High-Sensitivity C-Reactive Protein is a Predictor of Subsequent Atrial High-Rate Episodes in Patients with Pacemakers and Preserved Ejection Fraction

Atrial fibrillation (AF) is associated with morbidity and mortality. Modern pacemakers can detect atrial high-rate episodes (AHREs) as a surrogate for AF. It remains controversial whether inflammation is a cause or a consequence of AF. This study investigated whether the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) can predict subsequent AHREs. This study gathered prospective data from patients with pacemakers and a left ventricle EF ≥ 50% between 2015 and 2019. The hs-CRP and other cardiac biomarkers at baseline and device-detected AHREs, defined as atrial rate ≥ 180 bpm and duration ≥ 6 min, were determined. Cox regression analysis was used to estimate the independent predictors for AHREs. A total of 171 consecutive patients were included. During the median follow-up of 614 days, 66 patients (39%) developed subsequent AHREs. In the univariate Cox regression analysis, sick sinus syndrome (p = 0.005), prior AF (p < 0.001), mitral A velocity (p = 0.008), and hs-CRP (p = 0.013) showed significant association with the increased risk of AHREs. In the multivariate Cox regression model, hs-CRP (HR = 1.121, 95% confidence interval = 1.015–1.238, p = 0.024) retained its significance. Our results suggest that elevated hs-CRP could predict subsequent AHREs and that inflammation could play a role in AF pathogenesis in patients with preserved EF.

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Impact of Early C-Reactive Protein/Albumin Ratio on Intra-Hospital Mortality Among Patients with Spontaneous Intracerebral Hemorrhage

Journal of Clinical Medicine ◽

10.3390/jcm9041236 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1236 ◽

Cited By ~ 2

Author(s):

Michael Bender ◽

Kristin Haferkorn ◽

Michaela Friedrich ◽

Eberhard Uhl ◽

Marco Stein

Keyword(s):

Regression Analysis ◽

Intracerebral Hemorrhage ◽

Hospital Mortality ◽

Cox Regression ◽

Spontaneous Intracerebral Hemorrhage ◽

C Reactive Protein ◽

Albumin Ratio ◽

Cox Regression Analysis ◽

Reactive Protein ◽

The Impact

Objective: The impact of increased C-reactive protein (CRP)/albumin ratio on intra-hospital mortality has been investigated among patients admitted to general intensive care units (ICU). However, it was not investigated among patients with spontaneous intracerebral hemorrhage (ICH). This study aimed to investigate the impact of CRP/albumin ratio on intra-hospital mortality in patients with ICH. Patients and Methods: This retrospective study was conducted on 379 ICH patients admitted between 02/2008 and 12/2017. Blood samples were drawn upon admission and the patients’ demographic, medical, and radiological data were collected. The identification of the independent prognostic factors for intra-hospital mortality was calculated using binary logistic regression and COX regression analysis. Results: Multivariate regression analysis shows that higher CRP/albumin ratio (odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.193–2.317, p = 0.003) upon admission is an independent predictor of intra-hospital mortality. Multivariate Cox regression analysis indicated that an increase of 1 in the CRP/albumin ratio was associated with a 15.3% increase in the risk of intra-hospital mortality (hazard ratio = 1.153, 95% CI = 1.005–1.322, p = 0.42). Furthermore, a CRP/albumin ratio cut-off value greater than 1.22 was associated with increased intra-hospital mortality (Youden’s Index = 0.19, sensitivity = 28.8, specificity = 89.9, p = 0.007). Conclusions: A CRP/albumin ratio greater than 1.22 upon admission was significantly associated with intra-hospital mortality in the ICH patients.

