Performance of MPO-ANCA and PR3-ANCA immunoassays for the stratification of specific ANCA-associated vasculitis: A systematic review and meta-analysis.

OBJECTIVE: To determine the impact of myeloperoxidase (MPO) and proteinase 3 (PR3) antigen-specific immunoassays in the stratification of patients at-risk for anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) at diagnosis. METHODS: A Medline search was conducted to identify diagnostic accuracy studies using PR3-ANCA or MPO-ANCA for the evaluation of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Studies estimates were pooled using the bivariate method. RESULTS: Diagnostic accuracy varied by analyte and AAV subtype. PR3-ANCA had greater sensitivity than MPO-ANCA for GPA (74% vs 11%, p < 0.001) and MPO-ANCA greater sensitivity for MPA (73% vs 7%, p < 0.001). Specificities of both MPO-ANCA and PR3-ANCA were consistently high (mean 97%, range: 93-99%) for both AAV subtypes. There was insufficient data to perform meta-analysis for the diagnostic accuracy of EPGA. CONCLUSION: These results validate the use of high quality MPO-ANCA and PR3-ANCA immunoassays to screen patients at-risk for AAV as well as to categorize disease as GPA or MPA subtype. However, caution must be exercised in doing so, since some assays may not have optimal performance. Each laboratory should validate appropriate algorithms based on the tests used and testing population.

(1→3)-ß-D-glucan testing for the detection of invasive fungal infections in immunocompromised or critically ill people.

BACKGROUND: Invasive fungal infections (IFIs) are life-threatening opportunistic infections that occur in immunocompromised or critically ill people. Early detection and treatment of IFIs is essential to reduce morbidity and mortality in these populations. (1→3)-ß-D-glucan (BDG) is a component of the fungal cell wall that can be detected in the serum of infected individuals. The serum BDG test is a way to quickly detect these infections and initiate treatment before they become life-threatening. Five different versions of the BDG test are commercially available: Fungitell, Glucatell, Wako, Fungitec-G, and Dynamiker Fungus. OBJECTIVES: To compare the diagnostic accuracy of commercially available tests for serum BDG to detect selected invasive fungal infections (IFIs) among immunocompromised or critically ill people. SEARCH METHODS: We searched MEDLINE (via Ovid) and Embase (via Ovid) up to 26 June 2019. We used SCOPUS to perform a forward and backward citation search of relevant articles. We placed no restriction on language or study design. SELECTION CRITERIA: We included all references published on or after 1995, which is when the first commercial BDG assays became available. We considered published, peer-reviewed studies on the diagnostic test accuracy of BDG for diagnosis of fungal infections in immunocompromised people or people in intensive care that used the European Organization for Research and Treatment of Cancer (EORTC) criteria or equivalent as a reference standard. We considered all study designs (case-control, prospective consecutive cohort, and retrospective cohort studies). We excluded case studies and studies with fewer than ten participants. We also excluded animal and laboratory studies. We excluded meeting abstracts because they provided insufficient information. DATA COLLECTION AND ANALYSIS: We followed the standard procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened studies, extracted data, and performed a quality assessment for each study. For each study, we created a 2 × 2 matrix and calculated sensitivity and specificity, as well as a 95% confidence interval (CI). We evaluated the quality of included studies using the Quality Assessment of Studies of Diagnostic Accuracy-Revised (QUADAS-2). We were unable to perform a meta-analysis due to considerable variation between studies, with the exception of Candida, so we have provided descriptive statistics such as receiver operating characteristics (ROCs) and forest plots by test brand to show variation in study results. MAIN RESULTS: We included in the review 49 studies with a total of 6244 participants. About half of these studies (24/49; 49%) were conducted with people who had cancer or hematologic malignancies. Most studies (36/49; 73%) focused on the Fungitell BDG test. This was followed by Glucatell (5 studies; 10%), Wako (3 studies; 6%), Fungitec-G (3 studies; 6%), and Dynamiker (2 studies; 4%). About three-quarters of studies (79%) utilized either a prospective or a retrospective consecutive study design; the remainder used a case-control design. Based on the manufacturer's recommended cut-off levels for the Fungitell test, sensitivity ranged from 27% to 100%, and specificity from 0% to 100%. For the Glucatell assay, sensitivity ranged from 50% to 92%, and specificity ranged from 41% to 94%. Limited studies have used the Dynamiker, Wako, and Fungitec-G assays, but individual sensitivities and specificities ranged from 50% to 88%, and from 60% to 100%, respectively. Results show considerable differences between studies, even by manufacturer, which prevented a formal meta-analysis. Most studies (32/49; 65%) had no reported high risk of bias in any of the QUADAS-2 domains. The QUADAS-2 domains that had higher risk of bias included participant selection and flow and timing. AUTHORS' CONCLUSIONS: We noted considerable heterogeneity between studies, and these differences precluded a formal meta-analysis. Because of wide variation in the results, it is not possible to estimate the diagnostic accuracy of the BDG test in specific settings. Future studies estimating the accuracy of BDG tests should be linked to the way the test is used in clinical practice and should clearly describe the sampling protocol and the relationship of time of testing to time of diagnosis.

