RESUMEN
OBJECTIVE: To study the utility of Galactomannan (GM) antigen as a screening marker for diagnosing invasive pulmonary aspergillosis (IPA) in coronavirus disease 2019 (COVID-19) patients. PATIENTS AND METHODS: The serum samples from patients with severe COVID-19 diseases admitted to the Critical Care Unit were collected on the 5th day of admission for GM screening. The samples were analysed by enzyme linked immune sorbent assay (ELISA) and GM index of more than 1 was considered as positive. All GM positive patients were serially followed until discharge or death. RESULTS: The GM was raised in serum of 12 out of 38 patients, indicating an incidence of possible COVID-19 associated IPA (CAPA) in 31.57% of patients. The median age of these CAPA patients was 56.5 years, males were significantly more affected than females. The inflammatory marker serum ferritin was raised in all 12 patients (median value of 713.74 ng/ml), while IL-6 was raised in 9 patients (median value of 54.13 ng/ml). None of these patients received antifungals. Their median length of hospital stay was 20 days (IQR: 12, 34 days). All these patients succumbed to the illness. CONCLUSIONS: The serum GM appears to be sensitive diagnostic tool to identify early IPA in COVID-19 patients and pre-emptive antifungal therapy could play a role in salvaging these patients.
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COVID-19/diagnóstico , Galactosa/análogos & derivados , Aspergilosis Pulmonar Invasiva/diagnóstico , Mananos/sangre , Adulto , Anciano , COVID-19/complicaciones , COVID-19/virología , Ensayo de Inmunoadsorción Enzimática , Femenino , Galactosa/sangre , Humanos , Interleucina-6/metabolismo , Aspergilosis Pulmonar Invasiva/complicaciones , Tiempo de Internación , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , SARS-CoV-2/aislamiento & purificación , Factores SexualesRESUMEN
BACKGROUND: The use of galactomannan (GM) testing in plasma and bronchoalveolar lavage fluid (BALF) has improved the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with chronic obstructive pulmonary disease (COPD); however, the high false-positive rate leads to overdiagnosis. Pentraxin 3 (PTX3) as an indicator of inflammation plays an important role in resistance to Aspergillus infections. This study aimed to investigate the diagnostic value of PTX3 for diagnosing IPA with COPD. METHODS: We retrospectively collected data on patients with suspected COPD and IPA who had been hospitalized in the Third Affiliated Hospital of Soochow University between September 2017 and November 2020. PTX3 and GM were measured using enzyme-linked immunosorbent assays. RESULTS: A total of 165 patients were included in the study, of whom 35 had confirmed or probable IPA. The remaining 130 patients served as controls. The median plasma and BALF PTX3 levels were significantly higher in patients with IPA than in control patients (3.74 ng/mL vs. 1.29 ng/mL, P < 0.001; and 3.88 ng/mL vs. 1.58 ng/mL, P < 0.001 in plasma and BALF, respectively). The plasma GM, plasma PTX3, BALF GM, and BALF PTX3 assays had sensitivities of 60.0%, 77.1%, 78.6%, and 89.3%, respectively, and specificities of 73.8%, 69.2%, 80.7%, and 77.1%, respectively. The sensitivity of PTX3 in plasma and BALF was higher than that of GM. However, the specificity of PTX3 and GM did not differ significantly between the IPA group and the control group. The specificity of the assays for the diagnosis of IPA was > 90% in patients who were PTX3-positive and GM-positive in plasma and BALF. CONCLUSIONS: BALF and plasma PTX3 levels were significantly higher in COPD patients with IPA. The sensitivity of PTX3 was superior to that of GM for diagnosing IPA in patients with COPD. The combination of GM and PTX3 is useful for the diagnosis of IPA in patients with COPD.
