An exploratory analysis of routine ferritin measurement upon admission and the prognostic implications of low-grade ferritinemia during inflammation.

BACKGROUND: Serum ferritin is usually measured in the presence of anemia or in suspected iron overload syndromes. Ferritin is also an acute-phase protein that is elevated during systemic inflammation. However, the prognostic value of routinely measuring ferritin upon admission to a medical facility is not clear. Therefore, we examined the association between ferritin concentrations measured at the time of hospital admission with 30-day and long-term mortality. METHODS: We obtained routine ferritin measurements taken within 24 hours of admission in 2,859 patients hospitalized in an internal medicine department. Multiple clinical and laboratory parameters were used to assess the association between ferritin and overall mortality during a median follow-up of 15 months (interquartile range [IQR] 8-22). RESULTS: Ferritin levels were associated with increased 30-day mortality rates (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.03-1.06) for each 100 ng/ml increase. Patients with intermediate (78-220 ng/ml) and high (>221 ng/ml) ferritin concentrations (2nd and 3rd tertiles) had higher 30-day mortality rates even after adjustment for age, sex, and existing co-morbidities (OR 2.05, 95% CI 1.70-2.5). Long-term overall mortality rates demonstrated a similar pattern across ferritin tertiles (hazard ratio [HR] 1.54, 95% CI 1.39-1.71). CONCLUSIONS: Routine admission ferritin concentrations are linearly and independently correlated with excess mortality risk in hospitalized patients, even those with apparently "normal" ferritin concentrations (<300 mg/ml). Thus, low-grade ferritinemia might not be an innocent finding in the context of the inflammatory response. Its potential biological and therapeutic implications warrant future research.

The CRP troponin test (CTT) stratifies mortality risk in patients with non-ST elevation myocardial infarction (NSTEMI).

INTRODUCTION: The C-reactive protein (CRP)-troponin-test (CTT) comprises simultaneous serial measurements of CRP and cardiac troponin and might reflect the systemic inflammatory response in patients with acute coronary syndrome. We sought to test its ability to stratify the short- and long-term mortality risk in patients with non-ST elevation myocardial infarction (NSTEMI). METHODS: We examined 1,675 patients diagnosed with NSTEMI on discharge who had at least two successive measurements of combined CRP and cardiac troponin within 48 h of admission. A tree classifier model determined which measurements and cutoffs could be used to best predict mortality during a median follow-up of 3 years [IQR 1.8-4.3]. RESULTS: Patients with high CRP levels ( > 90th percentile, >54 mg/L) had a higher 30-day mortality rate regardless of their troponin test findings (16.7% vs. 2.9%, p < 0.01). However, among patients with "normal" CRP levels ( < 54 mg/L), those who had high troponin levels ( > 80th percentile, 4,918 ng/L) had a higher 30-day mortality rate than patients with normal CRP and troponin concentrations (7% vs. 2%, p < 0.01). The CTT test result was an independent predictor for overall mortality even after adjusting for age, sex, and comorbidities (HR = 2.28 [95% CI 1.56-3.37], p < 0.01 for patients with high troponin and high CRP levels). CONCLUSIONS: Early serial CTT results may stratify mortality risk in patients with NSTEMI, especially those with "normal" CRP levels. The CTT could potentially assess the impact of inflammation during myocardial necrosis on the outcomes of patients with NSTEMI and identify patients who could benefit from novel anti-inflammatory therapies.