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P3645Prognosis in relation to high-sensitivity C-reactive protein levels in patients with non-obstructive coronary artery disease

European Heart Journal ◽

10.1093/eurheartj/ehz745.0502 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

H W Zhang ◽

Y X Cao ◽

J L Jin ◽

Y L Guo ◽

Y Gao ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Obstructive Coronary Artery Disease ◽

High Sensitivity ◽

C Reactive Protein ◽

Development Fund ◽

Reactive Protein ◽

Increased Risk ◽

Hs Crp ◽

Artery Disease

Abstract Background It has been reported that coronary artery disease (CAD) is characterized by inflammation and non-obstructive CAD (NOCAD) increases the risk of cardiovascular events (CVEs) compared with ones with normal or near-normal coronary arteries (NNCA), even is similar to obstructive CAD (OCAD). We hypothesized that elevated high-sensitivity C-reactive protein (hs-CRP) may be linked to CVEs in those patients with NOCAD. Purpose To investigate the predictive role of hs-CRP in patients with NOCAD. Methods Of 7,746 consecutive patients with angina-like chest pain admissions, 4,662 eligible patients were enrolled who received coronary artery angiography (CAG) and followed up for the CVEs comprising all-cause mortality, myocardial infarction, stroke and late revascularization. According to the results of CAG, the patients were classified as NNCA group (<20% stenosis, n=698, 15.0%), NOCAD group (20–49% stenosis, n=639, 14.3%), and OCAD group (≥50% stenosis, n=3325, 70.7%). They were further subdivided into 3 groups according to baseline hs-CRP levels (<1, 1–3 and >3 mg/L). Proportional hazards models were used to assess the risk of CVEs in all patients enrolled. Results A total of 338 patients (7.3%) experienced CVEs during an average of 13403 person-years follow-up. Patients with NOCAD and OCAD had higher rates of CVEs compared to those with NNCA (p<0.05, respectively). In Cox's models after adjustment of confounders, the risk of CVEs elevated with the increasing degrees of CAD with hazard ratio of 2.01 [95% confidence interval (95% CI): 1.07–3.79, p=0.03] for patients with NOCAD and 2.81 (95% CI: 1.60–4.93, p<0.001) for patients with OCAD compared with the NNCA group. Moreover, elevated hs-CRP levels were associated with the severity of coronary lesions and an elevated increased risk of CVEs in patients with NOCAD and OCAD compared those with NNCA (p<0.05, respectively). Conclusions Patients with NOCAD had indeed worse outcomes and hs-CRP levels were positively in relation to the CVEs in those with NOCAD, which may help to the risk assessment in ones with NOCAD. Acknowledgement/Funding This study was partly supported by Capital Health Development Fund (201614035) and CAMS Innovation Fund for Medical Sciences (2016-I2M-1-011) awarded

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The Cumulative Exposure to High-Sensitivity C-Reactive Protein Predicts the Risk of Chronic Kidney Diseases

Kidney & Blood Pressure Research ◽

10.1159/000504251 ◽

2019 ◽

Vol 45 (1) ◽

pp. 84-94

Author(s):

Jingli Gao ◽

Aitian Wang ◽

Xiaolan Li ◽

Junjuan Li ◽

Hualing Zhao ◽

...

Keyword(s):

Kidney Diseases ◽

High Sensitivity ◽

Cox Proportional Hazards ◽

Exposed Group ◽

Cumulative Exposure ◽

C Reactive Protein ◽

Chronic Kidney Diseases ◽

Reactive Protein ◽

Increased Risk ◽

Hs Crp

Background and Objectives: This study was to characterize the association of cumulative exposure to increased high-sensitivity C-reactive protein (hs-CRP) with chronic kidney diseases (CKD). Methods: We included 35,194 participants with hs-CRP measured at three examinations in 2006, 2008, 2010. Participants were classiﬁed into nonexposed group (hs-CRP <3.0 mg/L in all 3 examinations), 1-exposed group (hs-CRP ≥3.0 mg/L in 1 of the 3 examinations), 2-exposed group (hs-CRP ≥3.0 mg/L in 2 of the 3 examinations), and 3-exposed group (hs-CRP ≥3.0 mg/L in 3 examinations). Cox proportional hazards models were used to assess the association of cumulative hs-CRP with incident CKD. CKD includes an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or urinary protein positive. Results: The study showed the risk of CKD as the number of years of exposure to hs-CRP increases. Participants in 3-exposed group had significantly increased CKD risk with hazard ratio (HR) (95% confidence interval, CI) of 1.70 (1.49–1.93), in comparison with 1.47 (1.34–1.62) for participants in the 2-exposed group, and 1.08 (1.00–1.16) for those in the 1-exposed group (p < 0.01); meanwhile, the similar and significant associations were also observed for eGFR <60 mL/min/1.73 m2, proteinuria positive, in participants of the 3-exposed group in comparison with the nonexposed group, with respective HRs (95% CI) of 1.27 (1.01–1.58) and 2.27 (1.87–2.76). Conclusions: Cumulative exposure to hs-CRP was associated with a subsequent increased risk of CKD and was of great value to risk prediction.