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Aspergilosis/sangre , Proteína C-Reactiva/análisis , Galactosa/análogos & derivados , Mananos/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Componente Amiloide P Sérico/análisis , Anciano , Anciano de 80 o más Años , Aspergilosis/diagnóstico , Biomarcadores , Líquido del Lavado Bronquioalveolar/microbiología , China , Diagnóstico Diferencial , Femenino , Galactosa/sangre , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Estudios RetrospectivosRESUMEN
The aim of this study was to evaluate diagnostic means, host factors, delay of occurrence, and outcome of patients with COVID-19 pneumonia and fungal coinfections in the intensive care unit (ICU). From 1 February to 31 May 2020, we anonymously recorded COVID-19-associated pulmonary aspergillosis (CAPA), fungemia (CA-fungemia), and pneumocystosis (CA-PCP) from 36 centers, including results on fungal biomarkers in respiratory specimens and serum. We collected data from 154 episodes of CAPA, 81 of CA-fungemia, 17 of CA-PCP, and 5 of other mold infections from 244 patients (male/female [M/F] ratio = 3.5; mean age, 64.7 ± 10.8 years). CA-PCP occurred first after ICU admission (median, 1 day; interquartile range [IQR], 0 to 3 days), followed by CAPA (9 days; IQR, 5 to 13 days), and then CA-fungemia (16 days; IQR, 12 to 23 days) (P < 10-4). For CAPA, the presence of several mycological criteria was associated with death (P < 10-4). Serum galactomannan was rarely positive (<20%). The mortality rates were 76.7% (23/30) in patients with host factors for invasive fungal disease, 45.2% (14/31) in those with a preexisting pulmonary condition, and 36.6% (34/93) in the remaining patients (P = 0.001). Antimold treatment did not alter prognosis (P = 0.370). Candida albicans was responsible for 59.3% of CA-fungemias, with a global mortality of 45.7%. For CA-PCP, 58.8% of the episodes occurred in patients with known host factors of PCP, and the mortality rate was 29.5%. CAPA may be in part hospital acquired and could benefit from antifungal prescription at the first positive biomarker result. CA-fungemia appeared linked to ICU stay without COVID-19 specificity, while CA-PCP may not really be a concern in the ICU. Improved diagnostic strategy for fungal markers in ICU patients with COVID-19 should support these hypotheses. IMPORTANCE To diagnose fungal coinfections in patients with COVID-19 in the intensive care unit, it is necessary to implement the correct treatment and to prevent them if possible. For COVID-19-associated pulmonary aspergillosis (CAPA), respiratory specimens remain the best approach since serum biomarkers are rarely positive. Timing of occurrence suggests that CAPA could be hospital acquired. The associated mortality varies from 36.6% to 76.7% when no host factors or host factors of invasive fungal diseases are present, respectively. Fungemias occurred after 2 weeks in ICUs and are associated with a mortality rate of 45.7%. Candida albicans is the first yeast species recovered, with no specificity linked to COVID-19. Pneumocystosis was mainly found in patients with known immunodepression. The diagnosis occurred at the entry in ICUs and not afterwards, suggesting that if Pneumocystis jirovecii plays a role, it is upstream of the hospitalization in the ICU.
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COVID-19/epidemiología , Coinfección/mortalidad , Fungemia/epidemiología , Neumonía por Pneumocystis/epidemiología , Aspergilosis Pulmonar/epidemiología , Anciano , Antifúngicos/uso terapéutico , COVID-19/mortalidad , COVID-19/patología , Coinfección/epidemiología , Cuidados Críticos , Femenino , Francia/epidemiología , Fungemia/tratamiento farmacológico , Fungemia/mortalidad , Galactosa/análogos & derivados , Galactosa/sangre , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Mananos/sangre , Persona de Mediana Edad , Neumonía por Pneumocystis/tratamiento farmacológico , Neumonía por Pneumocystis/mortalidad , Aspergilosis Pulmonar/tratamiento farmacológico , Aspergilosis Pulmonar/mortalidad , Estudios Retrospectivos , SARS-CoV-2 , Resultado del TratamientoRESUMEN
Invasive pulmonary aspergillosis (IPA) is mainly caused by Aspergillus fumigatus and other Aspergillus species. Galactomannan (GM) is a polysaccharide antigen that exists primarily in the cell walls of Aspergillus species. GM may be released into the blood and other body fluids even in the early stages of Aspergillus invasion; therefore, detection of the GM antigen level can be useful in making an early diagnosis of IPA.
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Antígenos Fúngicos/sangre , Líquido del Lavado Bronquioalveolar/microbiología , Diagnóstico Precoz , Galactosa/sangre , Aspergilosis Pulmonar Invasiva/sangre , Aspergilosis Pulmonar Invasiva/diagnóstico , Mananos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Galactosa/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Pruebas Serológicas/métodosRESUMEN
To achieve the measurement reliability of monosaccharides used as diagnostic markers in clinical fields, it is essential to establish certified reference materials (CRMs). The purpose of this study is to develop a serum CRM by adopting high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) as a new candidate reference measurement procedure for the measurement of glucose and galactose, common diagnostic markers of diabetes and galactosemia, respectively. Using various monosaccharides as internal standards, the accuracy of the HPAEC-PAD method was tested by measuring glucose CRM following treatment with three different deproteinization methods: ultrafiltration, protein precipitation by trichloroacetic acid (TCA), and protein precipitation by acetonitrile. Results showed that ultrafiltration and 5% TCA provided good accuracy with every tested monosaccharide as the internal standard. Accordingly, serum samples in this study were treated by ultrafiltration after adding 2-deoxy-D-glucose and arabinose, which were selected as internal standards for galactose and glucose, respectively. Both intra- and inter-day recovery tests showed good precision and accuracy within 2%. From the serum CRM batches prepared at two levels, 11 units were analyzed by exact-matched calibration methods, and the mass fractions of galactose and glucose were determined via HPAEC-PAD. The between-unit relative standard deviations were not more than 1.5%, showing homogeneity. The expanded uncertainties (%) of galactose and glucose for both levels were less than 3.6% and 2.3% at 95% confidence. The HPAEC-PAD method presented in this study can significantly improve the accuracy and precision of simultaneous monosaccharide analysis, allowing for the development of further serum CRMs for monosaccharides. Graphical abstract.
