Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel.

Background: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are syndromes commonly used as medical diagnoses. Since the existing literature has a mixture of diagnostic approaches, developing consensus-based recommendations would be helpful for clinicians, researchers, and patients. Methods: A modified Delphi process was performed from October 2022 to July 2023, involving 4 rounds of online surveys and 2 live video conferences. The panel comprised international experts recruited based on peer-reviewed published publications and studies. Results: Among 50 invited experts, 26 (52.0%) agreed to participate. Twenty-three panelists completed round 1 of the survey, 21 completed rounds 2 and 3, 20 completed round 4, and 7 participated in round 5 live video discussions. Of the participants, 18 (78.3%) were academic-based clinicians and researchers, 5 (21.7%) practiced in a community-based hospital, and 6 (26.1%) were female. Consensus was reached on 5 themes: (1) incorporating epidemiologic factors, such as geographic location and travel history; (2) updated criteria for classifying FUO or IUO; (3) initial evaluation approaches; (4) a classification system for diagnoses; and (5) recommendations for judicious limitation of empiric therapies. Experts strongly disagreed with using 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography as part of the diagnostic criteria for FUO. There were mixed opinions about the importance of the temperature measurement site, the 3-week minimum illness criterion, the need for a standard definition of relapsing fevers, and the use of similar evaluation strategies for FUO and IUO. Conclusions: These Delphi-generated consensus-based recommendations offer potential improvements compared with earlier definitions and a guide for clinical practice and future research.

Mapping the distribution of Lyme disease at a mid-Atlantic site in the United States using electronic health data.

Lyme disease is a spatially heterogeneous tick-borne infection, with approximately 85% of US cases concentrated in the mid-Atlantic and northeastern states. Surveillance for Lyme disease and its causative agent, including public health case reporting and entomologic surveillance, is necessary to understand its endemic range, but currently used case detection methods have limitations. To evaluate an alternative approach to Lyme disease surveillance, we have performed a geospatial analysis of Lyme disease cases from the Johns Hopkins Health System in Maryland. We used two sources of cases: a) individuals with both a positive test for Lyme disease and a contemporaneous diagnostic code consistent with a Lyme disease-related syndrome; and b) individuals referred for a Lyme disease evaluation who were adjudicated to have Lyme disease. Controls were individuals from the referral cohort judged not to have Lyme disease. Residential address data were available for all cases and controls. We used a hierarchical Bayesian model with a smoothing function for a coordinate location to evaluate the probability of Lyme disease within 100 km of Johns Hopkins Hospital. We found that the probability of Lyme disease was greatest in the north and west of Baltimore, and the local probability that a subject would have Lyme disease varied by as much as 30-fold. Adjustment for demographic and ecological variables partially attenuated the spatial gradient. Our study supports the suitability of electronic medical record data for the retrospective surveillance of Lyme disease.

Diabetes, SGLT-2 Inhibitors, and Urinary Tract Infection: a Review.

PURPOSE OF REVIEW: The aim of this review is to focus on epidemiology, pathogenesis, risk factors, management, and complications of UTI in people with diabetes as well as reviewing the association of SGLT-2 inhibitors with genitourinary infections. RECENT FINDINGS: Individuals diagnosed with T2DM are more prone to experiencing UTIs and recurrent UTIs compared to individuals without T2DM. T2DM is associated with an increased risk of any genitourinary infections (GUI), urinary tract infections (UTIs), and genital infections (GIs) across all age categories. SGLT2 inhibitors are a relatively new class of anti-hyperglycemic agents, and studies suggest that they are associated with an increased risk of genitourinary infections. The management of diabetes and lifestyle modifications with a patient-centric approach are the most recognized methods for preventing critical long-term complications including genitourinary manifestations of diabetes. The available data regarding the association of SGLT-2 inhibitors with genitourinary infections is more comprehensive compared to that with UTIs. Further research is needed to better understand the mechanisms underlining the association between SGLT-2 inhibitors and genital infections and UTIs.

Comparison of diagnostic spectrum between inflammation of unknown origin and fever of unknown origin: A systematic review and meta-analysis.