Clinical, Biomarker, and Research Tests Among US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: Since 2015, US government and related personnel have reported dizziness, pain, visual problems, and cognitive dysfunction after experiencing intrusive sounds and head pressure. The US government has labeled these anomalous health incidents (AHIs). Objective: To assess whether participants with AHIs differ significantly from US government control participants with respect to clinical, research, and biomarker assessments. Design, Setting, and Participants: Exploratory study conducted between June 2018 and July 2022 at the National Institutes of Health Clinical Center, involving 86 US government staff and family members with AHIs from Cuba, Austria, China, and other locations as well as 30 US government control participants. Exposures: AHIs. Main Outcomes and Measures: Participants were assessed with extensive clinical, auditory, vestibular, balance, visual, neuropsychological, and blood biomarkers (glial fibrillary acidic protein and neurofilament light) testing. The patients were analyzed based on the risk characteristics of the AHI identifying concerning cases as well as geographic location. Results: Eighty-six participants with AHIs (42 women and 44 men; mean [SD] age, 42.1 [9.1] years) and 30 vocationally matched government control participants (11 women and 19 men; mean [SD] age, 43.8 [10.1] years) were included in the analyses. Participants with AHIs were evaluated a median of 76 days (IQR, 30-537) from the most recent incident. In general, there were no significant differences between participants with AHIs and control participants in most tests of auditory, vestibular, cognitive, or visual function as well as levels of the blood biomarkers. Participants with AHIs had significantly increased fatigue, depression, posttraumatic stress, imbalance, and neurobehavioral symptoms compared with the control participants. There were no differences in these findings based on the risk characteristics of the incident or geographic location of the AHIs. Twenty-four patients (28%) with AHI presented with functional neurological disorders. Conclusions and Relevance: In this exploratory study, there were no significant differences between individuals reporting AHIs and matched control participants with respect to most clinical, research, and biomarker measures, except for objective and self-reported measures of imbalance and symptoms of fatigue, posttraumatic stress, and depression. This study did not replicate the findings of previous studies, although differences in the populations included and the timing of assessments limit direct comparisons.

Neuroimaging Findings in US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: US government personnel stationed internationally have reported anomalous health incidents (AHIs), with some individuals experiencing persistent debilitating symptoms. Objective: To assess the potential presence of magnetic resonance imaging (MRI)-detectable brain lesions in participants with AHIs, with respect to a well-matched control group. Design, Setting, and Participants: This exploratory study was conducted at the National Institutes of Health (NIH) Clinical Center and the NIH MRI Research Facility between June 2018 and November 2022. Eighty-one participants with AHIs and 48 age- and sex-matched control participants, 29 of whom had similar employment as the AHI group, were assessed with clinical, volumetric, and functional MRI. A high-quality diffusion MRI scan and a second volumetric scan were also acquired during a different session. The structural MRI acquisition protocol was optimized to achieve high reproducibility. Forty-nine participants with AHIs had at least 1 additional imaging session approximately 6 to 12 months from the first visit. Exposure: AHIs. Main Outcomes and Measures: Group-level quantitative metrics obtained from multiple modalities: (1) volumetric measurement, voxel-wise and region of interest (ROI)-wise; (2) diffusion MRI-derived metrics, voxel-wise and ROI-wise; and (3) ROI-wise within-network resting-state functional connectivity using functional MRI. Exploratory data analyses used both standard, nonparametric tests and bayesian multilevel modeling. Results: Among the 81 participants with AHIs, the mean (SD) age was 42 (9) years and 49% were female; among the 48 control participants, the mean (SD) age was 43 (11) years and 42% were female. Imaging scans were performed as early as 14 days after experiencing AHIs with a median delay period of 80 (IQR, 36-544) days. After adjustment for multiple comparisons, no significant differences between participants with AHIs and control participants were found for any MRI modality. At an unadjusted threshold (P < .05), compared with control participants, participants with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala. The structural MRI measurements were highly reproducible (median coefficient of variation <1% across all global volumetric ROIs and <1.5% for all white matter ROIs for diffusion metrics). Even individuals with large differences from control participants exhibited stable longitudinal results (typically, <±1% across visits), suggesting the absence of evolving lesions. The relationships between the imaging and clinical variables were weak (median Spearman ρ = 0.10). The study did not replicate the results of a previously published investigation of AHIs. Conclusions and Relevance: In this exploratory neuroimaging study, there were no significant differences in imaging measures of brain structure or function between individuals reporting AHIs and matched control participants after adjustment for multiple comparisons.