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Cromatografía por Intercambio Iónico/métodos , Monosacáridos/sangre , Glucemia/análisis , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Líquida de Alta Presión/normas , Cromatografía por Intercambio Iónico/normas , Galactosa/sangre , Humanos , Límite de Detección , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
Among immunologically normal hosts, patients with chronic obstructive pulmonary disease (COPD) are considered to be at high risk of invasive pulmonary aspergillosis (IPA), and early diagnosis and treatment are the key to improving the prognosis of patients. Here we aimed to evaluate whether interleukin (IL)-6 and IL-8 might be used in the detection and diagnosis of IPA in patients with COPD. We prospectively collected 106 patients with COPD and divided them into non-IPA (n=74), probable/possible IPA (n=26) and proven IPA (n=6). Platelia Aspergillus kit was used to detect galactomannan in bronchoalveolar lavage fluid (BALF), and serum and ELISA kit was used to detect IL-6 and IL-8 levels. Diagnostic efficiency of IL-6, IL-8 and galactomannan in serum and BALF was evaluated by receiver operating characteristic curve. Compared with the non-IPA group, the proven/probable IPA group showed significantly elevated levels of IL-6 and IL-8 in both serum and BALF, which were positively correlated with galactomannan levels. The sensitivity and specificity of IL-6 for diagnosing IPA were 74.32% and 81.25% (cut-off at 92.82 pg/mL, area under the curve (AUC)=0.8366) in serum and 68.92% and 71.88% (cut-off at 229.4 pg/mL, AUC=0.7694) in BALF. The sensitivity and specificity of IL-8 for diagnosing IPA were 83.78% and 81.25% (cut-off at 93.46 pg/mL, AUC=0.8756) in serum and 85.14% and 75.00% (cut-off at 325.4 pg/mL, AUC=0.8252) in BALF. The elevated levels of IL-6 and IL-8 in patients with IPA with COPD could be used as auxiliary indicators to diagnose IPA in addition to galactomannan.
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Interleucina-6 , Interleucina-8 , Aspergilosis Pulmonar Invasiva , Enfermedad Pulmonar Obstructiva Crónica , Líquido del Lavado Bronquioalveolar , Galactosa/análogos & derivados , Galactosa/análisis , Galactosa/sangre , Humanos , Interleucina-6/análisis , Interleucina-6/sangre , Interleucina-8/análisis , Interleucina-8/sangre , Aspergilosis Pulmonar Invasiva/diagnóstico , Mananos/análisis , Mananos/sangre , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Sensibilidad y EspecificidadRESUMEN
INTRODUCCIÓN: La actual pandemia provocada por SARS-CoV-2 ha provocado una alta carga en la salud pública y privada. Se han descrito casos y series de aspergilosis invasora asociada a pacientes con COVID-19 en ventilación mecánica. OBJETIVO: Describir el aumento en la positividad del biomarcador galactomanano (GM) durante la pandemia de COVID-19 en la Quinta Región: Valparaíso. MATERIALES Y MÉTODO: Estudio descriptivo, retrospectivo. Se revisó la cantidad y los resultados de GM, tanto de lavado bronco-alveolar (LBA) como en suero y los cultivos de LBA enviados al laboratorio de Micología de la Universidad de Valparaíso, desde enero y hasta septiembre del año 2020; luego se compararon con los exámenes recibidos en el mismo período del año 2019. RESULTADOS: Se observó un aumento significativo de los GM realizados en LBA, concentrándose principalmente entre los meses de julio y septiembre. El 29% de las muestras del año 2020 tenía el antecedente de ser de pacientes con COVID-19. Del total de muestras positivas durante el año de la pandemia, 5/12 fueron en pacientes con COVID-19. CONCLUSIONES: Hubo un aumento significativo de los GM realizados en LBA durante la pandemia, concentrándose principalmente entre los meses de julio-septiembre.
BACKGROUND: The current pandemic due to SARS-CoV-2 has caused a high burden on health. Cases and series of invasive aspergillosis associated with COVID-19 patients (CAPA) on mechanical ventilation have been described. AIM: To describe the increase in the positivity of the galactomannan (GM) biomarker during the COVID-19 pandemic in the Fifth Region: Valparaíso. METHOD: Retrospective descriptive study. The GM results in both broncho-alveolar lavage (BAL) and serum and the BAL cultures that were sent to the Mycology Laboratory of the University of Valparaíso from January to September 2020 were reviewed; then they were compared with the examinations of the same period of 2019. RESULTS: There was a significant increase in GMs carried out in LBA during the pandemic, concentrating mainly between the months of July-September. CONCLUSIONS: There was a significant increase in GM carried out in LBA during the pandemic, concentrating mainly between the months of July-September.