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Reduction in Serum High-Sensitivity C-Reactive Protein Favors Kidney Outcomes in Patients with Impaired Fasting Glucose or Diabetes

Journal of Diabetes Research ◽

10.1155/2020/2720905 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Lili Liu ◽

Bixia Gao ◽

Jinwei Wang ◽

Chao Yang ◽

Shouling Wu ◽

...

Keyword(s):

Kidney Function ◽

Impaired Fasting Glucose ◽

No Reduction ◽

Cox Regression ◽

Fasting Glucose ◽

High Sensitivity ◽

C Reactive Protein ◽

Reactive Protein ◽

Hs Crp ◽

Kidney Function Decline

Objective. We aimed to evaluate whether the reduction in serum high-sensitivity C-reactive protein (hs-CRP) favors kidney outcomes. Methods. This study was a subanalysis including patients with impaired fasting glucose or diabetes of the Kailuan cohort study. The predictor was based on two consecutive visits of hs-CRP levels in 2006 and 2008. A total of 3924 patients with hs-CRP≥3 mg/L in 2006 were divided into two groups according to whether the levels of hs-CRP were reduced in 2008: Group 1: no reduction: hs-CRP≥3 mg/L in 2008; Group 2: reduction: hs-CRP<3 mg/L in 2008. Kidney outcomes include kidney function decline and development and progression of proteinuria and were followed up until the end of 2015. Results. There were 3905, 2049, and 493 patients included into our analysis for the outcomes of kidney function decline and the development and progression of proteinuria, respectively. A total of 398, 297, and 47 events occurred after 5 years of follow-up, respectively. Cox regression revealed that patients with reduction in hs-CRP have lower risk of kidney function decline (HR 0.71, 95% CI 0.57-0.89, and P=0.002) and development of proteinuria (0.77, 0.61-0.99, and P=0.038) after controlling for potential confounders as compared to those with no reduction in hs-CRP levels. Conclusions. Reduction in serum hs-CRP levels favors kidney outcomes in patients with impaired fasting glucose or diabetes.

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The High-Sensitivity C-Reactive Protein to Prealbumin Ratio Predicts Adverse Cardiovascular Events after ST-Elevation Myocardial Infarction

The Heart Surgery Forum ◽

10.1532/hsf.3307 ◽

2021 ◽

Vol 24 (1) ◽

pp. E153-E157

Author(s):

Hongqiang Ren ◽

Li Zhao ◽

Yijun Liu ◽

Zhen Tan ◽

Guiquan Luo ◽

...

Keyword(s):

Myocardial Infarction ◽

Roc Curve ◽

Cardiovascular Events ◽

Cox Regression ◽

High Sensitivity ◽

St Elevation Myocardial Infarction ◽

C Reactive Protein ◽

Reactive Protein ◽

Increased Risk ◽

St Elevation

Background: This study evaluated the association of the high-sensitivity C-reactive protein to prealbumin ratio (CPR) with adverse cardiovascular events after ST-elevation myocardial infarction (STEMI) in patients undergoing primary percutaneous coronary intervention (PCI). Methods: The study included 682 patients who presented with STEMI and were treated with primary PCI. Patients were divided into 2 groups: high CPR (CPR ≥0.02) and low CPR (CPR <0.02). The primary endpoint of the study was the occurrence of major adverse cardiovascular events (MACE), defined as cardiovascular mortality or admission due to recurrent AMI or heart failure. Multivariate Cox regression models were used to assess the prognostic value of CPR on MACE in patients with STEMI. Results: During a median follow-up of 18 months, the accumulated incidence rate of MACE was significantly higher in the high-CPR group than in the low-CPR group (38.7% versus 12.0%, P < .01). Multivariate analysis revealed that CPR was an independent predictor for increased risk of MACE (hazard ratio = 3.27, 95% confidence interval [CI] 2.14 to 4.49, P < .01). Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curve for predicting the diagnosis of MACE was higher for CPR (0.82, 95% CI 0.77 to 0.87) than hs-CRP (0.70, 95% CI 0.65 to 0.75). Conclusion: CPR was independently associated with MACE and can be used for risk stratification in patients with STEMI.

