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Abstract. Background:. Since infections can lead to adverse outcomes in autoimmune bullous diseases (AIBD), this study aimed to analyze infection characteristics in AIBD, predict infection risk factors and provide probable suggestions to infection prevention, which will spot a light on early discovery and prevention of infections in AIBD patients. Methods:. This is a retrospective study of the medical records of inpatients diagnosed with AIBD at the Department of Infectious Diseases and Dermatology, Huashan Hospital from January 2017 to December 2021. We collected patients’ clinical manifestations and laboratory examination results. Risk factors for infections were evaluated using multivariate logistic regression. Results:. A total of 263 AIBD patients were included in the study. The overall incidence of infection was 42.2% (111/263). Pemphigus had a higher infection rate (74/142, 52.1%) than bullous pemphigoid (37/121, 30.6%). Among the patients with infections, 49.5% (55/111) had bacterial infections, 13.5% (15/111) had fungal infections, 2.7% (3/111) had virus infections, and 34.2% (38/111) had mixed infections. Staphylococcus aureus and Candida were the most common pathogens in localized infections, while Cryptococcus and Candida were predominant in systemic infections. In the multivariate logistic model, pemphigus (odds ratio [OR] = 2.56, 95% confidence interval [CI] 1.41–4.63), hypoalbuminemia (OR = 3.78, 95% CI 1.68–8.50), and systemic glucocorticoid treatment (OR = 4.67, 95% CI 2.51–8.68) were independent risk factors for infection in AIBD patients. Bullous pemphigoid (OR = 3.99, 95% CI 1.03–15.45), high-dose (average > 24 mg/day) compared to low-dose (average ≤ 6 mg/day) and medium-dose (average 6–24 mg/day) systemic glucocorticoid treatment (OR = 19.31, 95% CI 3.32–112.28, and OR = 5.71, 95% CI 1.37–23.79) were associated with increased risk factors of systemic infection in AIBD patients with systemic glucocorticoid treatment. A methylprednisolone dose averaging 14 mg/day over the past three months had a 75.0% positive predictive value for infections in AIBD patients. Conclusions:. The incidence of infection in AIBD patients is high, with a broad spectrum of pathogens and infection locations. AIBD patients undergoing systemic glucocorticoid treatment, especially those receiving high doses in the previous three months, should be cautious about infection.

Household contacts (HHCs) of patients with active tuberculosis (ATB) are at higher risk of Mycobacterium tuberculosis (M. tuberculosis) infection. However, the immune factors responsible for different defense responses in HHCs are unknown. Hence, we aimed to evaluate transcriptome signatures in human peripheral blood mononuclear cells (PBMCs) of HHCs to aid risk stratification. We recruited 112 HHCs of ATB patients and followed them for 6 years. Among the HHCs, only 2 developed ATB, while the remaining HHCs were classified into three groups: (1) HHC-1 group (n = 23): HHCs with consistently positive T-SPOT.TB test, negative chest radiograph, and no clinical symptoms or evidence of ATB during the 6-year follow-up period; (2) HHC-2 group (n = 15): HHCs with an initial positive T-SPOT result that later became negative without evidence of ATB; (3) HHC-3 group (n = 14): HHCs with a consistently negative T-SPOT.TB test and no clinical or radiological evidence of ATB. HHC-2 and HHC-3 were combined as HHC-23 group for analysis. RNA sequencing (RNA-seq) in PBMCs, with and without purified protein derivative (PPD) stimulation, identified significant differences in gene signatures between HHC-1 and HHC-23. Gene ontology analysis revealed functions related to bacterial pathogens, leukocyte chemotaxis, and inflammatory and cytokine responses. Modules associated with clinical features in the HHC-23 group were linked to the IL-17 signaling pathway, ferroptosis, complement and coagulation cascades, and the TNF signaling pathway. Validation using real-time PCR confirmed key genes like ATG-7, CXCL-3, and TNFRSF1B associated with infection outcomes in HHCs. Our research enhances understanding of disease mechanisms in HHCs. HHCs with persistent latent tuberculosis infection (HHC-1) showed significantly different gene expression compared to HHCs with no M. tuberculosis infection (HHC-23). These findings can help identify HHCs at risk of developing ATB and guide targeted public health interventions.

BackgroundTumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant disorder with a low incidence in Asia. The most frequent clinical manifestations include fever, rash, myalgia, joint pain and abdominal pain. Misdiagnosis rates are high because of the clinical and genetic variability of the disease. The pathogenesis of TRAPS is complex and yet to be fully defined. Early genetic diagnosis is the key to precise treatment.MethodsIn this study, a Chinese family with suspected TRAPS were analyzed by genome-wide SNP genotyping, linkage analysis and targeted sequencing for identification of mutations in causative genes. To study the pathogenicity of the identified gene mutation, we performed a conservation analysis of the mutation site and protein structure analysis. Flow cytometry was used to detect TNFRSF1A shedding and quantitative real-time PCR were used to assess the activation of unfolded protein response (UPR) in the mutation carriers and healthy individuals.ResultsA typical TRAPS family history, with a pattern of autosomal dominant inheritance, led to the identification of a rare mutation in the TNFRSF1A gene (c.G374A [p.Cys125Tyr]) with unknown significance. The patient responded well to corticosteroids, and long-term therapy with colchicine effectively reduced the inflammatory attacks. No amyloid complications occurred during the 6-year follow-up. In silico protein analysis showed that the mutation site is highly conversed and the mutation prevents the formation of intrachain disulfide bonds in the protein. Despite a normal shedding of the TNFRSF1A protein from stimulated monocytes in the TRAPS patients with p.C125Y mutation, the expression of CHOP and the splicing of XBP1 was significantly higher than healthy controls, suggesting the presence of an activation UPR.ConclusionThis is the first report of a Chinese family with the rare p.C125Y mutation in TNFRSF1A. The p.C125Y mutation does not result in aberrant receptor shedding, but instead is associated with an activated UPR in these TRAPS patients, which may provide new insights into the pathogenesis of this rare mutation in TRAPS.

Background: Epstein-Barr virus (EBV) is widely infected in humans and causes various diseases. Among them, microRNAs of EBV play a key role in the progression of EBV-associated febrile diseases. There're few specific indicators for rapid differential diagnosis of various febrile diseases associated with EBV, and the lack of more reliable screening methods with high diagnostic utility has led to spaces for improvement in the accurate diagnosis and efficient treatment of relevant patients, making EBV infection a complicated clinical problem. With recent advances in plasma microRNA testing, the apparent presence of EBV microRNAs in plasma can help screen for EBV infection. The gene networks targeted by these microRNAs can also indicate potential biomarkers of EBV-associated febrile diseases. This study aimed to identify some novel miRNAs as potential biomarkers for early diagnosis of respectively EBV-associated febrile diseases. Materials and methods: A total of 110 participants were recruited for this task. First, we performed high-throughput sequencing and preliminary PCR validation of differentially expressed miRNAs in 15 participants with EBV-associated fever (divided into 5 groups, common EBV carriers, infectious mononucleosis (IM) and chronic active EBV infection (CAEBV), EBV-associated Hemophagocytic Lymphohistiocytosis (EBV-HLH), and 3 healthy individuals). After a comprehensive analysis, 10 miRNAs with abnormal expression were screened, and then qRT-PCR was performed in the rest of 95 participants to detect the validation of miRNAs expression in plasma samples. Thereafter, we further investigated their potential for clinical application in EBV-related febrile diseases by using a combination of Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and Protein-protein interaction network analysis. Results: Through identification and detailed analysis of the obtained data, we found significant differences in the expression of Hsa-miR-320d, EBV-miR-BART22, and EBV-miR-BART2-3p in blood samples from patients with different EBV-related febrile diseases. We found that the expression levels of Hsa-miR-320d, EBV-miR-BART22, and EBV-miR-BART2-3p in plasma are indicative of determining different disease types of EBV-related febrile diseases, while EBV-miR-BART22 and EBV-miR-BART2-3p may be potential therapeutic targets. Conclusion: The expression levels of Hsa-miR-320d, EBV-miR-BART22, and EBV-miR-BART2-3p suggest that they may be used as transcriptional features for early differential diagnosis of EBV-related febrile diseases, and EBV-miR-BART22 and EBV-miR-BART2-3p may be potential therapeutic targets.