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Humanos , Aspergilosis Pulmonar Invasiva/diagnóstico , Galactosa/análogos & derivados , COVID-19 , Líquido del Lavado Bronquioalveolar , Biomarcadores , Estudios Retrospectivos , Sensibilidad y Especificidad , Aspergilosis Pulmonar Invasiva/complicaciones , Pandemias , Galactosa/sangre , SARS-CoV-2 , COVID-19/complicaciones , Mananos/sangreRESUMEN
BACKGROUND: The prevalence of fungal infection (FI) in developing countries is high, but the diagnosis of FI is still challenging to determine, so it is needed evaluation of biomarkers other than microbiological culture, because the culture has low sensitivity, high cost, not available in every laboratory and needs a long time. The detection of human galactomannan Aspergillus antigen (GAL) and 1,3-beta-D-glucan (BDG) on the fungal cell wall could be the promising biomarkers for fungal infection. Neutropenia, lymphopenia and CD4T cells in the immunocompromised patients are essential factors, but these cell associations with BDG and GAL levels have not been evaluated yet. The study aimed to evaluate GAL and BDG for detecting fungal infection and their association with total leucocyte count, neutrophil, monocyte, lymphocyte and CD4T cells. METHOD: A cross-sectional study was conducted among 86 patient with suspected FI. Fungal infection established using EORTC/MSG criteria. Serology test performed using ELISA. Leucocyte cells were measured using a haematology autoanalyser, and CD4T cells were analysed using BD FACSPresto. Statistical analysis obtained using Spearman's correlation coefficient, ROC curve analysis and 2 × 2 contingency table. RESULTS: Serum Galactomannan and BDG had a significant correlation with CD4T cells and total lymphocyte count (p < 0.05). The cut-off OD GAL >0.3 had sensitivity 54.6%, specificity 87.5% and AUC 0.71; meanwhile, the BDG cut-off >115.78 pg/ mL had sensitivity 71.2%, specificity 52.4% and AUC 0.63 for detecting fungal infection. CONCLUSIONS: The immunocompromised patients can undergo GAL for determining the diagnose of FI. The lower the CD4T cells and total lymphocyte count, the higher the GAL and BDG serum levels.
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Antígenos Fúngicos/sangre , Galactosa/análogos & derivados , Huésped Inmunocomprometido/inmunología , Mananos/sangre , Micosis/diagnóstico , beta-Glucanos/sangre , Adolescente , Adulto , Anciano , Aspergillus/química , Estudios Transversales , Femenino , Estudios de Seguimiento , Galactosa/sangre , Humanos , Masculino , Persona de Mediana Edad , Micosis/sangre , Micosis/inmunología , Micosis/microbiología , Pronóstico , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: There are limited data in real clinical practice on the diagnostic value of a bronchoalveolar lavage (BAL) fluid galactomannan (GM) assay in patients with suspected invasive pulmonary aspergillosis (IPA) who had negative serum GM results. Thus, we investigated the diagnostic performance of a BAL GM assay in patients with negative serum GM assay results who were suspected to have IPA. METHODS: This retrospective study was performed between May 2008 and April 2019 at a tertiary-care hospital in Seoul, South Korea. All patients with suspected IPA whose serum GM assays revealed negative results who sequentially underwent BAL were enrolled in this study. RESULTS: A total of 341 patients with suspected IPA including four cases of proven IPA, 38 cases of probable IPA, 107 cases of possible IPA and 192 patients without IPA were enrolled. Of these 341 patients, 107 (31%) with possible IPA were excluded from the final analysis. Of 42 patients with proven and probable IPA who had initial negative serum GM results, 24 (57%) had positive BAL GM results (n = 24) or BAL fungal culture results (n = 8). In addition, BAL revealed evidence of other opportunistic infections including Pneumocystis jirovecii pneumonia (14% [26/190]), cytomegalovirus (CMV) pneumonia (5% [9/188]) and respiratory viral pneumonia (6% [12/193]). CONCLUSION: Sequential BAL in patients with suspected IPA who had initial negative serum GM results provided additional diagnostic yield in approximately half of patients with evidence of another co-infection.
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Galactosa/análogos & derivados , Aspergilosis Pulmonar Invasiva , Mananos/análisis , Líquido del Lavado Bronquioalveolar/química , Galactosa/análisis , Galactosa/sangre , Humanos , Aspergilosis Pulmonar Invasiva/diagnóstico , Mananos/sangre , Resultados Negativos , República de Corea , Estudios Retrospectivos , Sensibilidad y Especificidad , Centros de Atención TerciariaRESUMEN
BACKGROUND: A colorimetric microassay for the quantitative determination of galactose in the blood was taken and updated. This method helps in diagnosis and follow-up of several inherited metabolic diseases connected to galactose metabolism deficiency such as galactosemia, glycogenosis, glycosylation, tyrosinemia and citrin deficiency. Galactose assay in the blood presents difficulties due to interference with glucose. In this study, we update a method to get around these difficulties. METHOD: This procedure was based on the incubation of whole blood with orcinol in a strongly acidic solution to form a galactose and glucose complexes able to absorb at two different wavelengths. RESULTS: The standard curve analysis for the individual solutions of these two sugars showed a wide range of linearity from 0 to 200 mg / l. Under optimal experimental conditions, the stirring time of the orcinol is 3 minutes, the heating time of the reaction is 20 minutes at 56 ° C, and the duration of the incubation in the dark is 40 minutes. The analysis is carried out on fresh blood. The maximum absorbance of galactose and glucose is respectively 569 nm and 421 nm. An adapted diagnosis algorithm was developed based on our results. CONCLUSION: this method could help in screening and identifying patients with hypergalactosemia that need further investigations. It could represent a promising method for neonatal screening in countries with limited resources.
