Diagnostic accuracy of clinical signs and symptoms of COVID-19: A systematic review and meta-analysis to investigate the different estimates in a different stage of the pandemic outbreak.

Background: The coronavirus (COVID-19) pandemic caused enormous adverse socioeconomic impacts worldwide. Evidence suggests that the diagnostic accuracy of clinical features of COVID-19 may vary among different populations. Methods: We conducted a systematic review and meta-analysis of studies from PubMed, Embase, Cochrane Library, Google Scholar, and the WHO Global Health Library for studies evaluating the accuracy of clinical features to predict and prognosticate COVID-19. We used the National Institutes of Health Quality Assessment Tool to evaluate the risk of bias, and the random-effects approach to obtain pooled prevalence, sensitivity, specificity, and likelihood ratios. Results: Among the 189 included studies (53 659 patients), fever, cough, diarrhoea, dyspnoea, and fatigue were the most reported predictors. In the later stage of the pandemic, the sensitivity in predicting COVID-19 of fever and cough decreased, while the sensitivity of other symptoms, including sputum production, sore throat, myalgia, fatigue, dyspnoea, headache, and diarrhoea, increased. A combination of fever, cough, fatigue, hypertension, and diabetes mellitus increases the odds of having a COVID-19 diagnosis in patients with a positive test (positive likelihood ratio (PLR) = 3.06)) and decreases the odds in those with a negative test (negative likelihood ratio (NLR) = 0.59)). A combination of fever, cough, sputum production, myalgia, fatigue, and dyspnea had a PLR = 10.44 and an NLR = 0.16 in predicting severe COVID-19. Further updating the umbrella review (1092 studies, including 3 342 969 patients) revealed the different prevalence of symptoms in different stages of the pandemic. Conclusions: Understanding the possible different distributions of predictors is essential for screening for potential COVID-19 infection and severe outcomes. Understanding that the prevalence of symptoms may change with time is important to developing a prediction model.

Cryptococcus gattii Infection as the Major Clinical Manifestation in Patients with Autoantibodies Against Granulocyte-Macrophage Colony-Stimulating Factor.

PURPOSE: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are a predisposing factor for pulmonary alveolar proteinosis (PAP) and Cryptococcus gattii cryptococcosis. This study aimed to investigate clinical manifestations in anti-GM-CSF Ab-positive patients with C. gattii cryptococcosis and analyze the properties of anti-GM-CSF Abs derived from these patients and patients with PAP. METHODS: Thirty-nine patients diagnosed with cryptococcosis (caused by C. neoformans or C. gattii) and 6 with PAP were enrolled in the present study. Clinical information was obtained from medical records. Blood samples were collected for analysis of autoantibody properties. We also explored the National Health Insurance Research Database (NHIRD) of Taiwan to investigate the epidemiology of cryptococcosis and PAP. RESULTS: High titers of neutralizing anti-GM-CSF Abs were identified in 15 patients with cryptococcosis (15/39, 38.5%). Most anti-GM-CSF Ab-positive cryptococcosis cases had central nervous system (CNS) involvement (14/15, 93.3%). Eleven out of 14 (78.6%) anti-GM-CSF Ab-positive CNS cryptococcosis patients were confirmed to be infected with C. gattii, and PAP did not occur synchronously or metachronously in a single patient from our cohort. Exploration of an association between HLA and anti-GM-CSF Ab positivity or differential properties of autoantibodies from cryptococcosis patients and PAP yielded no significant results. CONCLUSION: Anti-GM-CSF Abs can cause two diseases, C. gattii cryptococcosis and PAP, which seldom occur in the same subject. Current biological evidence regarding the properties of anti-GM-CSF Abs cannot provide clues regarding decisive mechanisms. Further analysis, including more extensive cohort studies and investigations into detailed properties, is mandatory to better understand the pathogenesis of anti-GM-CSF Abs.

Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response.

Anti-interferon (IFN)-γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ-reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD < 10-9 M) binding to IFN-γ, but only eight neutralized IFN-γ-STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I-III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1-IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody-IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ-responsive cells.