BACKGROUND: Patients with inflammation of unknown origin (IUO) and fever of unknown origin (FUO) are commonly considered a single population. Differences in underlying causes between both groups may steer the diagnostic work-up. METHODS: PubMed, Embase, Web of Science, and ClinicalTrials.gov were searched from July 2009 through December 2023. Studies including both FUO and IUO patients with a sample size of ≥20 were considered. The primary outcome was the difference in the rate of patients affected by predefined diagnostic categories according to meeting FUO or IUO criteria. Data were pooled using random-effects models. RESULTS: A total of 8 studies met criteria for inclusion, with a total of 1452 patients (466 with IUO and 986 with FUO). The median rate of IUO patients among the included studies was 32 % (range 25-39 %). Patients with IUO had a lower likelihood of infection (OR 0.59 [95 % CI; 0.36-0.95]; I2 0 %). There were no significant differences in the rate of noninfectious inflammatory disorders, malignancies, miscellaneous disorders, or remaining undiagnosed. Comparison of diagnostic subgroups revealed that IUO patients were less likely to have systemic autoinflammatory disorders (OR 0.17 [95 % CI, 0.05-0.58]; I2 42 %) and more likely to have vasculitis (OR 2.04 [95 % CI, 1.23-3.38]; I2 21 %) and rheumatoid arthritis or spondylarthritis (OR 3.52 [95 % CI, 1.16-10.69]; I2 0 %). CONCLUSION: Based on our findings, there is little reason to assume that FUO and IUO patients would benefit from a different initial diagnostic approach.

Development of a Consensus-Based List of Potential Quality Indicators for Fever and Inflammation of Unknown Origin.

With a growing emphasis on value-based reimbursement, developing quality indicators for infectious diseases has gained attention. Quality indicators for fever of unknown origin and inflammation of unknown origin are lacking. An assembled group of international experts developed 12 quality measures for these conditions, which could be validated with additional study.

Circulating antibody-secreting cells are a biomarker for early diagnosis in patients with Lyme disease.

BACKGROUND: Diagnostic immunoassays for Lyme disease have several limitations including: 1) not all patients seroconvert; 2) seroconversion occurs later than symptom onset; and 3) serum antibody levels remain elevated long after resolution of the infection. INTRODUCTION: MENSA (Medium Enriched for Newly Synthesized Antibodies) is a novel diagnostic fluid that contains antibodies produced in vitro by circulating antibody-secreting cells (ASC). It enables measurement of the active humoral immune response. METHODS: In this observational, case-control study, we developed the MicroB-plex Anti-C6/Anti-pepC10 Immunoassay to measure antibodies specific for the Borrelia burgdorferi peptide antigens C6 and pepC10 and validated it using a CDC serum sample collection. Then we examined serum and MENSA samples from 36 uninfected Control subjects and 12 Newly Diagnosed Lyme Disease Patients. RESULTS: Among the CDC samples, antibodies against C6 and/or pepC10 were detected in all seropositive Lyme patients (8/8), but not in sera from seronegative patients or healthy controls (0/24). Serum antibodies against C6 and pepC10 were detected in one of 36 uninfected control subjects (1/36); none were detected in the corresponding MENSA samples (0/36). In samples from newly diagnosed patients, serum antibodies identified 8/12 patients; MENSA antibodies also detected 8/12 patients. The two measures agreed on six positive individuals and differed on four others. In combination, the serum and MENSA tests identified 10/12 early Lyme patients. Typically, serum antibodies persisted 80 days or longer while MENSA antibodies declined to baseline within 40 days of successful treatment. DISCUSSION: MENSA-based immunoassays present a promising complement to serum immunoassays for diagnosis and tracking therapeutic success in Lyme infections.

Molecular Imaging of Infections: Emerging Techniques for Pathogen-Specific Diagnosis and Guided Therapy.

Evaluation of patients that may be infected is challenging. Imaging to identify or localize a site of infection is often limited because of the nonspecific nature of the findings on conventional imaging modalities. Available imaging methods lack the ability to determine if antibiotics are reaching the site of infection and are not optimized to follow response to therapy. Positron emission tomography (PET) is a method by which radiolabeled molecules can be used to detect metabolic perturbations or levels of expression of specific targets. The most common PET agent is the glucose analog 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG). 18F-FDG has some applicability to localizing a site of infection, but its lack of specificity limits its usefulness. There is a need for the development of pathogen-specific PET radiotracers to address the imaging shortcomings noted above. Preclinical and clinical progress has been made, but significant challenges remain.