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Análisis Químico de la Sangre/métodos , Colorimetría/métodos , Galactosa/sangre , Enfermedades Metabólicas/sangre , Enfermedades Metabólicas/diagnóstico , Diagnóstico Precoz , Galactosa/química , Humanos , Recién Nacido , Enfermedades Metabólicas/genética , Tamizaje Neonatal , Factores de TiempoRESUMEN
TLR7 has been linked to the pathogenesis of glomerulonephritis, but its precise roles are not clear. In this study, we evaluated the roles of TLR7 in IgA nephropathy (IgAN). TLR7 proteins were abundant in CD19+ B cells infiltrated in the kidneys of patients with IgAN. The intensities of both intrarenal TLR7 and CD19 proteins were closely associated with kidney function (estimated glomerular filtration rate [eGFR] and serum creatinine concentration) and renal histopathology (tubular atrophy, leukocyte infiltration, tubulointerstitial fibrosis, and global glomerulosclerosis) in patients with IgAN. Meanwhile, TLR7 mRNA levels were significantly increased in peripheral blood B cells of patients with IgAN. TLR7+CD19+ B cells expressed inflammatory cytokines (IL-6 and IL-12) in kidneys and produced high levels of IgA1 and galactose deficient-IgA1 (Gd-IgA1) in peripheral blood of patients with IgAN. Mechanistically, TLR7 activated B cells to produce high levels of Gd-IgA1 via the TLR7-GALNT2 axis in IgAN. Protein levels of GALNT2 were increased by overexpression of TLR7, while they were reduced by TLR7 knockdown in B cells. GALNT2 overexpression augmented Gd-IgA1 production in B cells derived from patients with IgAN. Taken together, high TLR7 expression in B cells has dual roles in the development and progression of IgAN, by facilitating renal inflammation and Gd-IgA1 antibody synthesis.
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Antígenos CD19/sangre , Glomerulonefritis por IGA/sangre , Inmunoglobulina A/sangre , N-Acetilgalactosaminiltransferasas/sangre , Receptor Toll-Like 7/sangre , Adolescente , Adulto , Linfocitos B/inmunología , Linfocitos B/patología , Biomarcadores/sangre , Femenino , Galactosa/sangre , Regulación de la Expresión Génica , Tasa de Filtración Glomerular/genética , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/patología , Humanos , Inmunidad Innata/genética , Inmunoglobulina A/biosíntesis , Inmunoglobulina A/inmunología , Inflamación/sangre , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Riñón/metabolismo , Riñón/patología , Masculino , Persona de Mediana Edad , ARN Mensajero/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/inmunología , Insuficiencia Renal Crónica/patología , Adulto Joven , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
Background: Mucosal immunity plays an important role in the pathogenesis of IgA nephropathy (IgAN). This study aimed to investigate if infection of Helicobacter pylori (H. pylori), a common bacteria in the gastrointestinal tract, associated with IgAN.Methods: This study included 261 patients with IgAN and 46 healthy controls. Clinical information and plasma samples were collected from patients and healthy controls. H. pylori infection was confirmed by western blot. Plasma IgA1 and galactose-deficient IgA1 (Gd-IgA1) levels were detected by specific enzyme-linked immunosorbent assay.Results: Total H. pylori infection rates showed no statistical differences between IgAN patients and healthy controls, but the infection rates of type I H. pylori in IgAN patients were significantly higher than those in healthy controls (44.4 vs. 28.3%, p = 0.040). Compared with uninfected patients, the systolic blood pressure, 24-h proteinuria, and blood urea nitrogen levels were significantly higher in patients with H. pylori infection (126.0 ± 15.5 vs. 119.6 ± 14.5 mmHg, p = 0.010; 1.8 ± 2.7 vs. 1.2 ± 1.4 g/24h, p = 0.013; 7.9 ± 5.4 vs. 6.7 ± 3.9 µmol/L, p = 0.042), especially in patients with type I infection (126.5 ± 15.4 vs. 119.6 ± 14.5 mmHg, p = 0.002; 1.9 ± 2.9 vs. 1.2 ± 1.4 g/24 h, p = 0.033; 8.1 ± 5.6 vs. 6.7 ± 3.9 µmol/L, p = 0.041). Similarly, patients with IgAN and type I H. pylori infection showed higher plasma Gd-IgA1 levels than uninfected patients (5.5 ± 2.2 vs. 4.5 ± 2.2 µg/mL, p = 0.037).Conclusions: Virulent type I H. pylori infection is more common in patients with IgAN. Patients with IgAN and type I H. pylori infection showed lower renal function and higher underglycosylation of plasma IgA1.
