The application of sequencing technology is shifting from research to clinical laboratories owing to rapid technological developments and substantially reduced costs. However, although thousands of microorganisms are known to infect humans, identification of the etiological agents for many diseases remains challenging as only a small proportion of pathogens are identifiable by the current diagnostic methods. These challenges are compounded by the emergence of new pathogens. Hence, metagenomic next-generation sequencing (mNGS), an agnostic, unbiased, and comprehensive method for detection, and taxonomic characterization of microorganisms, has become an attractive strategy. Although many studies, and cases reports, have confirmed the success of mNGS in improving the diagnosis, treatment, and tracking of infectious diseases, several hurdles must still be overcome. It is, therefore, imperative that practitioners and clinicians understand both the benefits and limitations of mNGS when applying it to clinical practice. Interestingly, the emerging third-generation sequencing technologies may partially offset the disadvantages of mNGS. In this review, mainly: a) the history of sequencing technology; b) various NGS technologies, common platforms, and workflows for clinical applications; c) the application of NGS in pathogen identification; d) the global expert consensus on NGS-related methods in clinical applications; and e) challenges associated with diagnostic metagenomics are described.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/smtd.202000792

High‐Throughput Metagenomics for Identification of Pathogens in the Clinical Settings

Fever has preoccupied physicians since the earliest days of clinical medicine. It has been the subject of scrutiny in recent decades. Historical convention has mostly determined that 37.0°C (98.6°F) should be regarded as normal body temperature, and more modern evidence suggests that fever is a complex physiological response involving the innate immune system and should not be characterized merely as a temperature above this threshold. Fever of unknown origin (FUO) was first defined in 1961 by Petersdorf and Beeson and continues to be a clinical challenge for physicians. Although clinicians may have some understanding of the history of clinical thermometry, how average body temperatures were established, thermoregulation, and pathophysiology of fever, new concepts are emerging. While FUO subgroups and etiologic classifications have remained unchanged since 1991 revisions, the spectrum of diseases, clinical approach to diagnosis, and management are changing. This review considers how newer data should influence both definitions and lingering dogmatic principles. Despite recent advances and newer imaging techniques such as 18-fluorodeoxyglucose-positron emission tomography, clinical judgment remains an essential component of care.

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Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma.

To determine the role of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)/computed tomography (CT) in children with fever of unknown origin (FUO). This retrospective single-center study included 110 children (0–18 years) with FUO who underwent FDG-PET/CT between 2010 and 2019. The diagnostic value of FDG-PET/CT for identifying cause of fever was calculated, treatment modifications after FDG-PET/CT were assessed, and logistic regression analyses were performed to identify clinical and biochemical factors associated with FDG-PET/CT outcome. In 53 out of 110 patients (48%), FDG-PET/CT identified a (true positive) cause of fever. Endocarditis (11%), systemic juvenile idiopathic arthritis (5%), and inflammatory bowel disorder (5%) were the most common causes of FUO. In 42 patients (38%), no cause of fever was found on FDG-PET/CT. In 58 out of 110 patients (53%), treatment modifications were made after FDG-PET/CT. FDG-PET/CT achieved a sensitivity of 85.5%, specificity of 79.2%, positive predictive value of 84.1%, and negative predictive value of 80.9%. On multivariate logistic regression, C-reactive protein was positively associated with finding a true positive focus of fever on FDG-PET/CT (OR = 1.01 (95% CI 1.00–1.02) per mg/L increase in CRP), while leukocyte count was negatively associated with finding a true positive focus of fever (OR = 0.91 (95% CI 0.85–0.97) per 109 leukocytes/L increase). FDG-PET/CT is a valuable diagnostic tool in the evaluation of children with FUO, since it may detect a true underlying cause in almost half (48%) of all cases where none was found otherwise. It allows full-body evaluation in patients without disease-specific symptoms on one examination. CRP and leukocyte count were significantly associated with FDG-PET/CT results, which may contribute to a priori assessment on the outcome of FDG-PET/CT. Future research could be aimed at evaluating more patient-specific factors to prospectively estimate the added value of FDG-PET/CT in children with FUO.

https://link.springer.com/content/pdf/10.1007/s00259-020-04707-z.pdf

Role of FDG-PET/CT in children with fever of unknown origin

FUO despite a high-quality workup after a reasonable amount of time has elapsed to rule out self-limited fevers remains a challenge. The clinician must pay close attention to the patient history, aided by the development of molecular diagnostic tests, to distinguish infections from other causes. 

Fever of Unknown Origin

Growing evidence suggests that 2-deoxy-2-[18F]fluoro-D-glucose (18FDG)-positron emission tomography/computed tomography (PET/CT) is a useful imaging technique for the evaluation of fever of unknown origin (FUO). This imaging technique allows for accurate localization of foci of hypermetabolism based on 18FDG uptake in glycolytically active cells that may represent inflammation, infection, or neoplasia. The presence of abnormal uptake can help direct further investigation that may yield a final diagnosis. A lack of abnormal uptake can be reasonably reassuring that these conditions are not present, thereby avoiding unnecessary additional testing. Insurers have not routinely covered outpatient 18FDG-PET/CT for the indication of FUO in the United States. However, data published since 2007 suggest early use in FUO diagnostic evaluations improves diagnostic efficiency and reduces costs. Clinicians and insurers should consider 18FDG-PET/CT as a useful tool when preliminary studies are unrevealing.