BackgroundsDifferentiation between benign and malignant diseases in EBV-positive patients poses a significant challenge due to the lack of efficient diagnostic tools. Metagenomic Next-Generation Sequencing (mNGS) is commonly used to identify pathogens of patients with fevers of unknown-origin (FUO). Recent studies have extended the application of Next-Generation Sequencing (NGS) in identifying tumors in body fluids and cerebrospinal fluids. In light of these, we conducted this study to develop and apply metagenomic methods to validate their role in identifying EBV-associated malignant disease.MethodsWe enrolled 29 patients with positive EBV results in the cohort of FUO in the Department of Infectious Diseases of Huashan Hospital affiliated with Fudan University from 2018 to 2019. Upon enrollment, these patients were grouped for benign diseases, CAEBV, and malignant diseases according to their final diagnosis, and CNV analysis was retrospectively performed in 2022 using samples from 2018 to 2019.ResultsAmong the 29 patients. 16 of them were diagnosed with benign diseases, 3 patients were diagnosed with CAEBV and 10 patients were with malignant diseases. 29 blood samples from 29 patients were tested for mNGS. Among all 10 patients with malignant diagnosis, CNV analysis suggested neoplasms in 9 patients. Of all 19 patients with benign or CAEBV diagnosis, 2 patients showed abnormal CNV results. The sensitivity and specificity of CNV analysis for the identification for tumors were 90% and 89.5%, separately.ConclusionsThe application of mNGS could assist in the identification of microbial infection and malignancies in EBV-related diseases. Our results demonstrate that CNV detection through mNGS is faster compared to conventional oncology tests. Moreover, the convenient collection of peripheral blood samples adds to the advantages of this approach.

ABSTRACT Silicosis is a well-established risk factor for Mycobacterium tuberculosis infection. This study aimed to estimate the burden and risk factors of M. tuberculosis infection. Silicosis patients from Zhejiang Province were screened for M. tuberculosis by sputum culture, chest radiographs, whole-blood gamma interferon (IFN-γ) release assay (QuantiFERON-TB Gold In-Tube [QFT-GIT]), and tuberculin skin test (TST). Potential risk factors for M. tuberculosis were identified. Data for 1,659 patients were obtained from 1,684 participants. Of these, 1,656 (99.8%) were men, and the average age was 58 (54 to 63) years. The prevalence of active tuberculosis (ATB) was 6,340/100,000 (6.34%) people; the proportion of patients with latent tuberculosis infection (LTBI) was 50.6%. Age (odds ratio [OR] = 1.059, 95% confidence interval [CI] = 1.020 to 1.099, P = 0.003), being underweight (OR = 2.320, 95% CI = 1.057 to 5.089, P = 0.036), and having a history of exposure to TB patients (OR = 4.329, 95% CI = 1.992 to 9.434, P

Background: There has been a great deal of evidence indicating that cytokines participate in meningeal inflammation. Different cytokine profiles may be presented in central nervous system (CNS) infection due to different pathogens. We have attempted to investigate cytokine profiles in cerebrospinal fluid (CSF) of patients with CNS infection. Methods: Forty-three patients with CNS infection including tuberculous meningitis, purulent meningitis and cryptococcal meningitis were enrolled and 11 patients with normal CSF were enrolled as control group. The concentrations of Th1-, Th2- and Th17-type cytokines in CSF were detected using multiplex cytokine assay. Furthermore, the correlation between CSF cytokines and CSF parameters in CNS infection was analyzed. Results: The CSF levels of IL-1β, IL-4, IL-6, IL-10, IL-17, IL-23, IL-33, IFN-γ, TNF-α and sCD40L among the patients with CNS infection were all higher than control group (all P

