Higher Serum Amyloid A Research Articles

Association of serum amyloid A and prognosis in people with diabetes and COVID-19: A retrospective cohort study.

Serum amyloid A (SAA) is an acute phase reactive protein that plays a vital role in the early diagnosis, risk prediction, efficacy observation and prognosis evaluation of infectious diseases. This study aimed to assess the association between SAA levels and the prognosis of patients with coronavirus disease 2019 (COVID-19) and diabetes. We carried out this retrospective cohort study from March 2022 to May 2022. The population was stratified by tertiles of SAA levels: low (<8.5 mg/L), medium (8.5-36 mg/L) and high (>36 mg/L). The primary outcome was whether the patient developed severe COVID-19, and secondary outcomes included the need for invasive mechanical ventilation and length of hospital stay. Logistic regression analyses were carried out to identify risk factors affecting the prognosis of patients with COVID-19 and diabetes. We analyzed 910 diabetes patients with COVID-19. The median age of the patients was 69 years, and 52.3% were men. As SAA levels increased, the proportion of severe COVID-19 (6.3% vs 7.3% vs 22.8%, P < 0.001) and the proportion of invasive mechanical ventilation also increased among the three groups. Patients with high SAA levels had a longer length of hospital stay compared with patients with medium SAA and low SAA levels. Univariate logistic regression analysis showed that SAA >36 mg/L further increased the odds ratio to 4.423 (P < 0.001) for the development of severe COVID-19 compared with low SAA. Multivariate logistic regression analysis, adjusted for age and sex, confirmed that SAA >36 mg/L remained an independent risk factor for the development of severe COVID-19 (adjusted odds ratio 3.038, P < 0.001). SAA levels are strongly associated with poor prognosis in patients with COVID-19 and diabetes.

Association between Serum Amyloid A Levels and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

To date, consistent data have not been reported on the association between serum amyloid A (SAA) levels and type 2 diabetes mellitus (T2DM). The purpose of this study was to systematically summarize their relationship. Databases including PubMed, Cochrane Library, Embase, Web of Science, and MEDLINE were searched until August 2021. Cross-sectional and case-control studies were included. Twenty-one studies with 1,780 cases and 2,070 controls were identified. SAA levels were significantly higher in T2DM patients than in healthy groups (standardized mean difference [SMD], 0.68; 95% confidence interval [CI], 0.39 to 0.98). A subgroup analysis showed that the mean age of participants and the continent that participants were from were related to differences in SAA levels between cases and controls. Furthermore, in T2DM patients, SAA levels were positively associated with body mass index (r=0.34; 95% CI, 0.03 to 0.66), triglycerides (r=0.12; 95% CI, 0.01 to 0.24), fasting plasma glucose (r=0.26; 95% CI, 0.07 to 0.45), hemoglobin A1c (r=0.24; 95% CI, 0.16 to 0.33), homeostasis model assessment for insulin resistance (r=0.22; 95% CI, 0.10 to 0.34), C-reactive protein (r=0.77; 95% CI, 0.62 to 0.91), and interleukin-6 (r=0.42; 95% CI, 0.31 to 0.54), but negatively linked with highdensity lipoprotein cholesterol (r=-0.23; 95% CI, -0.44 to -0.03). The meta-analysis suggests that high SAA levels may be associated with the presence of T2DM, as well as lipid metabolism homeostasis and the inflammatory response.

Serum amyloid A augments the atherogenic effects of cholesteryl ester transfer protein

Serum amyloid A (SAA) is predictive of CVD in humans and causes atherosclerosis in mice. SAA has many proatherogenic effects in vitro. However, HDL, the major carrier of SAA in the circulation, masks these effects. The remodeling of HDL by cholesteryl ester transfer protein (CETP) liberates SAA restoring its proinflammatory activity. Here, we investigated whether deficiency of SAA suppresses the previously described proatherogenic effect of CETP. ApoE−/− mice and apoE−/− mice deficient in the three acute-phase isoforms of SAA (SAA1.1, SAA2.1, and SAA3; “apoE−/− SAA-TKO”) with and without adeno-associated virus-mediated expression of CETP were studied. There was no effect of CETP expression or SAA genotype on plasma lipids or inflammatory markers. Atherosclerotic lesion area in the aortic arch of apoE−/− mice was 5.9 ± 1.2%; CETP expression significantly increased atherosclerosis in apoE−/− mice (13.1 ± 2.2%). However, atherosclerotic lesion area in the aortic arch of apoE−/− SAA-TKO mice (5.1 ± 1.1%) was not significantly increased by CETP expression (6.2 ± 0.9%). The increased atherosclerosis in apoE−/− mice expressing CETP was associated with markedly increased SAA immunostaining in aortic root sections. Thus, SAA augments the atherogenic effects of CETP, which suggests that inhibiting CETP may be of particular benefit in patients with high SAA.