Diagnostic Accuracy of ß-d-Glucan (Fungitell) Testing Among Patients With Hematologic Malignancies or Solid Organ Tumors: A Systematic Review and Meta-Analysis.

Objectives: To determine the accuracy of Fungitell, a ß-d-glucan (BDG) test, for the diagnosis of invasive fungal infection (IFI) among cancer patients. Methods: For this meta-analysis, MEDLINE and EMBASE were searched for references related to BDG testing. Study quality was evaluated using QUADAS-2. Statistical analysis was performed using Stata 14. Results: We screened 12,426 references and identified 189 studies for full-text review. Nineteen studies were included in the final meta-analysis. There was moderate heterogeneity between studies. Nine studies had a high risk of bias, which significantly elevated the overall specificity estimate. Restricting to only low-bias studies, the sensitivity and specificity were 80% and 63%, respectively. Conclusions: The overall sensitivity and specificity of Fungitell as a diagnostic test for IFI is moderate, and there is substantial heterogeneity between studies. Limiting studies to only low-bias risk reduced heterogeneity but also lowered the overall specificity estimate.

Molecular Testing Strategies for Pulmonary Adenocarcinoma: An Optimal Approach With Cost Analysis.

CONTEXT.­: Molecular analysis of lung adenocarcinoma for therapeutically important genes is standard of practice, with multiple professional organizations recommending testing of all adenocarcinomas for mutations in EGFR, ALK, and ROS1. Some organizations recommend analyzing these genes in association with a panel. Few data exist as to optimal testing method or optimal sequence of testing from a cost perspective. OBJECTIVE.­: To determine which order of gene testing was least costly and whether sequential, small panel, or next-generation sequencing (NGS) was cheapest. DESIGN.­: Recent recommendations propose a set of essential molecular tests (EGFR, ALK, and ROS1) and an optional set of molecular tests that may be useful for selection of clinical trials. We compared the costs of different testing sequencing strategies for both the 3 essential genes and for 5 optimal genes. Testing costs were determined by a survey of prices from large laboratories. The strategy most frequently rated as the lowest cost strategy was designated the optimal testing strategy. RESULTS.­: Sequential testing of the essential genes in the order EGFR-ROS1-ALK was optimal from a cost perspective. The expected cost of sequential testing was $2227 (95% CI, $1733-$2794). The cost of NGS was $2500. The expected cost per positive result was $11,362 using this strategy. CONCLUSIONS.­: Molecular testing of lung adenocarcinomas for the set of 3 essential genes and 5 optional genes can be performed by a variety of methods and in a variety of sequences. From a cost perspective, sequential testing in the order EGFR, ROS1, then ALK is optimal. NGS would be competitive if the price was less than $2200. NGS is optimal if testing for the 3 essential genes will be followed by testing for the 5 optional genes. NGS testing is optimal if the clinician plans to test both essential and optional genes.

Diagnostic Accuracy of Fine-Needle Aspiration Cytology for Discrimination of Squamous Cell Carcinoma from Adenocarcinoma in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the accuracy with which morphology alone can distinguish adenocarcinoma and squamous cell carcinoma in non-small cell lung cancer. METHODS: We performed a systematic review and meta-analysis. Three data bases (MEDLINE, EMBASE, Scopus) were searched for studies on the diagnostic accuracy of subtyping non-small cell lung cancer. Accuracy data was abstracted and synthesized using bivariate mixed effects logistic regression as implemented in the midas package in Stata 14. Heterogeneity was assessed using the Higgins I2. RESULTS: We included 17 studies (2,235 cases). Most studies had a low risk of bias. The pooled diagnostic accuracy for cytological diagnosis of adenocarcinoma resulted in a sensitivity of 63% (48-76%) and specificity of 95% (87-98%). The I2 values were 93 and 88% for sensitivity and specificity, respectively. The pooled diagnostic accuracy for the cytological diagnosis of squamous cell carcinoma resulted in a sensitivity of 84% (79-88%) and a specificity of 90% (84-94%). The I2 values were 69 and 86% for sensitivity and specificity, respectively. CONCLUSION: Accuracy varies widely by study and summary estimates do not provide a useful representation of accuracy. Squamous cell carcinoma was diagnosed more accurately than adenocarcinoma.

Burden of respiratory abnormalities in microwave popcorn and flavouring manufacturing workers.