Determining Carina and Clavicular Distance-Dependent Positioning of Endotracheal Tube in Critically Ill Patients: An Artificial Intelligence-Based Approach.

Early and accurate prediction of endotracheal tube (ETT) location is pivotal for critically ill patients. Automatic and timely detection of faulty ETT locations from chest X-ray images may avert patients' morbidity and mortality. Therefore, we designed convolutional neural network (CNN)-based algorithms to evaluate ETT position appropriateness relative to four detected key points, including tracheal tube end, carina, and left/right clavicular heads on chest radiographs. We estimated distances from the tube end to tracheal carina and the midpoint of clavicular heads. A DenseNet121 encoder transformed images into embedding features, and a CNN-based decoder generated the probability distributions. Based on four sets of tube-to-carina distance-dependent parameters (i.e., (i) 30-70 mm, (ii) 30-60 mm, (iii) 20-60 mm, and (iv) 20-55 mm), corresponding models were generated, and their accuracy was evaluated through the predicted L1 distance to ground-truth coordinates. Based on tube-to-carina and tube-to-clavicle distances, the highest sensitivity, and specificity of 92.85% and 84.62% respectively, were revealed for 20-55 mm. This implies that tube-to-carina distance between 20 and 55 mm is optimal for an AI-based key point appropriateness detection system and is empirically comparable to physicians' consensus.

Necessity of Local Modification for Deep Learning Algorithms to Predict Diabetic Retinopathy.

Deep learning (DL) algorithms are used to diagnose diabetic retinopathy (DR). However, most of these algorithms have been trained using global data or data from patients of a single region. Using different model architectures (e.g., Inception-v3, ResNet101, and DenseNet121), we assessed the necessity of modifying the algorithms for universal society screening. We used the open-source dataset from the Kaggle Diabetic Retinopathy Detection competition to develop a model for the detection of DR severity. We used a local dataset from Taipei City Hospital to verify the necessity of model localization and validated the three aforementioned models with local datasets. The experimental results revealed that Inception-v3 outperformed ResNet101 and DenseNet121 with a foreign global dataset, whereas DenseNet121 outperformed Inception-v3 and ResNet101 with the local dataset. The quadratic weighted kappa score (κ) was used to evaluate the model performance. All models had 5-8% higher κ for the local dataset than for the foreign dataset. Confusion matrix analysis revealed that, compared with the local ophthalmologists' diagnoses, the severity predicted by the three models was overestimated. Thus, DL algorithms using artificial intelligence based on global data must be locally modified to ensure the applicability of a well-trained model to make diagnoses in clinical environments.

Development and Feasibility of a Kinect-Based Constraint-Induced Therapy Program in the Home Setting for Children With Unilateral Cerebral Palsy.

Introduction: Cerebral palsy (CP) is the leading cause of childhood-onset physical disability. Children with CP often have impaired upper limb (UL) function. Constraint-induced therapy (CIT) is one of the most effective UL interventions for children with unilateral CP. However, concerns about CIT for children have been repeatedly raised due to frustration caused by restraint of the child's less-affected UL and lack of motivation for the intensive protocol. Virtual reality (VR), which can mitigate the disadvantages of CIT, potentially can be used as an alternative mediator for implementing CIT. Therefore, we developed a VR-based CIT program for children with CP using the Kinect system. Aims: The feasibility of the Kinect-based CIT program was evaluated for children with unilateral CP using a two-phase study design. Materials and Methods: In phase 1, ten children with unilateral CP were recruited. To confirm the achievement of the motor training goals, maximal UL joint angles were evaluated during gameplay. To evaluate children's perceptions of the game, a questionnaire was used. In phase 2, eight children with unilateral CP were recruited and received an 8 weeks Kinect-based CIT intervention. Performance scores of the game and outcomes of the box and block test (BBT) were recorded weekly. Results: In phase 1, results supported that the design of the program was CIT-specific and was motivational for children with unilateral CP. In phase 2, game performance and the BBT scores began showing stable improvements in the fifth week of intervention. Conclusion: It suggested the Kinect-based CIT program was beneficial to the motor function of the affected UL for children with unilateral CP. According to the results of this feasibility study, larger and controlled effectiveness studies of the Kinect-based CIT program can be conducted to further improve its clinical utility. Clinical Trial Registration: ClinicalTrials.gov, NCT02808195; Comparative effectiveness of a Kinect-based unilateral arm training system vs. CIT for children with CP.