Feasibility of and Experience with Free State Funded Telehealth Based Patient Self-referral for COVID-19 Monoclonal Antibody Therapy.

BACKGROUND: Monoclonal antibody (mAb) treatment for COVID-19 has been underutilized due to logistical challenges, lack of access and variable treatment awareness among patients and healthcare professionals. The use of telehealth during the pandemic provides an opportunity to increase access to COVID-19 care. METHODS: This is a single-center descriptive study of telehealth-based patient self-referral for mAb therapy between March 1, 2021, to October 31, 2021 at Baltimore Convention Center Field Hospital (BCCFH). RESULTS: Among the 1001 self-referral patients, the mean age was 47, and most were female (57%) white (66%), and had a primary care provider (62%). During the study period, self-referrals increased from 14 per month in March to 427 in October resulting in a 30-fold increase. About 57% of self-referred patients received a telehealth visit, and of those 82% of patients received mAb infusion therapy. The median time from self-referral to onsite infusion was 2 days (1-3 IQR). DISCUSSION: Our study shows the integration of telehealth with a self-referral process improved access to mAb infusion. A high proportion of self-referrals were appropriate and led to timely treatment. This approach helped those without traditional avenues for care and avoided potential delay for patients seeking referral from their PCPs.

Investigator-Determined Categories for Fever of Unknown Origin (FUO) Compared With International Classification of Diseases-10 Classification of Illness: A Systematic Review and Meta-analysis With a Proposal for Revised FUO Classification.

Background: Classifying fever of unknown origin (FUO) into categorical etiologies (ie, infections, noninfectious inflammatory, oncologic, miscellaneous, and undiagnosed disorders) remains unstandardized and subject to discrepancies. As some disease classifications change, a systematic review of studies would help physicians anticipate the frequency of illness types they may encounter that could influence care. Methods: We systematically reviewed prospective FUO studies published across the Medline (PubMed), Embase, Scopus, and Web of Science databases from January 1, 1997, to July 31, 2022. We performed a meta-analysis to estimate associated pooled proportions between the investigator-determined choice of disease category and those determined by the International Classification of Diseases, 10th edition (ICD-10), methodology. Results: The proportion of patients with a difference between the investigator and ICD-10-adjusted noninfectious inflammatory disorder category was 1.2% (95% CI, 0.005-0.021; P < .001), and the proportion was similar for the miscellaneous category at 1.5% (95% CI, 0.007-0.025; P < .001). The miscellaneous and noninfectious inflammatory disorders categories demonstrated significant across-study heterogeneity in the proportions of patients changing categories, with 52.7% (P = .007) and 51.0% (P = .010) I2 , respectively. Conclusions: Adjusting FUO-associated diagnoses by ICD-10 methodology was associated with a statistically significant risk of over- or underestimation of disease category frequency approximation when using a 5 FUO category system. An FUO diagnostic classification system that better reflects mechanistic understanding would assist future research and enhance comparability across heterogenous populations and different geographic regions. We propose an updated FUO classification scheme that streamlines categorizations, aligns with the current understanding of disease mechanisms, and should facilitate empirical decisions, if necessary.

Comparing the Epidemiology and Health Burden of Lyme Disease and Babesiosis Hospitalizations in the United States.

Background: Lyme disease (LD) and babesiosis are increasing in the United States. We sought to characterize and compare their epidemiology and health burden using a nationally representative sample of hospitalizations. Methods: Data were extracted from the National Inpatient Sample (NIS) pertaining to LD and babesiosis for 2018 and 2019. The NIS is a comprehensive database of all-payer inpatient hospitalizations, representing a stratified systematic random sample of discharges from US hospitals. Patient demographics, clinical outcomes, and admission costs were evaluated, in addition to hospital-level variables (eg, location/teaching status and census division). Annual incidence of hospitalizations was calculated using US Census Bureau data. Results: The annual incidence of hospitalizations of LD-related and babesiosis-related hospitalizations were 6.98 and 2.03 per 1 000 000 persons/year. Of the 4585 LD hospitalizations in 2018-2019, 60.9% were among male patients, 85.3% were White, and 39.0% were ≥60 years. Of the 1330 babesiosis hospitalizations in 2018-2019, 72.2% were among male patients, 78.9% were White, and 74.1% were ≥60 years; 70.0% of LD and 91.7% of babesiosis hospitalizations occurred in Middle Atlantic or New England. Lower disease severity was noted in 81.8% of LD hospitalizations compared with 49.3% of babesiosis hospitalizations, whereas those suffering from high severity were 2.3% and 6.0%, respectively. The mean hospital charges for LD and babesiosis hospitalizations were $33 440.8 and $40 689.8, respectively. Conclusions: Despite overlap between the 2 diseases, LD has a broader geographic range and a greater number of hospital admissions, whereas babesiosis is more severe, incurring longer hospital stays, higher inpatient costs, and deaths.