Background: Whether T-cell interferon-γ responses to Mycobacterium tuberculosis-specific antigens can be influenced by tuberculosis preventive treatment in a high-endemic country is uncertain. Methods: In this prospective, open-label, controlled study, 513 individuals with silicosis were randomly selected for TB preventive treatment with rifapentine and isoniazid or for observation. QuantiFERON-TB Gold in-tube (QFT-GIT) assay was used to measure IFN-γ response to M. tuberculosis antigens at baseline (T0) and at 6 (T1) and 33 (T2) months after completion of therapy. Results: A total of 220 subjects were included in the final analysis: 105 and 115 in the prevention and observation arms, respectively. The proportions of QFT-GIT reversion from baseline to T1 were similar in the prevention and observation arms (18.4% vs 12.8%, P = 0.566). However, reversion from baseline to T2 was more frequent in the prevention arm than in the observation arm, but the difference was not significant (24.2% vs 6.3%, P = 0.881). No significant difference was observed in the quantitative responses of QFT-GIT between the two arms during follow-up at T1 (P = 0.648) and T2 (P = 0.918). Conclusions: Preventive tuberculosis treatment has no effect on interferon-γ responses measured by serial QFT-GIT assays in a high tuberculosis-endemic country. Clinical Trials Registration: http://www.clinicaltrials.gov NCT02430259. Keywords: QuantiFERON TB-Gold in-tube, Tuberculosis preventive treatment, Serial tests, Randomized clinical trial

ABSTRACT QuantiFERON-TB Gold Plus (QFT-Plus) is an emerging QuantiFERON test after QuantiFERON-TB Gold In-Tube (QFT-GIT) for tuberculosis infection detection; it is an IFN-γ release assay. We compared QFTPlus, which has an additional TB antigen 2 (TB2) tube to induce cell-mediated (CD8+ T cell) immune responses, with QFT-GIT. We conducted this study to assess the agreement of the QFT-GIT and QFT-Plus assays in immunocompromised patients in a clinical setting. A total of 278 immunocompromised patients and 175 immunocompetent patients from different departments were continuously enrolled from August 2020 to March 2021, and each patient underwent both tests. Correlations between QFT-GIT and QFT-Plus assays showed good agreement (κ value = 0.859). Patients receiving long-term immunosuppressant therapy had the lowest concordance between QFT-GIT and QFT-Plus assays; 9 out of 11 positive latent tuberculosis infection (LTBI) cases were diagnosed by the QFT-Plus assay, implying that QFT-Plus may detect more LTBI than QFT-GIT does in these patients. Indeterminate results were associated with lower lymphocyte, CD4+ T cell, and CD8+ T cell absolute counts, and with lower CD4/CD8 ratios. In conclusion, we found that the QFT-GIT and QFT-Plus assays had high agreement not only in immunocompetent patients but also in immunocompromised patients. QFT-Plus may detect more LTBI than QFT-GIT in patients receiving long-term immunosuppressant therapy. Thresholds were established for lymphocyte absolute counts of >1.15 × 109 cells, and for CD4+ T cell absolute counts of >467.7 × 106 to 478.5 × 106 cells, which may lessen the incidence of indeterminate results. IMPORTANCE This study evaluated the performance of QFT-GIT and QFT-Plus in the diagnosis of M. tuberculosis infection in immunocompromised patients and found that QFT-Plus may detect more LTBI than QFT-GIT does in patients receiving long-term immunosuppressant therapy. We believe that our study makes a significant contribution to the literature because it highlights the different diagnostic accuracies of QFT-GIT and QFT-Plus in different subpopulations of immunocompromised and immunocompetent patients. Selecting a test with better performance, particularly in patients with a high risk of developing active TB, may assist the health sector in better managing TB. Furthermore, we believe that this study will be of significance to the diagnosis of LTBI.