Anti-interferon-γ autoantibody-associated immunodeficiency.

Anticytokine autoantibodies are an emerging disease etiology, through the disturbance of physiological functions of cognate cytokines. Anti-interferon (IFN)-γ autoantibodies (AIGAs) were first identified in patients with severe mycobacterial infections, and were considered to be an autoimmune phenocopy of inborn genetic errors of the IL-12/IFN-γ axis. More than 600 reported cases, most originating from Southeast Asia, have been diagnosed over the last decade. Specific HLA class II molecules are associated with these autoantibodies, which provide a genetic basis for the high prevalence of this immunodeficiency syndrome in certain ethnic groups. Salmonellosis and herpes zoster reactivation are observed in more than half the patients with AIGAs. Moreover, AIGAs have been shown to underlie severe Taralomyce marneffei infection in HIV-negative patients. AIGAs may, thus, be considered a new form of late-onset immunodeficiency conferring a predisposition not only to severe mycobacterial, but also to some bacterial and fungal infections.

Anti-IFN-γ autoantibodies underlie disseminated Talaromyces marneffei infections.

Talaromyces marneffei causes life-threatening opportunistic infections, mainly in Southeast Asia and South China. T. marneffei mainly infects patients with human immunodeficiency virus (HIV) but also infects individuals without known immunosuppression. Here we investigated the involvement of anti-IFN-γ autoantibodies in severe T. marneffei infections in HIV-negative patients. We enrolled 58 HIV-negative adults with severe T. marneffei infections who were otherwise healthy. We found a high prevalence of neutralizing anti-IFN-γ autoantibodies (94.8%) in this cohort. The presence of anti-IFN-γ autoantibodies was strongly associated with HLA-DRB1*16:02 and -DQB1*05:02 alleles in these patients. We demonstrated that adult-onset acquired immunodeficiency due to autoantibodies against IFN-γ is the major cause of severe T. marneffei infections in HIV-negative patients in regions where this fungus is endemic. The high prevalence of anti-IFN-γ autoantibody-associated HLA class II DRB1*16:02 and DQB1*05:02 alleles may account for severe T. marneffei infections in Southeast Asia. Our findings clarify the pathogenesis of T. marneffei infection and pave the way for developing novel treatments.

Comparison of the accuracy of neutrophil CD64, procalcitonin, and C-reactive protein for sepsis identification: a systematic review and meta-analysis.

BACKGROUND: Neutrophil CD64 is widely described as an accurate biomarker for the diagnosis of infection in patients with septic syndrome. We performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of neutrophil CD64, comparing it with C-reactive protein (CRP) and procalcitonin (PCT) for the diagnosis of infection in adult patients with septic syndrome, based on sepsis-2 criteria. We searched the PubMed and Embase databases and Google Scholar. Original studies reporting the performance of neutrophil CD64 for sepsis diagnosis in adult patients were retained. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and hierarchical summary receiver operating characteristic (SROC) curve were calculated. RESULTS: We included 14 studies (2471 patients) from 2006 to 2017 in the meta-analysis. The pooled sensitivity and specificity of neutrophil CD64 for diagnosing infection in adult patients with septic syndrome were 0.87 (95% CI 0.80-0.92) and 0.89 (95% CI 0.82-0.93), respectively. The area under the SROC curve and the DOR were 0.94 (95% CI 0.92-0.96) and 53 (95% CI 22-128), respectively. There was significant heterogeneity between the studies included. Subgroup analyses showed that this heterogeneity was due to differences in sample size and the proportions of patients with sepsis included in the studies. Six studies (927 patients) compared neutrophil CD64 and CRP determinations, and six studies (744 patients) compared neutrophil CD64 and PCT determinations. The area under the SROC curve was larger for neutrophil CD64 than for CRP (0.89 [95% CI 0.87-0.92] vs. 0.84 [95% CI 0.80-0.88], P < 0.05) or PCT (0.89 [95% CI 0.84-0.95] vs. 0.84 [95% CI 0.79-0.89], P < 0.05). CONCLUSIONS: In adult patients with septic syndrome, neutrophil CD64 levels are an excellent biomarker with moderate accuracy outperforming both CRP and PCT determinations.

