatory lung entity that presents with a huge variety of clinical, radiological and pathological patterns. Organizing pneumonia can be idiopathic or secondary to other diseases. Corticosteroid therapy is usually the first-line treatment showing clinical improvement in most cases. This report presents the case of a 56-year-old woman with systemic lupus erythematosus who was diagnosed with an organizing pneumonia and showed a poor response to steroid and azathioprine treatment. We considered the use of belimumab, which resulted in excellent clinical and radiological outcomes.

Commercially available immunoglobulins contain virus neutralizing antibodies against all major genotypes of polyomavirus BK.

Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype-specificity, and mechanism of action of anti-polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co-transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon-modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254 899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype-specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti-viral effects, until effective small molecule inhibitors of BKV replication can be developed.

[Factors associated to high-flow nasal cannula treatment failure in pediatric patients with respiratory failure in two pediatric intensive care units at high altitude]. / Factores asociados al fracaso de la terapia con cánulas nasales de alto flujo en pacientes pediátricos con insuficiencia respiratoria en dos unidades de cuidados críticos pediátricos a gran altitud.

INTRODUCTION: Acute respiratory failure is the leading cause of hospitalization in pediatrics. High-flow nasal cannulas (HFNCs) offer a new alternative, but the evidence and indications are still debated. The performance of HFNCs at high altitude has not been described to date. OBJECTIVE: To describe the use of HFNCs in pediatric patients admitted with respiratory failure and explore the factors associated with treatment failure. METHODOLOGY: A prospective cohort study was carried out in patients between 1 month and 18 years of age managed with HFNCs. The demographic and treatment response data were recorded at baseline and after 1, 6 and 24hours. The number of failures was determined, as well as the length of stay, complications and mortality. Patients with treatment failure were compared with the rest. RESULTS: A total of 539 patients were enrolled. Infants (70.9%) of male sex (58.4%) and airway diseases such as asthma and bronchiolitis (61.2%) were more frequent. There were 53 failures (9.8%), with 21 occurring in the first 24hours. The median length of stay was 4 days (IQR 4); there were 5 deaths (0.9%) and 13 adverse events (epistaxis) (2.2%). Improvement was observed in vital signs and severity over time, with differences in the group that failed, but without interactions. The final logistic model established an independent relationship of failure between the hospital (OR 2.78, 95%CI 1.48-5.21) and the initial respiratory rate (OR 1.56, 95%CI 1.21-2.01). CONCLUSIONS: HFNCs afford good clinical response, with few complications and a low failure rate. The differences found between institutions suggest a subjective relationship in the decision of therapy failure.

[Should pulmonary computed tomography be performed in children with tuberculosis infection without apparent disease?]. / Debe realizarse una tomografía computarizada torácica a los niños con infección tuberculosa sin enfermedad aparente?

BACKGROUND: During early childhood, in particular, there is a continuum between tuberculosis infection and disease. When establishing the diagnosis in a child with suspected tuberculosis, the distinction between infection and disease frequently depends on the interpretation of the chest X-ray. Some studies have shown hilar and mediastinal lymphadenopathies on computed tomography (CT) in children with tuberculosis infection without apparent disease, i.e., asymptomatic children with a positive tuberculin skin test and normal chest X-ray. These observations raise the issue of whether pulmonary CT should be performed in children with tuberculosis infection without apparent disease and whether different types of therapy should be administered depending on the results. METHODS: We reviewed the physiopathology of tuberculosis infection and disease, diagnostic methods and treatment, and the literature on the use of pulmonary CT scan in pediatric tuberculosis. RESULTS: Modern CT scanners indicate hilar and mediastinal lymphadenopathies in many of the children with tuberculosis infection with no apparent disease on chest X-rays. However, neither the size nor the morphology of these adenopathies allows active tuberculosis to be diagnosed. The natural history of childhood tuberculosis indicates that most children show hilar lymphadenopathies after the primary infection, although progression to disease is rare and is characterized by the presence of clinical symptoms. The exceptions are children younger than 4 years old and those with immune alterations who more frequently show progression of infection to disease and who require close follow-up. In addition, the experience accumulated over many years in the treatment of tuberculosis infection with isoniazid has shown this drug to be effective in both short- and long-term prevention of active disease. Official guidelines and expert opinion do not recommend systematic pulmonary CT scan in these children or modification of treatment according to the results. CONCLUSIONS: Hilar and mediastinal lymph nodes are frequently found in the CT scans of children with tuberculosis infection without apparent disease but there is no evidence that these adenopathies indicate active disease or that these children require different treatment. Consequently, until demonstrated otherwise, pulmonary CT scanning and changes in chemoprophylaxis are not justified in children with tuberculosis infection.