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Galactosa/deficiencia , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/etiología , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/aislamiento & purificación , Inmunoglobulina A/sangre , Adulto , Biomarcadores/sangre , Nitrógeno de la Urea Sanguínea , Estudios de Casos y Controles , Femenino , Galactosa/sangre , Glomerulonefritis por IGA/sangre , Glomerulonefritis por IGA/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/inmunología , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Proteinuria/complicacionesRESUMEN
INTRODUCTION: Recent studies noted that Henoch-Schönlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) share the feature of galactose-deficient IgA1 (Gd-IgA1)-oriented pathogenesis, although there are distinct clinical differences. We aimed to clarify the clinicopathologic differences between these 2 diseases. METHODS: We cross-sectionally analyzed adult patients with HSPN (n = 24) or IgAN (n = 56) who underwent renal biopsy (RB) between 2008 and 2018 at Showa University Hospital. Serum Gd-IgA1 (s-Gd-IgA1) levels at the time of RB were compared among study groups using enzyme-linked immunosorbent assay (ELISA) with anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for glomerular Gd-IgA1 (g-Gd-IgA1)-deposition using KM55. Serum inflammatory cytokines were measured using ELISA. RESULTS: Glomerular endothelial injury with subendothelial IgA deposition was significant in patients with HSPN. Serum IL-8, MCP-1, TNF-α, and IL-6 levels were significantly higher in patients with HSPN than IgAN. Levels of s-Gd-IgA1 were comparable among patients with HSPN and IgAN, and a similar degree of g-Gd-IgA1-deposition was detected in both diseases. Furthermore, g-Gd-IgA1-deposition was evident in patients with histopathologically advanced HSPN or IgAN. In HSPN, significant positive correlations between s-Gd-IgA1 levels and crescent formation or IL-6 elevation were confirmed, and g-Gd-IgA1 intensity showed a significant positive correlation with MCP-1 and a tendency to positively correlate with IL-8. Meanwhile, patients with IgAN showed no correlation between inflammatory cytokines and both-Gd-IgA1. Moreover, most g-Gd-IgA1-positive areas were not double stained with CD31 in HSPN. CONCLUSIONS: Although assessing both-Gd-IgA1 alone was insufficient to distinguish between HSPN and IgAN, patients with HSPN showed considerable glomerular capillaritis with subendothelial IgA deposition and significant elevation of serum inflammatory cytokines. Furthermore, such glomerular subendothelial IgA deposition might not contain Gd-IgA1, and factors associated with Gd-IgA1 were inconsistent among these 2 diseases. Thus, developmental mechanisms for IgAN might not apply to HSPN completely, and these 2 diseases still have different aspects.
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Glomerulonefritis por IGA/patología , Vasculitis por IgA/patología , Inmunoglobulina A/sangre , Adulto , Biomarcadores/sangre , Estudios Transversales , Citocinas/sangre , Femenino , Galactosa/sangre , Glomerulonefritis por IGA/sangre , Humanos , Vasculitis por IgA/sangre , Inflamación/sangre , Inflamación/patología , Glomérulos Renales/patología , MasculinoRESUMEN
OBJECTIVES: MRI is an important tool for evaluating inflammation levels and assessing treatment response in patients with ankylosing spondylitis (AS). However, it is expensive and requires experienced physicians. The goal of this study was to identify a biomarker correlated with the MRI score. METHODS: A total of 558 spondyloarthritis (SpA) patients including 527 AS patients, 10 psoriasis (PsA) patients, and 21 non-radiographic SpA (nr-SpA) patients and 725 controls were enrolled for the studies. Plasma IgG galactosylation (IgG-Gal) level was measured by mass spectrometry. Clinical indexes such as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP) were measured in all AS patients. MRIs and X-rays were obtained from 65 AS patients who were followed up for 6 months. RESULTS: The IgG-Gal ratio was twice as high in the AS patients compared with the controls. It correlated with inflammation indices which is evaluated by MRI according to SPARCC. (Pearson coefficient/p value was 0.6/7E10-6). In addition, AS patients with a higher IgG-Gal ratio at baseline tended to show greater improvement in inflammation scores by MRI both in 3-month follow-up and 6-month follow-up. CONCLUSION: The IgG-Gal ratio was significantly increased in AS patients. In clinical care, it may be used as a potential biomarker for diagnosis in the future. Key Points ⢠IgG galactosylation level was abnormal in SpA patients. ⢠IgG galactosylation level was associated with MRI indices.
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Galactosa/sangre , Inmunoglobulina G/sangre , Imagen por Resonancia Magnética , Espondiloartritis/diagnóstico , Adulto , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Espondiloartritis/sangre , Espondiloartritis/diagnóstico por imagen , Adulto JovenRESUMEN
Ustekinumab (UST), an interleukin (IL)-12/IL-23-blocking monoclonal antibody, is a novel therapeutic option for Crohn's disease (CD). We describe a 24-year-old man with CD who showed an abrupt decline in renal function after administration of UST. Twenty-nine months previously, the patient was diagnosed with CD, and abnormal urinalysis findings in health checkup were coincidentally found at that time. Three months previously, treatment for CD was switched from infliximab to UST because of therapy-resistant severe diarrhea and bloody stools. A single dose of UST (260 mg) was initially intravenously administered, followed by single subcutaneous administration (90 mg) 2 months later. Thereafter, the patient exhibited rapid renal dysfunction with significant urinary abnormalities, although his gastrointestinal symptoms had completely disappeared. He was admitted to our hospital for further examination and treatment. Renal pathologic findings were compatible with crescentic glomerulonephritis consisting of almost fibro-cellular crescents. Immunofluorescent study showed IgA and C3 deposition in the glomerular mesangial area and IgA subclass staining revealed predominant IgA1 with concomitant mild IgA2 deposition. Furthermore, galactose-deficient IgA1 (Gd-IgA1) was also positive in the mesangial area. In addition, serum-Gd-IgA1 level was moderately increased. UST treatment was stopped and he responded to intensive steroid therapy with a parallel reduction of serum creatinine and Gd-IgA1 levels without flare of gastrointestinal symptoms. To our knowledge, this is the first case of immunoglobulin A nephropathy (IgAN) in patient with CD that might be aggravated by UST treatment. We presume that inhibition of IL-12/23 signaling with UST may cause to form crescentic IgAN by enhancing Gd-IgA1 production.