Clinical features, outcomes, and molecular characteristics of an outbreak of Staphylococcus haemolyticus infection, among a mass-burn casualty patient group, in a tertiary center in northern Taiwan.

BACKGROUND/PURPOSE: We reported an outbreak of Staphylococcus haemolyticus (SH) infection in a group of young patients (mean age 21.6) simultaneously hospitalized due to a mass-burn incident. This study analyzed the clinical features of these patients and the microbiological characteristics of the outbreak. METHODS: All 50 patients hospitalized for burns were enrolled, and their clinical differences were analyzed based on culture results. A drug sensitivity test and pulsed-field gel electrophoresis (PFGE) were conducted to analyze the microbiological difference between SH isolates from the mass-burn casualty patients (the study group) and SH isolates from other patients hospitalized during the same period (the control group) with the intention of identifying the strain of SH outbreak. RESULTS: Patients with isolated SH (N = 36) had a significantly higher disease severity (higher revised Baux score, APACHE II score, and concurrent bacteremia rate), and a significantly poorer clinical outcome (longer ICU and hospital stay, and longer MV usage). Significant differences in the phenotype (antibiotics drug sensitivity test) and genotype (PFGE typing) were observed between the study and control groups. The dominant PFGE type C identified among the study group was related to poorer outcomes in a subgroup analysis. CONCLUSION: A dominant PFGE type of SH infection was found in these mass-burn casualty patients. Pathogenesis or virulence factors may have contributed to our results. Further study of isolated SH should be conducted.

Characterization of two novel variants of staphylococcal cassette chromosome mec elements in oxacillin-resistant Staphylococcus lugdunensis.

OBJECTIVES: Staphylococcus lugdunensis, a species of CoNS, has become an important hospital pathogen because of increasing resistance to ß-lactam antibiotics such as methicillin and oxacillin. Methicillin resistance is mainly due to the acquisition of the staphylococcal cassette chromosome (SCC) mec (SCCmec). Little is known about the structure of SCCmec in methicillin- or oxacillin-resistant CoNS. METHODS: WGS was performed to determine the structure of SCCmec elements of two clinical S. lugdunensis isolates: CMUH-22 and CMUH-25. RESULTS: These elements were found to be flanked by DRs and IRs with unique mosaic structures and a common integration site in the 3' end of the rlmH gene. The sequences of the regions located between rlmH and the ISSau4-like transposase genes of both elements were similar to those of SCCmec Vt of Staphylococcus aureus PM1. The SCCmec (type V, 5C2&4) of CMUH-25 harboured a novel ccrC complex and a C2-like mec complex in opposite orientations, similar to the type V SCCmec of S. aureus WIS. The sequences of the ccrA4B4 genes and J1 and J2 regions of CMUH-25 were similar to those of the SCC element of Staphylococcus haemolyticus NCTC 11042. In contrast, portions of the sequence of the J1 region of type Vt (5C2) SCCmec in strain CMUH-22 were highly similar to portions of those of Staphylococcus epidermidis RP62A and the composite SCCmec type V of S. aureus WAMRSA40. CONCLUSIONS: These observations suggest that the SCCmec elements of CMUH-25 and CMUH-22 evolved separately and assembled through different recombination events.

Comparison of diagnostic accuracy in sepsis between presepsin, procalcitonin, and C-reactive protein: a systematic review and meta-analysis.