[Respiratory function assessment in cooperative patients. Part I. Spiromery and bronchodilator reversibility testing]. / Estudio de la función pulmonar en el paciente colaborador. Parte I.

Assessment of respiratory function is the principal tool in the study of patients with lung diseases, allowing physiopathological alterations to be detected, and the severity of the process, its clinical course, and treatment response to be identified. Nowadays, assessment of respiratory function is among the investigations used by Spanish pediatricians. The Techniques Group of the Spanish Society of Pediatric Pneumology undertook the design of a protocol for the study of pulmonary function in children that would incorporate the most recent published consensus documents on basic pulmonary function assessment (spirometry and bronchodilator reversibility testing) and on airway hyperreactivity evaluation using nonspecific provocation tests. The aim of this protocol is to provide a guide to good clinical practice until new changes, based on scientific evidence, are produced.

Factores asociados al fracaso de la terapia con cánulas nasales de alto flujo en pacientes pediátricos con insuficiencia respiratoria en dos unidades de cuidados críticos pediátricos a gran altitud / Factors associated to high-flow nasal cannula treatment failure in pediatric patients with respiratory failure in two pediatric intensive care units at high altitude

Introducción: El fallo respiratorio agudo es la principal causa de hospitalización en pediatría. Las cánulas nasales de alto flujo (CNAF) ofrecen una nueva alternativa, pero sigue existiendo debate en torno a la evidencia e indicaciones. No se ha descrito su comportamiento en gran altitud. Objetivo Describir el uso de CNAF en pacientes pediátricos que ingresan con insuficiencia respiratoria y explorar los factores asociados al fracaso de la terapia. Metodología Estudio de cohortes prospectivo. Pacientes entre un mes y 18 años manejados con CNAF. Se describieron datos demográficos y se evaluó la respuesta al inicio, 1.a, 6.a y 24.a horas. Se determinó el número de fracasos, así como estancia, complicaciones y mortalidad. Se compararon los pacientes con fracaso al tratamiento. Resultados Ingresaron 539 pacientes. Fueron más frecuentes los lactantes (70,9%) de sexo masculino (58,4%) con afecciones respiratorias como asma y bronquiolitis (61,2%). Se presentaron 53 fracasos (9,8%), 21 en las primeras 24 horas. La mediana de estancia fue de 4 días (RIQ 4), hubo 5 éxitus (0,9%) y 13 eventos adversos –epistaxis– (2,2%). Se observó mejoría de signos vitales y gravedad en el tiempo con diferencias en el grupo que fracasó, pero sin interacciones. El modelo logístico final estimó una relación independiente del fracaso, entre el hospital (OR 2,78; IC95% 1,48-5,21) y la frecuencia respiratoria inicial (OR 1,56; IC95% 1,21-2,01). Conclusión La CNAF es un sistema con buena respuesta clínica, pocas complicaciones y una baja tasa de fracasos. Las diferencias entre las instituciones sugieren una relación subjetiva de la decisión del fracaso. (AU)