Climate change and the prevention of cardiovascular disease.

Climate change is a worsening global crisis that will continue negatively impacting population health and well-being unless adaptation and mitigation interventions are rapidly implemented. Climate change-related cardiovascular disease is mediated by air pollution, increased ambient temperatures, vector-borne disease and mental health disorders. Climate change-related cardiovascular disease can be modulated by climate change adaptation; however, this process could result in significant health inequity because persons and populations of lower socioeconomic status have fewer adaptation options. Clear scientific evidence for climate change and its impact on human health have not yet resulted in the national and international impetus and policies necessary to slow climate change. As respected members of society who regularly communicate scientific evidence to patients, clinicians are well-positioned to advocate on the importance of addressing climate change. This narrative review summarizes the links between climate change and cardiovascular health, proposes actionable items clinicians and other healthcare providers can execute both in their personal life and as an advocate of climate policies, and encourages communication of the health impacts of climate change when counseling patients. Our aim is to inspire the reader to invest more time in communicating the most crucial public health issue of the 21st century to their patients.

Diagnostic Testing for Lyme Disease.

Standard 2-tier testing (STTT), incorporating a screening enzyme immunoassay (EIA) or an immunofluorescence assay (IFA) that reflexes to IgM and IgG immunoblots, has been the primary diagnostic test for Lyme disease since 1995. In 2019, the Food and Drug Administration approved a modified 2-tier test strategy using 2 EIAs: offering a faster, less expensive, and more sensitive assay compared with STTT. New technologies examine early immune responses to Borrelia burgdorferi have the potential to diagnose Lyme disease in the first weeks of infection when existing serologic testing is not recommended due to low sensitivity.

Geographic Influence Upon Noninfectious Diseases Accounting for Fever of Unknown Origin: A Systematic Review and Meta-Analysis.

Background: Diagnostic outcomes for fever of unknown origin (FUO) remain with notable numbers of undiagnosed cases. A recent systemic review and meta-analysis of studies reported geographic variation in FUO-related infectious diseases. Whether geography influences types of FUO noninfectious diagnoses deserves examination. Methods: We systematically searched Medline (PubMed), Embase, Scopus, and Web of Science databases using medical subject headings published from January 1, 1997 to March 31, 2021. Prospective clinical studies investigating participants meeting adult FUO defining criteria were selected if they assessed final diagnoses. Meta-analyses were based on the random-effects model according to World Health Organization (WHO) geographical regions. Results: Nineteen studies with significant heterogeneity were analyzed, totaling 2667 participants. Noninfectious inflammatory disorders had a pooled estimate at 20.0% (95% confidence interval [CI], 17.0%-23.0%). Undiagnosed illness had a pooled estimate of 20.0% (95% CI, 14.0%-26.0%). The pooled estimate for cancer was 15.0% (95% CI, 12.0%-18.0%). Miscellaneous conditions had a pooled estimate of 6.0% (95% CI, 4.0%-8.0%). Noninfectious inflammatory disorders and miscellaneous conditions were most prevalent in the Western Pacific region with a 27.0% pooled estimate (95% CI, 20.0%-34.0%) and 9.0% (95% CI, 7.0%-11.0%), respectively. The highest pooled estimated for cancer was in the Eastern Mediterranean region at 25.0% (95% CI, 18.0%-32.0%). Adult-onset Still's disease (114 [58.5%]), systemic lupus (52 [26.7%]), and giant-cell arteritis (40 [68.9%]) predominated among the noninfectious inflammatory group. Lymphoma (164 [70.1%]) was the most common diagnosis in the cancer group. Conclusions: In this systematic review and meta-analysis, noninfectious disease diagnostic outcomes varied among WHO-defined geographies. Evaluations for FUO should include local variations in disease prevalence.