BACKGROUND: The soluble cluster of differentiation 14 (or presepsin) is a free fragment of glycoprotein expressed on monocytes and macrophages. Although many studies have been conducted recently, the diagnostic performance of presepsin for sepsis remains debated. We performed a systematic review and meta-analysis of the available literature to assess the accuracy of presepsin for the diagnosis of sepsis in adult patients and compared the performance between presepsin, C-reactive protein (CRP), and procalcitonin (PCT). METHODS: A comprehensive systemic search was conducted in PubMed, EMBASE, and Google Scholar for studies that evaluated the diagnostic accuracy of presepsin for sepsis until January 2017. The hierarchical summary receiver operating characteristic method was used to pool individual sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and area under the receiver operating characteristic curve (AUC). RESULTS: Eighteen studies, comprising 3470 patients, met our inclusion criteria. The pooled diagnosis sensitivity and specificity of presepsin for sepsis were 0.84 (95% CI 0.80-0.87) and 0.76 (95% CI 0.67-0.82), respectively. Furthermore, the pooled DOR, PLR, NLR, and AUC were 16 (95% CI 10-25), 3.4 (95% CI 2.5-4.6), 0.22 (95% CI 0.17-0.27), and 0.88 (95% CI 0.85-0.90), respectively. Significant heterogeneity was found in both sensitivities (Cochrane Q = 137.43, p < 0.001, I 2 = 87.63%) and specificities (Cochrane Q = 180.76, p < 0.001, I 2 = 90.60%). Additionally, we found no significant difference between presepsin and PCT (AUC 0.87 vs. 0.86) or CRP (AUC 0.85 vs. 0.85). However, for studies conducted in ICU, the pooled sensitivity of presepsin was found to be higher than PCT (0.88, 95% CI 0.82-0.92 vs. 0.75, 95% CI 0.68-0.81), while the pooled specificity of presepsin was lower than PCT (0.58, 95% CI 0.42-0.73 vs. 0.75, 95% CI 0.65-0.83). CONCLUSION: Based on the results of our meta-analysis, presepsin is a promising marker for diagnosis of sepsis as PCT or CRP, but its results should be interpreted more carefully and cautiously since too few studies were included and those studies had high heterogeneity between them. In addition, continuing re-evaluation during the course of sepsis is advisable.

Disseminated Cryptococcosis Due to Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in the Absence of Pulmonary Alveolar Proteinosis.

INTRODUCTION: Autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) can cause acquired pulmonary alveolar proteinosis (PAP). Cases of acquired PAP susceptible to typical respiratory pathogens and opportunistic infections have been reported. Anti-GM-CSF autoantibodies have been reported in a few patients with cryptococcal meningitis. This study evaluated the presence of neutralizing anti-GM-CSF autoantibodies in patients without known congenital or acquired immunodeficiency with severe pulmonary or extrapulmonary cryptococcal infection but without PAP. METHODS: We took a clinical history and performed an immunologic evaluation and screening of anti-cytokine autoantibodies in patients with cryptococcal meningitis. The impact of autoantibodies to GM-CSF on immune function was assessed by intracellular staining of GM-CSF-induced STAT5 phosphorylation and MIP-1α production in normal peripheral blood mononuclear cells incubated with plasma from patients or normal control subjects. RESULTS: Neutralizing anti-GM-CSF autoantibodies were identified in four patients with disseminated cryptococcosis, none of whom exhibited PAP. Plasma from patients blocked GM-CSF signaling and inhibited STAT5 phosphorylation and production of MIP-1α. One patient died of disseminated cryptococcosis involving the central nervous system, which was associated with defective GM-CSF activity. CONCLUSIONS: Anti-GM-CSF autoantibodies increase susceptibility to cryptococcal infection in adults without PAP. Cryptococcal central nervous system infection associated with anti-GM-CSF autoantibodies could result in neurological sequelae or be life-threatening. Therefore, timely detection of neutralizing anti-GM-CSF autoantibodies and development of an effective therapy are necessary to prevent deterioration of cryptococcal infection in these patients.

Systemic inflammatory response syndrome is more associated with bacteremia in elderly patients with suspected sepsis in emergency departments.