Larval cyathostominosis: Clinicopathological data and treatment outcomes of 38 hospitalised horses (2009–2020)

SummaryBackgroundThere is limited evidence regarding the treatment and outcomes of larval cyathostominosis.ObjectivesTo describe the presentation, treatment and outcomes of horses with larval cyathostominosis in two equine hospitals.Study designRetrospective, multicentred cohort study.MethodsClinical records were reviewed (2009–2020). Inclusion criteria included a diagnosis of larval cyathostominosis (determined by faecal assessment and/or post‐mortem examination). Data were assessed for normality. Descriptive analysis was performed for frequency results and central tendencies. Statistical analysis between survivors and nonsurvivors was determined by Chi‐square/Fisher's exact test for categorical variables, and Student's t‐test/Mann–Whitney for continuous variables.ResultsOf 38 cases, 21 (55%) were nonsurvivors (3/38 dead on arrival). Nonsurvivors died by 2.9 days ± 2.4. Tachycardia (mean 61 beats/min ± 14), leucocytosis (mean 17.1 × 109/L ± 9.1), neutrophilia (mean 14.1 × 109/L ± 8.5), hypoalbuminaemia (mean 21.6 g/L ± 6.0), hyperfibrinogenaemia (mean 7.4 g/L ± 2.6) and elevated serum amyloid A (SAA) (median 315.0 mg/L, interquartile range [IQR] 117.0–1460.0) were consistent findings. Faecal shedding of Salmonella spp. occurred in four cases. The mean last recorded albumin was 18.6 g/L ± 4.5 and total protein (TP) 52.3 g/L ± 13.6. Crystalloids were administered in 25/35, synthetic colloids in 5/35 and plasma in 17/35 cases. Anthelmintic treatment was administered in 25/35 cases, of which 22 also received corticosteroids. Recumbency prior to admission (p = 0.037) and administration of isotonic fluid therapy (p = 0.027) were associated with nonsurvival. From peripheral blood analysis, lower TP (p = 0.006) and higher SAA (p = 0.050) concentrations at admission as well as lower last recorded TP (p = 0.002) and lower last recorded albumin concentrations (p = 0.028) were associated with nonsurvival.Main limitationsResults may not be applicable to other populations.ConclusionsReferred cases of larval cyathostominosis have a low survival rate. Several variables are associated with reduced survival: history of recumbency, isotonic fluid therapy, elevated SAA at admission, low TP at admission, low last recorded TP and low last recorded albumin.

Serum Amyloid a Predicts Prognosis and Chemotherapy Efficacy in Patients with Advanced Pancreatic Cancer.

There is an urgent need to discover a predictive biomarker to help patients with advanced pancreatic cancer (APC) choose appropriate chemotherapy regimens. This study aimed to determine whether baseline serum amyloid A (SAA) levels were associated with overall survival (OS), progression-free survival (PFS), and treatment response in patients with APC received chemotherapy. This retrospective study included 268 patients with APC who received first-line chemotherapy at the Sun Yat-Sen University Cancer Center between January 2017 and December 2021. We examined the effect of baseline SAA on OS, PFS and chemotherapy response. The X-Tile program was used to determine the critical value for optimizing the significance of segmentation between Kaplan-Meier survival curves. The Kaplan-Meier curves and Cox regression analyses were used to analyze OS and PFS. The best cut-off value of baseline SAA levels for OS stratification was 8.2 mg/L. Multivariate analyses showed that SAA was an independent predictor of OS (Hazard Ratio (HR) = 1.694, 95% Confidence Interval (CI) = 1.247-2.301, p = 0.001) and PFS (HR = 1.555, 95% CI = 1.152-2.098, p = 0.004). Low SAA was associated with longer OS (median, 15.7 months vs 10.0 months, p < 0.001) and PFS (median, 7.6 months vs 4.8 months, p < 0.001). The patients with a low SAA who received mFOLFIRINOX had longer OS (median, 28.5 months vs 15.1 months, p = 0.019) and PFS (median, 12.0 months vs 7.4 months, p = 0.035) than those who received nab-paclitaxel plus gemcitabine (AG) or SOXIRI, whereas there was no significant difference among the three chemotherapy regimens in patients with a high SAA. Owing to the rapid and simple analysis of peripheral blood, baseline SAA might be a useful clinical biomarker, not only as a prognostic biomarker for patients with APC, but also as a guide for the selection of chemotherapy regimens.