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Troponin T but not C reactive protein is associated with future surgery for aortic stenosis: a population-based nested case-referent study

Open Heart ◽

10.1136/openhrt-2020-001325 ◽

2020 ◽

Vol 7 (2) ◽

pp. e001325

Author(s):

Anders Holmgren ◽

Johan Ljungberg ◽

Johan Hultdin ◽

Bengt Johansson ◽

Ingvar A Bergdahl ◽

...

Keyword(s):

Aortic Stenosis ◽

Troponin T ◽

High Sensitivity ◽

C Reactive Protein ◽

Myocardial Mass ◽

Time To Surgery ◽

Reactive Protein ◽

Potential Biomarker ◽

Increased Risk ◽

Hs Crp

AimsHigh-sensitivity troponin T (hs-TnT) and high-sensitivity C reactive protein (hs-CRP) may convey prognostic information in patients with aortic stenosis (AS). This study evaluated if hs-TnT and hs-CRP associate with myocardial mass, and risk of future surgery for AS.MethodsIn total, 336 patients (48% women) with surgery for AS with previous participation in large population surveys were identified. Preoperatively, myocardial mass and the presence of coronary artery disease (CAD) were assessed. Two matched referents were allocated for each case, and hs-TnT and hs-CRP were determined in stored plasma from the baseline survey. Conditional logistic regression analysis was used to estimate the risk (OR (95% CI)) related to one (natural logarithm) SD increase in hs-TnT and hs-CRP. Kaplan-Mayer and Cox regression analyses were used to evaluate time to surgery.ResultsMedian age (IQR) was 59.8 (10.3) years at survey, and median time between survey and surgery was 10.9 (9.3) years. Hs-TnT was independently associated with surgery for AS (1.24 (1.06–1.44)) irrespective of CAD, whereas Hs-CRP was not (1.05 (0.90–1.22)). Elevated hs-TnT levels at survey associated with shorter time to surgery (p<0.001), and with increased myocardial mass (p=0.002). Hs-CRP did not associate with time to surgery or with myocardial mass.ConclusionsHs-TnT—but not hs-CRP—was associated with increased risk of—and shorter time to—future surgery for AS. Hs-TnT associated with myocardial mass at surgery which indicates that hs-TnT could be a potential biomarker for determining intervention.

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HUBUNGAN ANTARA WHR DENGAN KADAR Hs-CRP SERUM PADA MAHASISWA OBES DAN TIDAK OBES DI FAKULTAS KEDOKTERAN UNIVERSITAS SAM RATULANGI MANADO

Jurnal e-Biomedik ◽

10.35790/ebm.1.1.2013.1626 ◽

2013 ◽

Vol 1 (1) ◽

Author(s):

Ezra Toreh ◽

Shirley E. S. Kawengian ◽

Alexander S. L. Bolang

Keyword(s):