Early diagnosis of bacteremia for patients with suspected sepsis is 1 way to improve prognosis of sepsis. Systemic inflammatory response syndrome (SIRS) has long been utilized as a screening tool to detect bacteremia by front-line healthcare providers. The value of SIRS to predict bacteremia in elderly patients (≥65 years) with suspected sepsis has not yet been examined in emergency departments (EDs).We aimed to evaluate the performance of SIRS components in predicting bacteremia among elderly patients in EDs.We retrospectively evaluated patients with suspected sepsis and 2 sets of blood culture collected within 4 hours after admitting to ED in a tertiary teaching hospital between 2010 and 2012. Patients were categorized into 3-year age groups: young (18-64 years), young-old (65-74 years), and old patients (≥75 years). Vital signs and Glasgow Coma Scale with verbal response obtained at the triage, comorbidities, sites of infection, blood cultures, and laboratory results were retrieved via the electronic medical records.A total of 20,192 patients were included in our study. Among them, 9862 (48.9%) were the elderly patients (young-old and old patients), 2656 (13.2%) developed bacteremia. Among patients with bacteremia, we found the elderly patients had higher SIRS performance (adjusted odds ratio [aOR]: 2.40, 95% confidence interval [CI]: 1.90-3.03 in the young-old and aOR: 2.66, 95% CI: 2.19-3.23 in the old). Fever at the triage was most predictive of bacteremia, especially in the elderly patients (aOR: 2.19, 95% CI: 1.81-2.65 in the young-old and aOR: 2.27, 95% CI: 1.95-2.63 in the old), and tachypnea was not predictive of bacteremia among the elderly patients (all P > 0.2).The performance of SIRS to predict bacteremia was more suitable for elderly patients in EDs observed in this study. The elderly patients presented with more fever and less tachypnea when they had bacteremia.

Tigecycline-based versus sulbactam-based treatment for pneumonia involving multidrug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex.

BACKGROUND: The treatment options for pneumonia involving multidrug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii (MDR Acb) complex are limited, and the optimal treatment has not been established. METHODS: To compare the efficacy of tigecycline-based with sulbactam (or ampicillin/sulbactam)-based therapy for pneumonia involving MDR Acb complex, we conducted a retrospective study comparing 84 tigecycline-treated adult patients during the period August 2007 to March 2010 with 84 sulbactam or ampicillin/sulbactam-treated adult patients during the period September 2004 to July 2007. Both groups had the matched Acute Physiology and Chronic Health Evaluation (APACHE) II score and received treatment for at least 7 days. RESULTS: The mean APACHE II score was 20.1 for both groups. More patients in sulbactam group had ventilator use (89.3 % versus 69.0 %), bilateral pneumonia (79.8 % versus 60.7 %) and combination therapy (84.5 % versus 53.6 %), particularly with carbapenems (71.4 % versus 6.0 %), while more patients in tigecycline group had delayed treatment (41.7 % versus 26.2 %) (P <0.05). At the end of treatment, more patients in sulbactam group had airway MDR Acb complex eradication (63.5 % versus 33.3 %, P <0.05). The clinical resolution rate was 66.7 % for both groups. The mortality rate during treatment was 17.9 % in sulbactam group, and 25.0 % in tigecycline group (P = 0.259). The multivariate analysis showed that bilateral pneumonia was the only independent predictor for mortality during treatment (adjusted odds ratio, 2.717; 95 % confidence interval, 1.015 to 7.272). CONCLUSIONS: Patients treated with either tigecycline-based or sulbactam-based therapy had a similar clinical outcome, but tigecycline group had a lower microbiological eradiation rate.

Identification of a major epitope by anti-interferon-γ autoantibodies in patients with mycobacterial disease.