Prospective Studies Comparing Structured vs Nonstructured Diagnostic Protocol Evaluations Among Patients With Fever of Unknown Origin: A Systematic Review and Meta-analysis.

Importance: Patients meeting the criteria for fever of unknown origin (FUO) can be evaluated with structured or nonstructured approaches, but the optimal diagnostic method is unresolved. Objective: To analyze differences in diagnostic outcomes among patients undergoing structured or nonstructured diagnostic methods applied to prospective clinical studies. Data Sources: PubMed, Embase, Scopus, and Web of Science databases with librarian-generated query strings for FUO, PUO, fever or pyrexia of unknown origin, clinical trial, and prospective studies identified from January 1, 1997, to March 31, 2021. Study Selection: Prospective studies meeting any adult FUO definition were included. Articles were excluded if patients did not precisely fit any existing adult FUO definition or studies were not classified as prospective. Data Extraction and Synthesis: Abstracted data included years of publication and study period, country, setting (eg, university vs community hospital), defining criteria and category outcome, structured or nonstructured diagnostic protocol evaluation, sex, temperature threshold and measurement, duration of fever and hospitalization before final diagnoses, and contribution of potential diagnostic clues, biochemical and immunological serologic studies, microbiology cultures, histologic analysis, and imaging studies. Structured protocols compared with nonstructured diagnostic methods were analyzed using regression models. Main Outcomes and Measures: Overall diagnostic yield was the primary outcome. Results: Among the 19 prospective trials with 2627 unique patients included in the analysis (range of patient ages, 10-94 years; 21.0%-55.3% female), diagnoses among FUO series varied across and within World Health Organization (WHO) geographic regions. Use of a structured diagnostic protocol was not significantly associated with higher odds of yielding a diagnosis compared with nonstructured protocols in aggregate (odds ratio [OR], 0.98; 95% CI, 0.65-1.49) or between Western Europe (Belgium, France, the Netherlands, and Spain) (OR, 0.95; 95% CI, 0.49-1.86) and Eastern Europe (Turkey and Romania) (OR, 0.83; 95% CI, 0.41-1.69). Despite the limited number of studies in some regions, analyses based on the 6 WHO geographic areas found differences in the diagnostic yield. Western European studies had the lowest percentage of achieving a diagnosis. Southeast Asia led with infections at 49.0%. Noninfectious inflammatory conditions were most prevalent in the Western Pacific region (34.0%), whereas the Eastern Mediterranean region had the highest proportion of oncologic explanations (24.0%). Conclusions and Relevance: In this systematic review and meta-analysis, diagnostic yield varied among WHO regions. Available evidence from prospective studies did not support that structured diagnostic protocols had a significantly better rate of achieving a diagnosis than nonstructured protocols. Clinicians worldwide should incorporate geographical disease prevalence in their evaluation of patients with FUO.

Geographic Variation of Infectious Disease Diagnoses Among Patients With Fever of Unknown Origin: A Systematic Review and Meta-analysis.

Background: Fever of unknown origin (FUO) investigations yield a substantial number of patients with infectious diseases. This systematic review and meta-analysis aimed to quantify more common FUO infectious diseases etiologies and to underscore geographic variation. Methods: Four databases (PubMed, Embase, Scopus, and Web of Science) were searched for prospective studies reporting FUO rates among adult patients from 1 January 1997 to 31 March 2021. The pooled proportion for infectious diseases etiology was estimated using the random-effects meta-analysis model. Results: Nineteen prospective studies were included with 2667 total cases. No studies were available for Africa or the Americas. Overall, 37.0% (95.0% confidence interval [CI], 30.0%-44.0%) of FUO patients had an infectious disease etiology. Infections were more likely from Southeastern Asia (pooled proportion, 0.49 [95% CI, .43-.55]) than from Europe (pooled proportion, 0.31 [95% CI, .22-.41]). Among specifically reported infectious diseases (n = 832), Mycobacterium tuberculosis complex predominated across all geographic regions (n = 285 [34.3%]), followed by brucellosis (n = 81 [9.7%]), endocarditis (n = 62 [7.5%]), abscesses (n = 61 [7.3%]), herpesvirus (eg, cytomegalovirus and Epstein-Barr virus) infections (n = 60 [7.2%]), pneumonia (n = 54 [6.5%]), urinary tract infections (n = 54 [6.5%]), and enteric fever (n = 40 [4.8%]). Conclusions: FUO patients from Southeastern Asia were more likely to have an infectious diseases etiology when compared to other regions. The predominant factor for this finding appears to be differences in disease prevalence among various geographical locations or other factors such as access to timely care and diagnosis. Noting epidemiological disease factors in FUO investigations could improve diagnostic yields and clinical outcomes.