Abstract Background With the rising utilization of cardiovascular implantable electronic devices (CIEDs), infections secondary to device implantation are increasingly encountered. Staphylococcus aureus and coagulase-negative staphylococci are usually the predominant causative organisms. A CIED infection due to non-tuberculous mycobacteria (NTM) is extremely rare. Case presentation A 68-year-old man was admitted to our hospital with a history of pain and swelling at his cardiac resynchronization therapy-defibrillator (CRT-D) pocket site, for 4 days. The CRT-D had been implanted 2 weeks prior. The exudate smear was positive for acid-fast bacilli and culture results revealed rapidly growing nontuberculous mycobacteria (RGM). After an urgent removal of the device followed by 1 year of antibiotic treatment, the patient was completely cured. A new device was finally implanted, 3 years later. Conclusions Infections caused by nontuberculous mycobacteria following the implantation of cardiac devices are very rare. The typical manifestations of post-implantation CIED infections caused by RGMs include an early onset, with local redness, swelling, and spontaneous drainage. Systemic symptoms such as fever, chills, and fatigue are absent. Mycobacterium fortuitum is the most common species of RGM implicated in CIED infections, the manifestations of which usually appear within several weeks of the implantation procedure. An urgent removal of the device and appropriate antibiotic therapy are essential therapeutic measures. This is the first such reported case, in which the patient has been re-implanted with another device at the same site, after achieving a complete cure. We followed-up the patient for an additional 3 years and observed that the patient remained free of infection. Our case report shows that though an RGM infection is rare and difficult to treat, it can be completely cured. In addition, we demonstrated that it is subsequently possible to safely re-implant a CIED for the patient, at the same site.

BackgroundThe aim of this study was to explore potential risk factors for cytomegalovirus (CMV) reactivation and their impact on liver failure patient outcomes.MethodsA 10-year retrospective case–control study was conducted in adult participants, who were diagnosed with liver failure and had undergone CMV DNA tests. CMV reactivation cases were matched with controls at a 2:1 ratio based on age, sex, and year of admission. Univariate and multivariate analyses were used to explore risk factors for CMV reactivation.ResultsBetween January 2011 and April 2020, 198 adult patients with liver failure and available CMV DNA test results were enrolled into the study. Among them, 33 patients had detectable CMV DNA in their plasma (16.7%). Clinical manifestations and liver function were comparable between the CMV reactivation and non-reactivation groups. However, CMV reactivation may triple mortality in patients with liver failure. We found that nearly 50% of patients in the CMV-positive group received glucocorticoids, compared to 13.6% in the CMV-negative group (P=0.000). The median total glucocorticoid dose included 836.5 mg of methylprednisolone (IQR 308.7-1259.0 mg) in the CMV-positive group, which was significantly higher than that in the CMV-negative group. A multivariate analysis revealed that glucocorticoid use significantly increased the risk of CMV reactivation (adjusted OR, 4.84; 95% CI, 1.61–14.49; P=0.005). Patients with CMV reactivation tended to be associated with higher white cell counts (adjusted OR, 1.21; 95% CI, 1.08–1.36; P=0.002).ConclusionsHigh intravenous glucocorticoid doses may be the most important risk factor for CMV reactivation in liver failure.

Background: Magnetic resonance imaging (MRI) is widely used in the diagnosis of tuberculous meningitis (TBM) and its complications. We aimed to explore the relationship between MRI features and neurological deficits and TBM patients’ prognosis. Methods: patients diagnosed with TBM were subjected to a neurological evaluation on admission and divided into groups based on the Medical Research Council (MRC) scale. After several years of follow-up, the patients were further divided into groups according to the Modified Rankin Score (MRS). Their MR images were analyzed for meningeal enhancement, tuberculomas, infarction, hydrocephalus, and abscess, including the location and size of the lesion. Any changes in MRI features during the follow-up were recorded. MRI features between groups were compared, and the relationship between dynamic changes in images and Rankin grading was explored. Results: We found significant differences in acute cerebral infarction (ACI) and old cerebral infarctions (OCI) between the MRC groups, and the ORs of ACI and OCI were 21.818 (95% CI: 2.440–195.075) and 6.788 (95% CI: 1.516–30.392), respectively. There were significant differences in ACI, OCI, and Evan’s ratio between the MRS groups (p < 0.05), and the ORs of ACI, OCI, and hydrocephalus were 6.375 (95% CI: 1.501–27.080), 5.556 (95% CI: 1.332–23.177), and 9.139 (95% CI: 2.052–40.700), respectively. The changes of Evan’s ratio were related to the MRS grading (r = 0.335, p = 0.040). Conclusions: For patients with TBM, the presence of ACI or OCI is associated with neurological deficits, and ACI, OCI, and hydrocephalus can be regarded as poor prognostic predictors. Changes in Evan’s ratio will affect the outcome.