The binding of autoantibodies (autoAbs) to interferon (IFN)-γ in people with mycobacterial diseases has become an emerging medical concern. Many patients display specific human leukocyte antigen (HLA) class II haplotypes, which suggests that a common T cell-dependent and B cell-dependent mechanism might underlie the production of specific anti-IFN-γ autoAbs. We show here that these autoAbs target a major epitope (amino acids 121-131, designated position (P)121-131) in a region crucial for IFN-γ receptor (IFN-γR) activation to impair IFN-γ-mediated activities. The amino acid sequence of this epitope is highly homologous to a stretch in the Noc2 protein of Aspergillus spp., which was cross-reactive with autoAbs from patients. Rats immunized with Aspergillus Noc2 developed antibodies that reacted with human IFN-γ. We generated an epitope-erased variant of IFN-γ (EE-IFN-γ), in which the major neutralizing epitope region was altered. The binding affinity of anti-IFN-γ autoAbs for EE-IFN-γ was reduced by about 40%, as compared to that for IFN-γ1-131. Moreover, EE-IFN-γ activated the IFN-γR downstream signaling pathway ex vivo, irrespectively of anti-IFN-γ autoAbs. In conclusion, we identified a common, crucial B cell epitope that bound to anti-IFN-γ autoAbs in patients, and we propose a molecular-mimicry model for autoAb development. In addition, treatment with EE-IFN-γ might be worth investigating in patients producing anti-IFN-γ autoAbs.

Clinical manifestations, course, and outcome of patients with neutralizing anti-interferon-γ autoantibodies and disseminated nontuberculous mycobacterial infections.

Neutralizing anti-interferon-γ autoantibody (nAIGA)-associated immunodeficiency is an emerging medical issue worldwide. In the present study, we describe and discuss the clinical features and outcomes of patients with nAIGAs and disseminated infections by nontuberculous mycobacteria (dNTM).We thoroughly reviewed the medical records of all patients. Microorganisms and nAIGAs were identified using previously described methods with modifications. All data were calculated and analyzed using SPSS software.Among 46 adult patients with dNTM infections, we identified 45 cases (97.8%) with nAIGAs. The average patient age was 58.6 years, and there was no sex predominance. Cervical lymphadenitis (81.8%) was the most common clinical manifestation. Endocrine disorder was the leading comorbidity (7 cases). Malignancies were found in 4 patients, and all of the malignancies originated from the T-cell/macrophage lineage. More than half of the identifiable isolates were slow-growing NTMs. Twenty-eight (62.2%) and 18 (40.0%) patients had a history of zoster and salmonellosis, respectively. A high proportion of patients with recurrent episodes of NTM infection or a history of zoster and dNTM infection had initial nAIGA titers ≥10 dilution (P < 0.05). Twenty-seven patients (60.0%) required long-term antimycobacterial therapy and had at least 1 episode of recurrent NTM disease. No mortality was related to dNTM infection.In Taiwan, nAIGAs are a recently recognized mechanism of dNTM infection. Long term of antibiotic treatment and adherence to medical advice are necessary to improve the clinical outcome of patients with nAIGAs.

Clinical Features, Outcomes, and Molecular Characteristics of Community- and Health Care-Associated Staphylococcus lugdunensis Infections.

Staphylococcus lugdunensis is a major cause of aggressive endocarditis, but it is also responsible for a broad spectrum of infections. The differences in clinical and molecular characteristics between community-associated (CA) and health care-associated (HA) S. lugdunensis infections have remained unclear. We performed a retrospective study of S. lugdunensis infections between 2003 and 2014 to compare the clinical and molecular characteristics of CA and HA isolates. We collected 129 S. lugdunensis isolates in total: 81 (62.8%) HA isolates and 48 (37.2%) CA isolates. HA infections were more frequent than CA infections in children (16.0% versus 4.2%, respectively; P = 0.041) and the elderly (38.3% versus 14.6%, respectively; P = 0.004). The CA isolates were more likely to cause skin and soft tissue infections (85.4% versus 19.8%, respectively; P < 0.001). HA isolates were more frequently responsible for bacteremia of unknown origin (34.6% versus 4.2%, respectively; P < 0.001) and for catheter-related bacteremia (12.3% versus 0%, respectively; P = 0.011) than CA isolates. Fourteen-day mortality was higher for HA infections than for CA infections (11.1% versus 0%, respectively). A higher proportion of the HA isolates than of the CA isolates were resistant to penicillin (76.5% versus 52.1%, respectively; P = 0.004) and oxacillin (32.1% versus 2.1%, respectively; P < 0.001). Two major clonal complexes (CC1 and CC3) were identified. Sequence type 41 (ST41) was the most common sequence type identified (29.5%). The proportion of ST38 isolates was higher for HA than for CA infections (33.3% versus 12.5%, respectively; P = 0.009). These isolates were of staphylococcal cassette chromosome mec element (SCCmec)type IV, V, or Vt. HA and CA S. lugdunensis infections differ in terms of their clinical features, outcome, antibiotic susceptibilities, and molecular characteristics.