Genetic and Epigenetic Regulation of MEFV Gene and Their Impact on Clinical Outcome in Auto-Inflammatory Familial Mediterranean Fever Patients.

Epigenetic modifications play a pivotal role in autoimmune/inflammatory disorders and could establish a bridge between personalized medicine and disease epidemiological contexts. We sought to investigate the role of epigenetic modifications beside genetic alterations in the MEFV gene in familial Mediterranean fever (FMF). The study comprised 63 FMF patients diagnosed according to the Tel Hashomer criteria: 37 (58.7%) colchicine-responders, 26 (41.3%) non-responders, and 19 matched healthy controls. MEFV mutations were detected using a CE/IVD-labeled 4-230 FMF strip assay. DNA methylation of MEFV gene exon 2 was measured using bisulfite modification and related to pyrin level, phenotypic picture, MEFV mutations, disease severity, serum amyloid A (SAA), CRP, ESR, disease severity, and colchicine response. Our results showed that FMF patients exhibited significantly higher methylation percentage (p < 0.001) and lower pyrin levels (p < 0.001) compared to the control. The MEFV gene M694I mutation was the most commonly reported mutation (p < 0.004). High methylation percentage of the MEFV exon 2 and low pyrin concentration were correlated with disease severity, high SAA, ESR levels, H-pylori, and renal calculi. In conclusion, this study highlights the relation between high methylation percentage, reduced pyrin level, and different biomarkers in FMF, which underscores their role in the pathogenesis of FMF and could be considered as potential therapeutic targets.

Clinical performance evaluation of serum amyloid A module of Mindray BC-7500CS automated hematology analyzer.

Laboratory detection of high values of serum amyloid A (SAA) is impaired by the hook effect. In response to this problem, Mindray has launched the new generation BC-7500CS automated hematology analyzer with an SAA autodilution (SAA-D) function. The present study aimed to verify the performance of the SAA module. Venous whole-blood specimens anticoagulated with EDTA-K2 were randomly collected from outpatients and inpatient of the Children's Hospital of Nanjing Medical University (CH). Background, repeatability, precision, linear range, intermode comparison, and interference of the SAA module of the Mindray BC-7500CS were evaluated, and the performance of the SAA-D function was verified. The Mindray BC-7500CS showed an SAA background of 0.14 mg/L, well below that claimed by the manufacturer. Repeatability of SAA with standard deviation (SD) <0.6 mg/L and coefficient of variation (CV) <6%, the quality control (QC) precision was less than 8%. The measured value of the linear range was essentially consistent with the theoretical value, and the maximum measured values could reach 1932.38 mg/L. The deviation between whole-blood mode and micro-whole-blood mode was small (r=0.999), and the SAA module displayed high anti-interference ability. In addition, the measured results of specimens with high SAA concentration diluted by SAA-D were close to those after manual dilution (r=0.993). The SAA module of the Mindray BC-7500CS had excellent performance, and the SAA-D function was highly accurate at measuring specimens with high SAA concentration, enabling reliable SAA detection in the laboratory and clinical practice.

The Association Between Inflammatory Biomarkers and Vitamin D Level With the Evolution and Severity of Stroke.

Vitamin D deficiency has been linked to the evolution of ischemic stroke, but the data regarding the association between stroke severity and vitamin D level is scarce. Patients with first-ever ischemic stroke in the middle cerebral artery territory, within seven days after the stroke, were recruited. The control group included age- and gender-matched individuals. We compared 25-OH vitamin D (vitamin D), high sensitive C-reactive protein (hsCRP), serum amyloid A (SAA), and osteopontin levels between stroke patients and the control group. The association between stroke severity according to the National Institutes of Health Stroke Scale (NIHSS) and the Alberta stroke program early CT score (ASPECTS) and levels of vitamin D and inflammatory biomarkers were also studied. There was an association between hypertension (P=0.035), diabetes mellitus (P=0.043), smoking (P=0.016), history of ischemic heart disease (P=0.002), higher SAA (P<0.001), higher hsCRP (P<0.001), and lower vitamin D levels (P=0.002) and stroke evolution in a case-control study. Meanwhile, in stroke patients, its severity was associated with higher SAA (P=0.04) and hsCRP (P=0.001), and lower vitamin D levels (P=0.043) according to clinical scale (higher admission NIHSS). According to the ASPECT score, higher SAA (P=0.017) and hsCRP (P=0.007), but not lower vitamin D levels, were associated with more infarct areas (P=0.149). Vitamin D may play a role in both the evolution and severity of stroke.