OBJECTIVES: Diacetyl, a butter flavour compound used in food and flavouring production, is a respiratory toxin. We characterised the burden of respiratory abnormalities in workers at popcorn and flavouring manufacturing facilities that used diacetyl as evaluated through US National Institute for Occupational Safety and Health (NIOSH) health hazard evaluations. METHODS: We performed analyses describing the number and percentage of current and former workers from popcorn and flavouring manufacturing facilities where NIOSH administered a respiratory health questionnaire and spirometry testing who met case definitions of suspected flavouring-related lung disease. Case definitions were pathologist reported: lung biopsy pathology report stating supportive of/consistent with constrictive bronchiolitis or bronchiolitis obliterans; probable: obstructive/mixed spirometric pattern with forced expiratory volume in 1 s (FEV1) <60% predicted; possible: obstructive/mixed spirometric pattern with FEV1 ≥60% or any spirometric restriction; symptoms only: normal spirometry plus exertional dyspnoea or usual cough. RESULTS: During 2000-2012, NIOSH collected questionnaire and spirometry data on 1407 workers (87.0% current, 13.0% former) at nine facilities in eight states. After applying case definitions, 4 (0.3%) were classified as pathologist reported, 48 (3.4%) as probable, 234 (16.6%) as possible and 404 (28.7%) as symptoms only. The remaining 717 (51.0%) workers had normal spirometry without exertional dyspnoea or usual cough. Seven of 11 workers with biopsies did not meet the pathologist-reported case definition, although four met probable and three met possible. CONCLUSIONS: This approach demonstrates the substantial burden of respiratory abnormalities in these workers. A similar approach could quantify the burden of respiratory abnormalities in other industries that use diacetyl.

Rapid On-Site Evaluation of Fine-Needle Aspiration by Non-Cytopathologists: A Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies for Adequacy Assessment.

OBJECTIVE: Rapid on-site evaluation (ROSE) has been shown to improve adequacy rates and reduce needle passes. ROSE is often performed by cytopathologists who have limited availability and may be costlier than alternatives. Several recent studies examined the use of alternative evaluators (AEs) for ROSE. A summary of this information could help inform guidelines regarding the use of AEs. The objective was to assess the accuracy of AEs compared to cytopathologists in assessing the adequacy of specimens during ROSE. STUDY DESIGN: This was a systematic review and meta-analysis. Reporting and study quality were assessed using the STARD guidelines and QUADAS-2. All steps were performed independently by two evaluators. Summary estimates were obtained using the hierarchal method in Stata v14. Heterogeneity was evaluated using Higgins' I2 statistic. RESULTS: The systematic review identified 13 studies that were included in the meta-analysis. Summary estimates of sensitivity and specificity for AEs were 97% (95% CI: 92-99%) and 83% (95% CI: 68-92%). There was wide variation in accuracy statistics between studies (I2 = 0.99). CONCLUSIONS: AEs sometimes have accuracy that is close to cytopathologists. However, there is wide variability between studies, so it is not possible to provide a broad guideline regarding the use of AEs.

Changes in respiratory and non-respiratory symptoms in occupants of a large office building over a period of moisture damage remediation attempts.

There is limited information on the natural history of building occupants' health in relation to attempts to remediate moisture damage. We examined changes in respiratory and non-respiratory symptoms in 1,175 office building occupants over seven years with multiple remediation attempts. During each of four surveys, we categorized participants using a severity score: 0 = asymptomatic; 1 = mild, symptomatic in the last 12 months, but not frequently in the last 4 weeks; 2 = severe, symptomatic at least once weekly in the last 4 weeks. Building-related symptoms were defined as improving away from the building. We used random intercept models adjusted for demographics, smoking, building tenure, and microbial exposures to estimate temporal changes in the odds of building-related symptoms or severity scores independent of the effect of microbial exposures. Trend analyses of combined mild/severe symptoms showed no changes in the odds of respiratory symptoms but significant improvement in non-respiratory symptoms over time. Separate analyses showed increases in the odds of severe respiratory symptoms (odds ratio/year = 1.15‒1.16, p-values<0.05) and severity scores (0.02/year, p-values<0.05) for wheezing and shortness of breath on exertion, due to worsening of participants in the mild symptom group. For non-respiratory symptoms, we found no changes in the odds of severe symptoms but improvement in severity scores (-0.04‒-0.01/year, p-values<0.05) and the odds for mild fever and chills, excessive fatigue, headache, and throat symptoms (0.65-0.79/year, p-values<0.05). Our study suggests that after the onset of respiratory and severe non-respiratory symptoms associated with dampness/mold, remediation efforts might not be effective in improving occupants' health.

Identification of mold and dampness-associated respiratory morbidity in 2 schools: comparison of questionnaire survey responses to national data.

BACKGROUND: Dampness and mold problems are frequently encountered in schools. Approximately one third of US public schools require extensive repairs or need at least 1 building replaced. This study illustrates how national data can be used to identify building-related health risks in school employees and students. METHODS: School employees (n = 309) in 2 elementary schools (schools A and B) with dampness and mold problems completed standardized questionnaires. Responses were compared with participant responses from the 3rd National Health and Nutrition Examination Survey and were indirectly standardized for gender, age, smoking status, and (for school B) race. Uncontrolled comparisons were made to responses from a study of office workers, as well as between responses from school employees in different sections of the school buildings designated by decade of construction. RESULTS: Employees from both schools had excess work-related throat and lower respiratory symptoms, as well as eye, nasal, sinus, and wheezing symptoms. School B employees also had excess physician-diagnosed asthma and work-related fatigue, headache, and skin irritation. Employees in sections of the school buildings that were categorized as having greater dampness and mold contamination had more frequent upper and lower respiratory symptoms than employees working in other building sections. CONCLUSIONS: This noncostly type of analysis of indoor air quality complaints can be used to motivate and prioritize building remediation in public schools where funds for building remediation are usually limited.