Introduction: Acute respiratory failure is the leading cause of hospitalization in pediatrics. High-flow nasal cannulas (HFNCs) offer a new alternative, but the evidence and indications are still debated. The performance of HFNCs at high altitude has not been described to date. Objective To describe the use of HFNCs in pediatric patients admitted with respiratory failure and explore the factors associated with treatment failure. Methodology A prospective cohort study was carried out in patients between 1 month and 18 years of age managed with HFNCs. The demographic and treatment response data were recorded at baseline and after 1, 6 and 24hours. The number of failures was determined, as well as the length of stay, complications and mortality. Patients with treatment failure were compared with the rest. Results A total of 539 patients were enrolled. Infants (70.9%) of male sex (58.4%) and airway diseases such as asthma and bronchiolitis (61.2%) were more frequent. There were 53 failures (9.8%), with 21 occurring in the first 24hours. The median length of stay was 4 days (IQR 4); there were 5 deaths (0.9%) and 13 adverse events (epistaxis) (2.2%). Improvement was observed in vital signs and severity over time, with differences in the group that failed, but without interactions. The final logistic model established an independent relationship of failure between the hospital (OR 2.78, 95%CI 1.48-5.21) and the initial respiratory rate (OR 1.56, 95%CI 1.21-2.01). Conclusions HFNCs afford good clinical response, with few complications and a low failure rate. The differences found between institutions suggest a subjective relationship in the decision of therapy failure. (AU)

[Impact of introducing an enterovirus polymerase chain reaction in the management of aseptic meningitis]. / Impacto de la implantación de la reacción en cadena de la polimerasa a enterovirus en el manejo de la meningitis aséptica.

INTRODUCTION: The diagnosis of aseptic meningitis, based on an enterovirus PCR (EV-PCR) in cerebrospinal fluid, is a rapid and sensitive test. OBJECTIVE: To assess the impact of introducing EV-PCR on the use of antibiotics and hospital length of stay in aseptic meningitis. MATERIAL AND METHODS: A prospective study that included children with aseptic meningitis during one year. The patients prior to the introduction of the test formed the control group. RESULTS: The performance of the PCR test was associated with less use of antibiotics compared to the control group (16.2% vs 41.4%, P=.029) and with fewer days of administration (.54 vs. 2 days, P=.014). A non-significant decrease in length of stay (3.57 vs. 4.21 days, P=.376) was also observed in the study group. CONCLUSION: The introduction of the EV-PCR test decreases the use of antibiotics and hospital length of stay.

Developmentally regulated expression of a unique small heat shock protein in Brugia malayi.

A screen of an expression library from the fourth larval stage (L4) of the parasitic nematode Brugia malayi resulted in the identification of a 727 bp full-length cDNA with 29-40% identity to members of the small heat shock family of proteins (Bm-hsp-s1). The open reading frame encoded a protein of approximately 18 kDA (Bm-HSP-s1). An alignment of the Bm-HSP-s1 sequence with the sequences of small HSPs from vertebrate and invertebrate species demonstrated that a majority of the identity was concentrated in the central alpha-crystallin domain. Bm-HSP-s1 was constitutively produced by L4 and adult parasites and at low levels by third-stage larvae (L3), but not by first-stage larvae (microfilariae). In adult parasites, Bm-HSP-s1 was localized to the body wall muscle cells and to the cells of the hypodermis/lateral cord. Bm-HSP-s1 production was induced in adult and L3 incubated at 42 degrees C and in L3s during the developmental transition from vector-stage to vertebrate-stage parasites at 37 degrees C. Neither increased nor decreased temperatures induced Bm-HSP-s1 production in microfilariae. Nitric oxide induced low-level, transient Bm-HSP-s1 synthesis in adults, but not in microfilariae. Bm-HSP-s1 did not function as a molecular chaperone to prevent heat-induced aggregation of a test substrate. The developmentally regulated expression and inducable nature of Bm-HSP-s1 suggests that it may have a stage-restricted role in maintaining parasite homeostasis.

Tuberculosis in children-is PCR the diagnostic solution?