Imaging a Fever—Redefining the Role of 2-deoxy-2-[18F]Fluoro-D-Glucose–Positron Emission Tomography/Computed Tomography in Fever of Unknown Origin Investigations

The differential diagnosis of Fever of Unknown Origin (FUO) is very extensive, and includes infectious diseases (ID), neoplasms and noninfectious inflammatory diseases (NIID). Many FUO remain undiagnosed. Factors influencing the final diagnosis of FUO are unclear. To identify factors associated with FUO diagnostic categories, we performed a systematic review of classical FUO case-series published in 2005–2015 and including patients from 2000. Moreover, to explore changing over time, we compared these case-series with those published in 1995–2004. Eighteen case-series, including 3164 patients, were included. ID were diagnosed in 37.8% of patients, NIID in 20.9%, and neoplasm in 11.6%, FUO were undiagnosed in 23.2%. NIIDs significantly increased over time. An association exists between study country income level and ID (increasing when the income decreases) and undiagnosed FUO (increasing when the income increases); even if not significant, the use of a pre-defined Minimal Diagnostic Work-up to qualify a fever as FUO seems to correlate with a lower prevalence of infections and a higher prevalence of undiagnosed FUO. The multivariate regression analysis shows significant association between geographic area, with ID being more frequent in Asia and Europe having the higher prevalence of undiagnosed FUO. Significant associations were found with model of study and FUO defining criteria, also. Despite advances in diagnostics, FUO still remains a challenge, with ID still representing the first cause. The main factors influencing the diagnostic categories are the income and the geographic position of the study country.

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Fever of unknown origin (FUO): which are the factors influencing the final diagnosis? A 2005–2015 systematic review

Abstract Background Because of poor knowledge of risks and benefits, prophylactic explantation of high BIA-ALCL risk breast implant (BI) is not indicated. Several surgical risks have been associated with BI surgery, with mortality being the most frightening. Primary aim of this study is to assess mortality rate in patients undergoing breast implant surgery for aesthetic or reconstructive indication. Materials and Methods In this retrospective observational cohort study, Breast Implant Surgery Mortality rate (BISM) was calculated as the perioperative mortality rate among 99,690 patients who underwent BI surgery for oncologic and non-oncologic indications. Mean age at first implant placement (A1P), implant lifespan (IL), and women’s life expectancy (WLE) were obtained from a literature review and population database. Results BISM rate was 0, and mean A1P was 34 years for breast augmentation, and 50 years for breast reconstruction. Regardless of indication, overall mean A1P can be presumed to be 39 years, while mean BIL was estimated as 9 years and WLE as 85 years. Conclusion This study first showed that the BISM risk is 0. This information, and the knowledge that BI patients will undergo one or more revisional procedures if not explantation during their lifetime, may help surgeons in the decision-making process of a pre-emptive substitution or explant in patients at high risk of BIA-ALCL. Our recommendation is that patients with existing macrotextured implants do have a relative indication for explantation and total capsulectomy. The final decision should be shared between patient and surgeon following an evaluation of benefits, surgical risks and comorbidities. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . 

https://link.springer.com/content/pdf/10.1007/s00266-022-03138-5.pdf

Mortality Rate in Breast Implant Surgery: Is an Additional Procedure Worthwhile to Mitigate BIA-ALCL Risk?


 
 
 The outcome of patients with acute myocardial infarction (AMI) may vary substantially based on baseline risk. We aimed at analyzing the impact of gender, age and heart failure (HF) on mortality trends, based on a nationwide, comprehensive and universal administrative database of AMI.
 
 
 
 This is a nationwide cohort study of patients admitted with AMI from 2009 to 2018 in all Italian hospitals. In–hospital mortality rate (I–MR) and 1–year post–discharge mortality rate (1–Y–MR) were assessed.
 
 
 
 Among the 1,000,965 AMI events included in the analysis, 43.6% occurred in patients aged ≥75 years, 34.7% in females and 21.8% in AMI complicated by HF at the index hospitalization (Figure 1). Both I–MR and 1–Y–MR significantly decreased over time (from 8.87% to 6.72%; mean annual change − 0.23%; confidence intervals (CI): − 0.26% to − 0.20% and from 12.24% to 10.59%; mean annual change − 0.18%; CI: − 0.24% to − 0.13%, respectively). This trend was confirmed in younger and elderly AMI patients, in both sexes (Figure 2). In AMI patients complicated by HF, both I–MR and 1–Y–MR were markedly high, regardless of age and gender.
 
 
 
 This contemporary, nationwide study suggests that I–MR and 1–Y–MR are still elevated, albeit decreasing over time. Elderly patients and those with HF at the time of index admission, present a particularly high risk of fatal events, regardless of gender.


P206 impact of age, gender and heart failure on mortality trends after acute myocardial infarction in italy

Comment on “Reply to Mortality Rate in Breast Implant Surgery: Is an Additional Procedure Worthwhile to Mitigate BIA-ALCL Risk”

/pdf/acute-myocardial-infarction-in-a-decade-in-italy-impact-of-2ujssmk0.pdf

Stefano Domenico Cicala

Papers

Fever of unknown origin (FUO): which are the factors influencing the final diagnosis? A 2005–2015 systematic review

Mortality Rate in Breast Implant Surgery: Is an Additional Procedure Worthwhile to Mitigate BIA-ALCL Risk?

P206 impact of age, gender and heart failure on mortality trends after acute myocardial infarction in italy

Comment on “Reply to Mortality Rate in Breast Implant Surgery: Is an Additional Procedure Worthwhile to Mitigate BIA-ALCL Risk”

Acute myocardial infarction in a decade in italy: Impact of age, gender and heart failure