Statistical Analysis ◽

High Sensitivity ◽

Medical Faculty ◽

C Reactive Protein ◽

Cross Sectional ◽

Waist To Hip Ratio ◽

Reactive Protein ◽

Increased Risk ◽

Hs Crp ◽

Spearman Test

Abstract: Central obesity is recognized as a major factor that associated with increased risk for some chronic diseases. Waist to hip ratio described the increase in visceral adipose tissue and subcutaneous fat on waist circumference and hip circumference.C-reactive protein is the detection of cardiovascular disease risk in conventional but not sensitive enough to detect cardiovascular risk so beused the new method is of high sensitivity C-reactive protein.The research have purpose to know the difference and relationship of waist to hip ratio and high sensitivity c-reactive protein level between obese and non-obese students at Medical Faculty of Sam Ratulangi University Manado. This research was an observational analytic cross-sectional approach. The results of statistical analysis using the Mann-Whitney U test revealed that there were significant differences (p = 0.000 <0.05) both WHR and hs-CRP level in both groups of students are. Conclusion: The results of statistical analysis using the Spearman test showed that there is a positive very weak relationship (r = 0309) and significant (p = 0017 <0.05) between the values of WHR with hs-CRP level in obese and non-obese students at Medical Faculty of Sam Ratulangi University Manado. Key Words: WHR, hs-CRP Abstrak: Obesitas sentral diakui sebagai factor utama yang dikaitkan dengan peningkatan resiko untuk beberapa penyakit kronis. Waist to hip ratio (WHR) menggambarkan peningkatan jaringan adiposa visceral dan lemak subkutan pada lingkar pinggang dan lingkar pinggul. C-reactive protein (CRP) merupakan deteksi risiko penyakit kardiovaskular tapi secara konvensional tidak cukup sensitif untuk mendeteksi risiko kardiovaskular sehingga digunakan metode baru yaitu high sensitivity C-reactive protein (hsCRP). Penelitian bertujuan untuk mengetahui perbedaan dan hubungan waist to hip ratio (WHR) dengan kadar high sensitivity c-reactive protein (hs-CRP) serum pada mahasiswa obes dan tidak-obes di Fakultas Kedokteran Universitas Sam Ratulangi Manado. Penelitian ini bersifat observasional analitik dengan menggunakan pendekatan cross-sectional. Hasil analisis statistic dengan menggunakan uji Mann-Whitney U menunjukan terdapat perbedaan yang bermakna (p=0.000<0.05) baik WHR maupun kadar hs-CRP serum pada kedua kelompok mahasiswa tersebut. Simpulan: Hasil analisis statistic dengan mengguna-kan uji Spearman menunjukan bahwa terdapat hubungan yang positif sangat lemah (r=0.309) dan bermakna (p=0.017<0.05) antara nilai WHR dengan kadar hs-CRP serum mahasiswa obes dan tidak-obes pada Fakultas Kedokteran Universitas Sam Ratulangi Manado. Kata Kunci: WHR, hs-CRP

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Coronary tortuosity is associated with an elevated high-sensitivity C-reactive protein concentration and increased risk of ischemic stroke in hypertensive patients

Journal of International Medical Research ◽

10.1177/0300060517748527 ◽

2018 ◽

Vol 46 (4) ◽

pp. 1579-1584 ◽

Cited By ~ 4

Author(s):

Yang Li ◽

Abdul Qadir Nawabi ◽

Yi Feng ◽

Genshan Ma ◽

Jiayi Tong ◽

...

Keyword(s):

Cerebrovascular Accident ◽

High Sensitivity ◽

Lacunar Infarction ◽

C Reactive Protein ◽

Hypertensive Patients ◽

Reactive Protein ◽

Increased Risk ◽

Hs Crp ◽

Coronary Tortuosity ◽

N 93

Objective The clinical implication of coronary tortuosity is unclear. The present study was conducted to determine the relationships between coronary tortuosity and the high-sensitivity C-reactive protein (hs-CRP) concentration and between coronary tortuosity and cerebrovascular accident in hypertensive patients without coronary artery disease. Methods In total, 236 patients with normal coronary angiography findings were categorized into 3 different groups: control participants (n = 58), who had neither hypertension nor coronary tortuosity; patients with hypertension but no coronary tortuosity (H-NCT group, n = 93); and patients with both hypertension and coronary tortuosity (H-CT group, n = 85). The hs-CRP concentration was measured in every patient, and 168 hypertensive patients were followed up for at least 2 years to check for the development of cerebrovascular accident. Results The hs-CRP concentration was significantly higher in the H-CT group than in the control and H-NCT groups (4.33 ± 3.15 vs. 1.52 ± 1.31 and 2.31 ± 2.09 mg/L, respectively). The incidence of lacunar infarction was higher in the H-CT than H-NCT group during the follow-up. Conclusions Hypertensive patients with coronary tortuosity have a higher serum hs-CRP level concentration and have a higher incidence of lacunar infarction than hypertensive patients without coronary tortuosity.