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Enfermedad de Crohn/tratamiento farmacológico , Galactosa/deficiencia , Glomerulonefritis por IGA/inducido químicamente , Interleucina-12/efectos adversos , Riñón/fisiopatología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Inmunológicos/uso terapéutico , Administración Intravenosa , Anticuerpos Monoclonales/efectos adversos , Complemento C3/metabolismo , Galactosa/sangre , Mesangio Glomerular/metabolismo , Mesangio Glomerular/patología , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina A/metabolismo , Inyecciones Subcutáneas , Interleucina-12/administración & dosificación , Interleucina-12/uso terapéutico , Riñón/patología , Masculino , Esteroides/administración & dosificación , Esteroides/uso terapéutico , Resultado del Tratamiento , Privación de Tratamiento , Adulto JovenRESUMEN
The current gold-standard diagnostic technique for IgA nephropathy (IgAN), the leading form of primary glomerulonephritis, is renal biopsy. CD89 (the main IgA receptor) is expressed on the surface of monocytes and plays a role in disease pathogenesis. Immunocomplexes formed by sCD89 (soluble form) and Gd-IgA1 are related to disease prognosis. We hypothesize that reduced CD89 surface expression on monocytes may be a marker of disease severity. We aimed to analyze leukocyte subpopulations in peripheral blood and CD89 surface expression on monocytes in a prospective study of 22 patients and 12 healthy subjects (HS). Leukocyte subpopulations and CD89 expression were analyzed by flow cytometry. IgAN patients had a higher percentage of activated and effector memory CD4+ and CD8+ T lymphocytes, a lower percentage of transitional B lymphocytes and plasmablasts, and a higher percentage of CD56dimCD16+ NK cells and myeloid dendritic cells compared with HS. Correlations between reduced CD89 expression levels on nonclassical monocytes, histological findings of a poor prognosis on renal biopsy and baseline renal function were observed. IgAN patients show a characteristic immunological pattern in peripheral blood. A reduced expression level of CD89 on nonclassical monocytes identifies patients with a worse renal prognosis.
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Glomerulonefritis por IGA/inmunología , Fluorescencia , Galactosa/sangre , Humanos , Inmunoglobulina A/sangre , Inmunofenotipificación , Leucocitos/inmunologíaRESUMEN
Classic galactosemia (CG) is a potentially lethal inborn error of galactose metabolism that results from deleterious mutations in the human galactose-1 phosphate uridylyltransferase (GALT) gene. Previously, we constructed a GalT-/- (GalT-deficient) mouse model that exhibits galactose sensitivity in the newborn mutant pups, reduced fertility in adult females, impaired motor functions, and growth restriction in both sexes. In this study, we tested whether restoration of hepatic GALT activity alone could decrease galactose-1 phosphate (gal-1P) and plasma galactose in the mouse model. The administration of different doses of mouse GalT (mGalT) mRNA resulted in a dose-dependent increase in mGalT protein expression and enzyme activity in the liver of GalT-deficient mice. Single intravenous (i.v.) dose of human GALT (hGALT) mRNA decreased gal-1P in mutant mouse liver and red blood cells (RBCs) within 24 h with low levels maintained for over a week. Repeated i.v. injections increased hepatic GalT expression, nearly normalized gal-1P levels in liver, and decreased gal-1P levels in RBCs and peripheral tissues throughout all doses. Moreover, repeated dosing reduced plasma galactose by 60% or more throughout all four doses. Additionally, a single intraperitoneal dose of hGALT mRNA overcame the galactose sensitivity and promoted the growth in a GalT-/- newborn pup.