Polymerase chain reaction (PCR) has been recently incorporated as a diagnostic tool for the diagnosis of tuberculosis. The benefit of rapid results and greater sensitivity compared with traditional microbiological methods makes PCR a suitable technique in childhood tuberculosis, especially when diagnosis is difficult or when urgent diagnosis is needed. However, the possibility of false-positive results must be considered, especially if the clinical and epidemiologic context of the child make the diagnosis of tuberculosis improbable. The commercial 'Amplicor PCR test' lacks good sensitivity and specificity and it would be necessary to develop other commercial easy-to-use PCR kits that provides better yield.

Diagnosis of tuberculosis in children using a polymerase chain reaction.

We investigated the value of the polymerase chain reaction (PCR) in the diagnosis of active tuberculosis in children and evaluated the relationship between PCR results in children with tuberculous infections and mediastinal adenopathies detected by computerized tomography (CT-Scan). This was a controlled, blinded, prospective study comparing nested PCR, mycobacterial cultures and the clinical diagnosis based on 350 clinical specimens from 117 children referred for evaluation of suspected pulmonary tuberculosis. All children with tuberculous infection but without active disease underwent a chest CT-scan to detect the presence of mediastinal adenopathies not evident on chest x-ray. The sensitivity of PCR was 56.8% in children with clinically active disease (culture: 37.8%; smears: 13.5%). A major advantage of PCR over cultures was noted when there was no parenchymal involvement on chest radiograph and when the patient was undergoing anti-tuberculous treatment. There were nine specimens with false-negative PCR results due to the presence of amplification reaction inhibitors. PCR was positive in five children with tuberculous infection without active disease and these children presented mediastinal adenopathies on the CT-scan that were not evident on chest radiography. There were no false-positive PCR results in the control groups of children. We conclude that nested PCR is a rapid and sensitive method for the early diagnosis of tuberculosis in children. It is especially useful when the diagnosis of active tuberculosis is difficult. In our study children with tuberculous infection without apparent disease who have positive PCR results have mediastinal adenopathies on CT-scan.

Impacto de la implantación de la reacción en cadena de la polimerasa a enterovirus en el manejo de la meningitis aséptica / Impact of introducing an enterovirus polymerase chain reaction in the management of aseptic meningitis

INTRODUCCIÓN: El diagnóstico de meningitis aséptica basado en la reacción en cadena de la polimerasa (PCR) frente a enterovirus en líquido cefalorraquídeo es un método rápido y sensible. OBJETIVO: Valorar la influencia de la implantación de la PCR a enterovirus en el uso de antibióticos y la estancia hospitalaria en meningitis aséptica. MATERIAL Y MÉTODOS: Estudio prospectivo de ni˜nos con meningitis aséptica durante un a˜no, utilizando como grupo control a pacientes previos a la implantación de la técnica. RESULTADOS: La realización de la PCR se asoció a un menor uso de antibióticos respecto al grupo control (16,2% vs. 41,4%; p = 0,029), a un menor tiempo de administración (0,54 vs. 2 días; p = 0,014) y a una disminución no significativa de la duración del ingreso (3,57 vs. 4,21 días; p = 0,376). CONCLUSIÓN: La implantación de la PCR a enterovirus disminuye la utilización de antibióticos y la estancia hospitalaria

INTRODUCTION: The diagnosis of aseptic meningitis, based on an enterovirus PCR (EV-PCR) in cerebrospinal fluid, is a rapid and sensitive test. OBJECTIVE: To assess the impact of introducing EV-PCR on the use of antibiotics and hospital length of stay in aseptic meningitis. MATERIAL AND METHODS: A prospective study that included children with aseptic meningitis during one year. The patients prior to the introduction of the test formed the control group. RESULTS: The performance of the PCR test was associated with less use of antibiotics compared to the control group (16.2% vs 41.4%, P = .029) and with fewer days of administration (.54 vs. 2 days, P=.014). A non-significant decrease in length of stay (3.57 vs. 4.21 days, P=.376) was also observed in the study group. CONCLUSION: The introduction of the EV-PCR test decreases the use of antibiotics and hospital length of stay

Lesiones cutáneas ampollosas en un paciente con lupus eritematoso sistémico / Cutaneous Blisters in a Patient With Systemic Lupus Erythematosus

No disponible

NHPV16 VLP vaccine induces human antibodies that neutralize divergent variants of HPV16.