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Depression, inflammation and coronary heart disease: prognostical value of c reactive protein and depressive symptoms

European Psychiatry ◽

10.1016/s0924-9338(11)72318-5 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 611-611

Author(s):

A. Bruschi ◽

M. Mazza ◽

D. Harnic ◽

P. Grandinetti ◽

C. Battaglia ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Depressive Symptoms ◽

Statistical Significance ◽

High Sensitivity ◽

C Reactive Protein ◽

Cardiac Events ◽

Reactive Protein ◽

Increased Risk ◽

Hs Crp

IntroductionThe aim of this preliminary study is to assess, in a sample of patients with Coronary Heart Disease (CHD), the specific association between depressive symptoms and systemic inflammation.MethodsSixty-One inpatients with CHD, 31 Unstable Angina and 28 Myocardial Infarction, participated in the study. The plasma levels of C Reactive Protein were measured using Dade Behring’s High Sensitivity CRP assay (hs-CRP) at T0, T30 and T90.At the same timings, they were tested by an examiner, unaware of their diagnosis, with a psychometric battery (SCL90-R, HDRS, MADRS, BDI, QlesQ).ResultsThe elevation of hs-CRP occurs during the whole observation period, with maximum significance at T90 (p = 0,031).A multivariate analysis at T0 indicates a statistical correlation between SCL90-R scores and hs-CRP levels (p = 0.02).The SCL90-R is also associated with the risk of further cardiac events (p = 0.013).Also the BDI could be useful as a prognostic factor (p = 0.026).We found a trend towards correlation between CRP values and depressive symptoms, but it never reaches statistical significance for the other scales.ConclusionsThe feelings of loss and the fear of death, related to the environmental and emotional situation of the hospitalization, may prevail in the acute phase of CHDs.Some patients may overcome this reactive depression, while others may exhibit a biological depression, related to the high level of CRP and thus to an increased risk of re-infarction and other coronary events.

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Prospective Study of High-Sensitivity C-Reactive Protein as a Determinant of Mortality: Results from the MONICA/KORA Augsburg Cohort Study, 1984–1998

Clinical Chemistry ◽

10.1373/clinchem.2007.100271 ◽

2008 ◽

Vol 54 (2) ◽

pp. 335-342 ◽

Cited By ~ 105

Author(s):

Wolfgang Koenig ◽

Natalie Khuseyinova ◽

Jens Baumert ◽

Christa Meisinger

Keyword(s):

Chronic Diseases ◽

Cancer Mortality ◽

High Sensitivity ◽

Medical Attention ◽

C Reactive Protein ◽

Middle Aged ◽

Cox Regression Analysis ◽

Reactive Protein ◽

Risk Of Death ◽

Increased Risk

Abstract Background: C-reactive protein (CRP), an exquisitely sensitive systemic marker of inflammation, has emerged as an independent predictor of cardiovascular diseases (CVD). Because other chronic diseases are also associated with an inflammatory response, we sought to assess the association of high-sensitivity CRP (hsCRP) with total and cause-specific mortality in a large cohort of middle-aged men. Methods: We measured hsCRP at baseline in 3620 middle-aged men, randomly drawn from 3 samples of the general population in the Augsburg area (Southern 0Germany) in 1984–85, 1989–90, and 1994–95. Outcome was defined as all deaths, fatal CVD, fatal coronary heart disease (CHD) including sudden cardiac deaths, and cancer deaths. Results: During an average follow-up of 7.1 years, 408 deaths occurred (CVD 196, CHD 129, cancer 127). In multivariable Cox regression analysis, subjects with hsCRP >3 mg/L at baseline showed an almost 2-fold increased risk to die vs those with hsCRP <1 mg/L [hazard ratio (HR) 1.88, 95% CI 1.41–2.52]. HRs were 2.15 (95% CI 1.39–3.34) for fatal CVD, 1.74 (1.04–2.92) for fatal CHD, and 1.65 (1.01–2.68) for cancer mortality. In contrast, neither total nor HDL cholesterol significantly predicted all-cause or cancer mortality, and cholesterol had only modest effects on CVD mortality. Conclusions: Our results suggest that increased circulating hsCRP concentrations are associated with an increased risk of death from several widespread chronic diseases. Persistently increased hsCRP is a sensitive and valuable nonspecific indicator of an ongoing disease process that deserves serious and careful medical attention.

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