Investigation of two different human d-dimer assays in the horse

BackgroundD-dimer has value as a marker of thrombosis in critically ill horses and can provide additional information about prognosis. However, there are currently no equine species-specific d-dimer assays available, nor has there been any formal investigation of the applicability of human d-dimer assays in horses, so it is unknown, which assay performs best in this species. The aim of this study was therefore to evaluate and compare two human d-dimer assays for their applicability in horses.The study included four groups of horses: clinically healthy horses, horses with gastrointestinal (GI) disease and mild systemic inflammation based on low serum amyloid A (SAA) (low SAA group), horses with GI disease and strong systemic inflammation based on high SAA (high SAA group) and, horses with thrombotic GI disease caused by Strongylus vulgaris (also called non-strangulating intestinal infarction (NSII)) (NSII group). The assays evaluated were the STAGO STA-Liatest D-di + (Stago) and NycoCard™ D-dimer (NycoCard). Intra- and inter-coefficients of variation (CV) were assessed on two d-dimer concentrations, and linearity under dilution was evaluated. A group comparison was performed for both assays across the four groups of horses. A Spaghetti plot, Spearman Correlation, Passing Bablok regression and Bland–Altman plot were used to compare methods in terms of agreement.ResultsTen horses were included in the clinically healthy group, eight in the low SAA group, eight in the high SAA group, and seven in the NSII group. For the Stago assay, intra- and inter-CVs were below the accepted level except for one inter-CV. The NycoCard assay did not meet the accepted level for any of the CVs. The linearity under dilution was acceptable for both the Stago and NycoCard. In the group comparison, both methods detected a significantly higher d-dimer concentration in the high SAA and NSII groups compared to the clinically healthy group. Method agreement showed slightly higher d-dimer concentrations with NycoCard compared to Stago. The overall agreement was stronger for the lower d-dimer concentrations.ConclusionBoth the Stago and the NycoCard were found to be applicable for use in horses but were not directly comparable.

Inflammatory, degeneration and neuritic growth biomarkers predict cognitive decline and dementia in Parkinson’s disease

AbstractBackgroundCognitive decline is common in Parkinson’s disease (PD) and has been associated with cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers such as Aβ1‐42, total tau and phosphorylated tau in addition to inflammatory proteins. VGF, a nerve growth factor, is a promising marker that has recently been implicated in cognitive decline in dementia with Lewy bodies and could potentially play a role in PD. The aim of this study is to assess a wide panel of CSF biomarkers reflecting different neuropathological processes to determine which best predict cognitive decline and conversion to dementia in PD.MethodWe included 174 PD patients from the Swedish BioFINDER study, who were followed for up to 10 years. At baseline, 47 CSF biomarkers were measured, including Aβ1‐42, Aβ42/40, total tau, phosphorylated tau, α‐synuclein as well as markers of neurodegeneration, vascular, inflammatory, synaptic and lysosomal dysfunction. Cox regression analyses were applied to identify biomarkers predicting dementia, adjusting for age, sex, education and disease duration. We then used linear mixed effects models to assess whether the significant biomarkers predicted longitudinal cognitive decline in MMSE, memory and semantic fluency, controlling for age, sex, education and disease duration.ResultOf the PD patients, 29% converted to dementia during follow‐up (4.9 ± 2.2 years). At baseline, converters were older (p&lt;0.001) and had worse memory and semantic fluency tests (&lt;0.008) compared with non‐converters. Levels of CSF Aβ1‐42, Aβ42/40, tau, Neurofilament light, Serum Amyloid A (SAA), Interleukin 7, Interferon‐gamma‐inducible Protein‐10 (IP‐10) and VGF (p&lt;0.037) significantly predicted conversion to dementia in univariate models. When these biomarkers were included in a multivariable regression model, only higher tau (p&lt;0.001), lower VFG (p&lt;0.001) and higher SAA (p=0.028) independently predicted dementia. Further, CSF tau predicted cognitive decline in MMSE and semantic fluency (p&lt;0.005), lower VGF predicted decline in memory (0.012) and SAA predicted decline in MMSE (p=0.011).ConclusionThese findings suggest that CSF tau, SAA and VGF are useful markers to predict conversion to dementia and cognitive decline in PD. VGF is emerging as an additional prognostic biomarker for cognitive decline in PD.