Genital HPV genotypes are generally distinct serotypes, but whether variants within a genotype can represent serologic subtypes is unclear. In this study we used serum from human volunteers vaccinated with HPV16 L1 VLPs from variant 114K, to examine cross-neutralization of variants from each of the five major phylogenetic branches of HPV16. Recombinant Semliki Forest virus-derived pseudovirions for each variant were generated and combined with serum from vaccines, and the mixture was monitored for infectivity in a standard C127 cell focal transformation assay. Sera from all 10 VLP-immunized individuals had neutralizing activity against each of the variant pseudovirions. For each of the sera, variant titers differed by only fourfold or less from the median titer. Therefore, from a vaccine perspective, HPV16 variants belong to a single serotype. Vaccination with HPV16 114K L1 VLPs generates antibodies that should confer a similar degree of protection against all known phylogenetic branches of HPV16.

Effect of preexisting neutralizing antibodies on the anti-tumor immune response induced by chimeric human papillomavirus virus-like particle vaccines.

Chimeric human papillomavirus virus-like particles (HPV cVLPs) carrying HPV16 E7 protein are potent vaccines for inducing cell-mediated immunity (CMI) against HPV-induced tumors in animal models. We tested the hypothesis that virion-neutralizing antibodies generated during an initial vaccination might prevent effective boosting of CMI to the cVLPs. Mice with circulating HPV16-neutralizing antibodies, generated by direct immunization with wild-type VLPs or by passive transfer of hyperimmune anti-HPV16 VLP mouse sera, were subsequently vaccinated with HPV16 E7-containing cVLPs. Mice with preexisting neutralizing antibodies were not protected from HPV16 E7-positive TC-1 tumor challenge, compared to the protection seen in mice lacking these antibodies. Antibody-coated VLPs bound very inefficiently to receptor-positive cell lines, suggesting that one of the mechanisms of antibody interference is blocking of VLP binding to its receptor and thereby uptake of VLPs by antigen-presenting cells. Our results suggest that repetitive vaccination with a cVLP for induction of cellular immune responses to an incorporated antigen may be of limited effectiveness due to the presence of neutralizing antibodies against the capsid proteins induced after the first application. This limitation could potentially be overcome by boosting with cVLPs containing the same target antigen incorporated into other papillomavirus-type VLPs.

Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor.

Filarial nematode parasites establish long-term chronic infections in the context of an antiparasite immunity that is strongly biased toward a Th2 response. The mechanisms that lead to this Th2 bias toward filarial antigens are not clear, but one possibility is that the parasites produce molecules that have the capacity to proactively modify their immunological environment. Here we report that filarial parasites of humans secrete a homologue of the human proinflammatory cytokine macrophage migration inhibitory factor (MIF) that has the capability of modifying the activity of human monocytes/macrophages. A cDNA clone isolated from a Brugia malayi infective-stage larva expression library encoded a 12.5-kDa protein product (Bm-MIF) with 42% identity to human and murine MIF. MIF homologues were also found to be expressed in the related filarial species Wuchereria bancrofti and Onchocerca volvulus. Bm-mif was transcribed by adult and larval parasites, and the protein product was found in somatic extracts and in the parasite's excretory-secretory products. Immunohistocytochemistry revealed that Bm-MIF was localized to cells of the hypodermis/lateral chord, the uterine wall, and larvae developing in utero. Unexpectedly, the activities of recombinant Bm-MIF and human MIF on human monocytes/macrophages were found to be similar. When placed with monocytes/macrophages in a cell migration assay, Bm-MIF inhibited random migration. When placed away from cells, Bm-MIF induced an increase in monocyte/macrophage migration that was specifically inhibited by neutralizing anti-Bm-MIF antibodies. Bm-MIF is the first demonstration that helminth parasites produce cytokine homologues that have the potential to modify host immune responses to promote parasite survival.