Mistaken Identity: Many Diagnoses are Frequently Misattributed to Lyme Disease.

BACKGROUND: Prior studies have demonstrated that Lyme disease is frequently over-diagnosed. However, few studies describe which conditions are misdiagnosed as Lyme disease. METHODS: This retrospective observational cohort study evaluated patients who lacked evidence for Borrelia burgdorferi infection referred for Lyme disease to a Mid-Atlantic academic center from 2000-2013. The primary outcome is clinically described diagnoses contributing to symptoms. Secondary outcomes included symptom duration and determination whether diagnoses were new or attributed to existing medical conditions. RESULTS: Of 1261 referred patients, 1061 (84%) had no findings of active Lyme disease, with 690 (65%) receiving other diagnoses; resulting in 405 (59%) having newly diagnosed medical conditions, 134 (19%) attributed to pre-existing medical issues, and 151 (22%) with both new and pre-existing conditions. Among the 690 patients, the median symptom duration was 796 days, and a total of 139 discrete diagnoses were made. Infectious disease diagnoses comprised only 3.2%. Leading diagnoses were anxiety/depression 222 (21%), fibromyalgia 120 (11%), chronic fatigue syndrome 77 (7%), migraine disorder 74 (7%), osteoarthritis 62 (6%), and sleep disorder/apnea 48 (5%). Examples of less frequent but non-syndromic diseases newly diagnosed included multiple sclerosis (n = 11), malignancy (n = 8), Parkinson's disease (n = 8), sarcoidosis (n = 4), or amyotrophic lateral sclerosis (n = 4). CONCLUSIONS: Most patients with long-term symptoms have either new or pre-existing disorders accounting for their symptoms other than Lyme disease, suggesting overdiagnosis in this population. Patients referred for consideration of Lyme disease for chronic symptoms deserve careful assessment for diagnoses other than Borrelia burgdorferi infection.

Progress Report: Next-Generation Sequencing, Multiplex Polymerase Chain Reaction, and Broad-Range Molecular Assays as Diagnostic Tools for Fever of Unknown Origin Investigations in Adults.

Even well into the 21st century, infectious diseases still account for most causes of fever of unknown origin (FUO). Advances in molecular technologies, including broad-range polymerase chain reaction (PCR) of the 16S ribosomal RNA gene followed by Sanger sequencing, multiplex PCR assays, and more recently, next-generation sequencing applications, have transitioned from research methods to more commonplace in some clinical microbiology laboratories. They have the potential to supplant traditional microbial identification methods and antimicrobial susceptibility testing. Despite the remaining challenges with these technologies, publications in the past decade justify excitement about the potential to transform FUO investigations. We discuss available evidence using these molecular methods for FUO evaluations, including potential cost-benefits and future directions.

Fever of Unknown Origin (FUO) - A Call for New Research Standards and Updated Clinical Management.

Prolonged fever of 38.3°C or higher for at least 3 weeks' duration has been termed fever of unknown origin if unexplained after preliminary investigations. Initially codified in 1961, classification with subgroups was revised in 1991. Additional changes to the definition were proposed in 1997, recommending a set of standardized initial investigations. Advances in diagnosis and management and diagnostic testing over the last 3 decades have prompted a needed update to the definition and approaches. While a 3-week fever duration remains part of the criteria, a lower temperature threshold of 38°C and revised minimum testing criteria will assist clinicians and their patients, setting a solid foundation for future research.