Serum amyloid A levels and alpha 2 and gamma globulins on serum protein electrophoresis in cats exposed to and infected with Leishmania infantum

BackgroundDogs are the main reservoir hosts of Leishmania infantum; nevertheless, recent investigations indicate a likely role for cats in the epidemiology of Leishmania infection. Feline leishmaniosis (FeL) remains poorly characterised, partly due to the lack of suitable diagnostic tools. This study aimed to compare serum amyloid A (SAA) levels and serum protein electrophoresis (SPE) profiles (specifically, alpha 2 and gamma globulins) in cats naturally exposed to or infected by L. infantum from southern Italy versus those of healthy controls and versus cats with neoplastic or inflammatory conditions from non-endemic areas.MethodsSerum or plasma samples from four cohorts of cats were analysed for SAA levels and by SPE: (i) G1: healthy controls from Leishmania-non-endemic regions of Switzerland; (ii) G2: cats pre-diagnosed with neoplastic or inflammatory conditions available from the University of Cambridge sample archive; (iii) G3: L. infantum-seropositive, quantitative (q)PCR-negative cats from southern Italy; (iv) G4: L. infantum-seropositive and qPCR-positive cats from southern Italy. SAA data were assessed for normality and homoscedasticity using the Shapiro–Wilk and Levene’s tests, respectively; the Kruskall–Wallis test, followed by Dunn’s test with Bonferroni correction were subsequently used to compare SAA serum levels between groups. A weighted generalised linear model with a binomial distribution was used to assess statistically significant differences in the numbers of animals displaying elevated gamma globulins and increased alpha 2 globulins between groups.ResultsOverall, 68 samples were analysed (G1: n = 16, G2: n = 20, G3: n = 20, G4: n = 12). Cats suffering from neoplastic and inflammatory conditions (G2 ) showed significantly higher SAA levels than healthy controls (G1) (median values [interquartile range]: G1: 0.00 [0.00–0.00] mg/l versus G2: 0.85 [0.00–49.55] mg/l). G2, G3 and G4 cats showed higher percentages of individuals with increased alpha 2 globulins (percentages ± standard error: G1 = 20.0% ± 10.3, G2 = 80.0% ± 8.9, G3 = 70.0% ± 10.2, G4 = 75.0% ± 12.5) and gamma globulins (G1 = 0.0% ± 0, G2 = 65.0% ± 10.7, G3 = 50.0% ± 11.2, G4 = 58.3% ± 14.2) than healthy control cats (G1). For all three markers, no significant difference between cats within G2, G3 and G4 was recorded.ConclusionsThis study indicates that the proportions of animals with elevated levels of alpha 2 and gamma globulins are significantly higher in cats exposed to and infected with L. infantum. Levels of SAA and alpha 2 and gamma globulins may not be used to differentiate between L. infantum infection or exposure, and neoplastic and/or inflammatory conditions.Graphical

Sex dimorphism in inflammatory response to obesity in childhood

BackgroundChildhood overweight and obesity are a global concern, with prevalence rising dramatically over the last decades. The condition is caused by an increase in energy intake and reduction of physical activity, leading to excessive fat accumulation, followed by systemic chronic inflammation and altered function of immune cell responses. This study aimed at providing new insights regarding sex-specificity on the inflammatory response to obesity in the young patient.DesignForty-three Brazilian obese adolescents (Female = 22 and Male=21, BMI (body mass index) Z-score average = 2.78 ± 0.51) and forty-nine eutrophic adolescents (Female = 24 and Male = 25, BMI Z-score average = −0.35 ± 0.88) were enrolled in the study. Anthropometrical analyses and blood cell counts were carried out. Using Luminex®xMAP™ technology, circulating serum cytokines, chemokines, and inflammatory biomarkers were analyzed. Two-way ANOVA test, Tukey’s test, and Spearman’s correlation coefficient were employed, with a significance threshold set at p < 0.05.ResultsWe identified increased levels of serum amyloid A (SAA), platelets, and leukocytes solely in male obese patients. We found a noteworthy sex-dependent pattern in regard to inflammatory response: obese boys showed higher TNFβ, IL15, and IL2 and lower IL10 and IL13, while obese girls showed increased TNFα, CCL3, CCL4, and IP10 content in the circulation. BMI Z-score was significantly linearly correlated with neutrophils, leukocytes, platelets, SAA, TNFα, CCL3, CCL4, IP10, and IL13 levels within the entire cohort (non-sex-dependent).ConclusionsOur data support a complex relationship between adiposity, blood cell count, and circulating inflammatory cytokine content. High SAA levels suggest that this factor may play a critical role in local and systemic inflammation. In the eutrophic group, females presented a lower status of inflammation, as compared to males. Both obese boys and girls showed an increased inflammatory response in relation to eutrophic counterparts. Taken together, results point out to clear sex dimorphism in the inflammatory profile of obese adolescents.