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Modelos Animales de Enfermedad , Galactosa/sangre , Galactosemias/terapia , ARN Mensajero/administración & dosificación , UTP-Hexosa-1-Fosfato Uridililtransferasa/administración & dosificación , Animales , Animales Recién Nacidos , Células Cultivadas , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Fibroblastos/metabolismo , Galactosemias/patología , Galactosafosfatos/metabolismo , Humanos , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Transducción de Señal/efectos de los fármacos , Transfección , Resultado del Tratamiento , UTP-Hexosa-1-Fosfato Uridililtransferasa/genéticaRESUMEN
BACKGROUND: Immunoglobulin A (IgA) vasculitis nephritis (IgAV-N) is the most common secondary IgA nephropathy (IgAN). Many studies have demonstrated that galactose-deficient IgA1 (Gd-IgA1) in the IgA1 hinge region is associated with the development and also progression of primary IgAN. In this study, we aimed to evaluate the roles of Gd-IgA1 in kidney disease progression in a large Chinese cohort of IgAV-N patients. METHODS: This cohort study enrolled 112 patients with IgAV-N, 15 patients with IgA vasculitis (IgAV) without kidney involvement and 108 patients with IgAN. Plasma IgA1 and Gd-IgA1 levels at kidney biopsy were measured by enzyme-linked immunosorbent assay. The primary endpoint was a 30% decline in estimated glomerular filtration rate or end-stage renal disease or death. RESULTS: The levels of Gd-IgA1 in IgAV-N and IgAN patients were higher than in healthy controls (mean ± SD, 302.86 ± 54.93 U/mL versus 303.16 ± 59.43 U/mL versus 281.30 ± 43.74 U/mL, respectively; P = 0.047), as well as compared with those with IgAV without kidney involvement (272.65 ± 53.14 U/mL; P = 0.036). After adjusting clinical data, higher levels of Gd-IgA1 were found to be independently associated with a greater risk for kidney failure [hazard ratio (HR) = 1.703 per 1 SD, 95% confidence interval (CI) 1.233-2.352; P = 0.001]. Compared with the first Gd-IgA1 quartile group (as reference), the fourth Gd-IgA1 quartile group retained a predictive value for poor renal outcome (HR = 3.740, 95% CI 1.204-11.619; P = 0.023). CONCLUSIONS: These data indicate that Gd-IgA1 levels were similarly elevated in adult patients with IgAN and those with IgAV-N. Moreover, increased Gd-IgA1 levels were associated with both the development and progression of IgAV-N, as observed in IgAN.
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Galactosa/deficiencia , Glomerulonefritis por IGA/complicaciones , Vasculitis por IgA/complicaciones , Inmunoglobulina A/sangre , Enfermedades Renales/diagnóstico , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Galactosa/sangre , Tasa de Filtración Glomerular , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/etiología , Masculino , Pronóstico , Estudios ProspectivosRESUMEN
OBJECTIVE: To evaluate vitamin D levels and bone mineral density in patients with dietary limitations due to inborn errors of metabolism (IEM) and its correlation with diets. STUDY DESIGN: Retrospective study. PLACE AND DURATION OF STUDY: Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, Gazi University Hospital, Turkey, from March to Semtember 2016. METHODOLOGY: The study is a retrospective review of 115 patients. Information about vitamin D status, bone mineral density (BMD) measurement and anthropometric parametres were collected. Patients were divided into two major groups, receiving protein-restricted diets (n=83) and lactose-restricted diets (n=32). Data of 110 healthy children were used as the control group. RESULTS: Mean vitamin D level of patients with special diets 28.1 ±14.9 ng/ml while mean level of healthy controls was 26.6 ±12.27 ng/ml. Levels of 26.8% (n=26/97) patients were found to be deficient and 34% (n=33/97) were found to be insufficient. No statistically significant differences were found between vitamin D levels and BMD of patients and healthy controls. BMD was not influenced by vitamin D levels. CONCLUSION: Low BMD may be encountered in IEM, independent of vitamin D levels and revision of diet for adequacy of essential nutrients; and follow-up for dietary compliance is inevitable.
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Densidad Ósea , Dieta/métodos , Errores Innatos del Metabolismo/sangre , Vitamina D/sangre , Biomarcadores/sangre , Preescolar , Femenino , Estudios de Seguimiento , Galactosa/sangre , Humanos , Masculino , Errores Innatos del Metabolismo/dietoterapia , Errores Innatos del Metabolismo/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the leading cause of end-stage kidney disease. Previous mRNA microarray profiling studies of IgAN revealed inconsistent data. We sought to identify the aberrantly expressed genes and biological pathways by integrating IgAN gene expression datasets in blood cells and performing systematically experimental validation. We also explored the relationship between target genes and galactose-deficient IgA1 (Gd-IgA1) in IgAN. METHODS: We retrieved Gene Expression Omnibus (GEO) datasets of IgAN. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for functional analysis. Deep sequencing on RNA isolated from B cells was used for microarray validation. The relationship between target mRNA expressions and Gd-IgA1 levels in serum were also studied. RESULTS: Three studies with microarray expression profiling datasets met our inclusion criteria. We identified 655 dyregulated genes, including 319 up-regulated and 336 down-regulated genes in three GEO datasets with a total of 35 patients of IgAN and 19 healthy controls. Based on biological process in GO term, these dyregulated genes are mainly related to pentose-phosphate shunt, non-oxidative branch, post-embryonic camera-type eye development and leukocyte activation. KEGG pathway analysis of microarray data revealed that these aberrantly expressed genes were enriched in human T-cell leukemia virus 1 infection, proteoglycans in cancer, intestinal immune network for IgA production and autophagy. We further performed deep sequencing on mRNAs isolated from B cells of an independent set of five patients with IgAN and three healthy persons with the same clinical and demographic characteristics. Seventy-seven genes overlapped with 655 differentially regulated genes mentioned above, including 43 up-regulated and thirty-four down-regulated genes. We next investigated whether these genes expression correlated with Gd-IgA1 levels in IgAN patients. Pearson correlation analyses showed PTEN (phosphatase and tensin homolog) was the most powerful gene negatively correlated with Gd-IgA1 levels. CONCLUSIONS: These results demonstrated that dyregulated genes in patients with IgAN were enriched in intestinal immune network for IgA production and autophagy process, and PTEN in B cells might be involved in the mechanism of Gd-IgA1 production.