Molecular Characteristics of Disease-Causing and Commensal Staphylococcus lugdunensis Isolates from 2003 to 2013 at a Tertiary Hospital in Taiwan.

OBJECTIVES: Staphylococcus lugdunensis can cause community- and healthcare-associated infections. This study investigated the molecular characteristics of S. lugdunensis isolates collected at our hospital and compared the characteristics of the infectious and commensal isolates. METHODS: We collected the S. lugdunensis isolates between 2003 and 2013. The antimicrobial resistance test, SCCmec typing, accessory gene regulator (agr) typing, pulsed-field gel electrophoresis (PFGE), and δ-like hemolysin activity were performed. RESULTS: In total, 118 S. lugdunensis isolates were collected, of which 67 (56.8%) were classified into the infection group and 51 (43.2%) into the commensal group. The oxacillin resistance rate was 36.4%. The most common SCCmec types were SCCmec types V (51.4%) and II (32.6%). In total, 34 pulsotypes were identified. The PFGE typing revealed five clones (pulsotypes A, J, M, N, and P) at our hospital. Pulsotypes A and N caused the spread of high oxacillin resistance. In total, 10.2% (12 of 118) of the isolates lacked δ-like hemolysin activity. Compared with the infection group, the commensal group showed a higher percentage of multiple drug resistance and carried a higher percentage of SCCmec type II (11 of 22, 50% and 3 of 21, 14.3%) and a lower percentage of SCCmec type V (8 of 22, 36.4% and 14 of 21, 66.7%). The commensal group (27 PFGE types) showed higher genetic diversity than did the infection group (20 PFGE types). No difference was observed in the distribution of the five main pulsotypes, agr typing, and the presence of δ-like hemolysin activity between the two groups. CONCLUSIONS: Five main clones were identified at our hospital. The commensal group showed higher genetic diversity, had a higher percentage of multidrug resistance, and carried a higher percentage of SCCmec type II and a lower percentage of SCCmec type V than did the infection group.

Persistence of a major endemic clone of oxacillin-resistant Staphylococcus lugdunensis sequence type 6 at a tertiary medical centre in northern Taiwan.

OBJECTIVES: The aim of this study was to investigate the molecular epidemiology and clinical characteristics of a major clone of oxacillin-resistant Staphylococcus lugdunensis in a tertiary hospital. METHODS: All S. lugdunensis isolated from sterile sites between June 2003 and May 2013 were collected for analysis. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were performed to study their genetic relationships. RESULTS: A total of 118 S. lugdunensis isolates were analysed by PFGE. Three major PFGE pulsotypes were found: A, H, and L. Most of the pulsotype A isolates were oxacillin-resistant, and SCCmec type V and type VT. Isolates from another major clonal group that consisted primarily of pulsotype L were oxacillin-resistant and SCCmec type II. These 14 SCCmec type II S. lugdunensis isolates demonstrated high PFGE similarity and were obtained in the study hospital over a period of 40 months. Three of these 14 patients had clinically significant bacteraemia, and all three cases were in the intensive care unit. Further MLST analysis of the isolates identified an endemic S. lugdunensis strain of sequence type 6, clonal complex 1. CONCLUSIONS: This study identified a major endemic clone of S. lugdunensis that is oxacillin-resistant, SCCmec type II, ST6, and capable of long-term persistence in the hospital. Continuous infection control surveillance and monitoring of S. lugdunensis should be considered in endemic areas.