Comparison of amplicor, in-house polymerase chain reaction, and conventional culture for the diagnosis of tuberculosis in children.

A total of 251 clinical specimens (235 gastric aspirates and 16 bronchoalveolar lavages) from 88 children were prospectively tested in a blinded manner for the presence of Mycobacterium tuberculosis complex, by use of the Amplicor M. tuberculosis test and by means of in-house polymerase chain reaction (PCR). The results were compared with those obtained by conventional culture and by direct microscopy. All of the children underwent extended follow-up to verify or exclude the clinical diagnosis of tuberculosis. The results of the different tests, when compared to the final clinical diagnosis, were a sensitivity of 60% and a specificity of 96.8% for in-house PCR, 44% and 93.7% respectively for the Amplicor test, 44% and 100% for mycobacterial culture and 12% and 100% for microscopy. Amplicor tests presented false-positive findings in children without tuberculous infection. We conclude that both in-house PCR and the Amplicor test are rapid methods that can be helpful for difficult or urgent diagnosis of tuberculosis in children. However, efforts should be aimed toward improvement of the sensitivity and specificity of an easy-to-use PCR kit.

Tuberculosis en el niño / Tuberculosis in the child

La tuberculosis continúa siendo una de las principales causas de morbimortalidad en todo el mundo incluyendo a los niños. El diagnóstico microbiológico puede intentarse tras nebulización de suero hipertónico y aspirado nasofaríngeo aunque el rendimiento sigue siendo bajo. Cuando se consigue aislar el germen, siempre debe hacerse un estudio de sensibilidad a fármacos por la creciente incidencia de cepas con resistencia a uno o varios fármacos. Las técnicas basadas en la PCR aceleran la obtención de resultados a los principales fármacos. La resistencia a isoniacida y rifampicina (MDR) y en ocasiones a alguna fluoroquinolona, junto con alguna de los fármacos inyectables de segunda línea (XDR), complica extraordinariamente el tratamiento, obligando a utilizar drogas menos efectivas y con más efectos secundarios. En España se aconseja el tratamiento con cuatro fármacos en la fase inicial, siendo el etambutol el utilizado generalmente, en espera del estudio de sensibilidad del niño o de su fuente de contagio. En el diagnóstico de la infección tuberculosa las técnicas b asadas en la liberación de interferón gamma son especialmente útiles en niños vacunados con BGC. Como tratamiento de la infección tuberculosa latente puede utilizarse el régimen de isoniazida y rifampicina durante 3 meses, que mejora el cumplimiento (AU)

Tuberculosis continues to be one of the principal causes or morbidity-mortality in the world, including children. The microbiological diagnosis may be attempted after hypertonic serum nebulization and nasopharyngeal aspirate, although yield continues to be low. Once it has been possible to isolate the germ, a drug sensitivity study should also be performed due to the growing incidence of strains with resistance to one or several drugs. The polymerase chain reaction (PCR) based techniques accelerate the obtaining of results to the principal drugs. Resistance to isoniazid and rifampicin (MDR) and sometimes to some fluoroquinolone together with some of the second-line injectable drugs (XDR) extremely complicate the treatment, requiring the use of less effective drugs with more side effects. In Spain, treatment with four drugs in the initial phase is recommended, ethambutol generally being used, while waiting for the sensitivity study of the child or of their source of infection. In the diagnosis of the tuberculous infection, the interferon gamma release assays are especially useful in BCG vaccinated children. As treatment of latent tuberculous infection, the isoniazid and rifampicin combination during 3 months can be used, which improves compliance (AU)