Kinetics of serum amyloid A during the treatment period of foals with pneumonia

The ultrasonographic examination of foals with pneumonia has been proven successful in monitoring the course of the disease during treatment. However, the question arises whether another parameter, such as the acute phase protein serum amyloid A (SAA), could also be suitable for evaluating the response to treatment, the course during treatment or the decision to terminate the treatment in foals with pneumonia. The course of moderate or severe pneumonia was recorded by several diagnostic tests in a prospective study performed on 52 foals. Clinical and ultrasonographical examination of the thorax and blood values (SAA, white blood cell count) of these foals were measured on the day of diagnosis and weekly during treatment. Foals with a pulmonary abscess score of 15–19.5 cm determined by sonography of the thorax (moderate pneumonia) were assigned to group 1 (n = 31) and received a treatment with rifampin and tulathromycin. If the abscess score was > 20 cm (severe pneumonia), the foals were included in group 2 (n = 21) and were treated with rifampin and azithromycin. All foals recovered during the treatment period. Sonography of the thorax of the foals with moderate pneumonia (group 1) showed no more pathologic findings after ten days, and the foals with severe pneumonia (group 2) after eleven days of treatment. At diagnosis the median SAA value at diagnosis was 367 mg/L (median; 25th/75th: 23–937) in foals with moderate pneumonia and 216 mg/L (median; 25th/75th: 16–690) in those with severe pneumonia. The SAA values of foals with initially elevated values decreased significantly until they reached normal values < 40 mg/L after five days in the foals with moderate pneumonia and four days in the those with severe pneumonia. The time between the day SAA reached normal values and ultrasonography of the lung revealed no more abnormalities was three days in foals with moderate pneumonia and seven days in those with severe pneumonia. The SAA as a diagnostic method had a sensitivity of 68 % in the case of moderate pneumonia and 71 % in the case of severe pneumonia on the day of diagnosis. If only the foals with pneumonia and fever were considered, 91 % showed an initially increased SAA. During treatment, the SAA correlated with the abscess score, the clinical score and the age at diagnosis, but not with the number of white blood cells. In conclusion, the ultrasonographic examination remains the most precise tool to diagnose pneumonia and follow its progress during treatment in foals. However, the SAA can be used as an additional parameter for evaluating the treatment success. Especially foals with fever and younger foals show high SAA values in patients with pneumonia. By observing the kinetics of SAA in a patient, this blood parameter could be a support to adjust the date of the final ultrasonographic examination. Thereby, the duration of treatment can be individually adapted.

Clinical analysis of risk factors for severe COVID-19 patients with type 2 diabetes

AimsTo describe characteristics of COVID-19 patients with type 2 diabetes and to analyze risk factors for severity. MethodsDemographics, comorbidities, symptoms, laboratory findings, treatments and outcomes of COVID-19 patients with diabetes were collected and analyzed. ResultsSeventy-fourCOVID-19 patients with diabetes were included. Twenty-seven patients (36.5%) were severe and 10 patients (13.5%) died. Higher levels of blood glucose, serum amyloid A (SAA), C reactive protein and interleukin 6 were associated with severe patients compared to non-severe ones (P<0.05). Levels of albumin, cholesterol, high density lipoprotein, small and dense low density lipoprotein and CD4+T lymphocyte counts in severe patients were lower than those in non-severe patients (P<0.05). Logistic regression analysis identified decreased CD4+T lymphocyte counts (odds ratio [OR]=0.988, 95%Confidence interval [95%CI] 0.979–0.997) and increased SAA levels (OR=1.029, 95%CI 1.002–1.058) as risk factors for severity of COVID-19 with diabetes (P<0.05). ConclusionsType 2 diabetic patients were more susceptible to COVID-19 than overall population, which might be associated with hyperglycemia and dyslipidemia. Aggressive treatment should be suggested, especially when these patients had low CD4+T lymphocyte counts and high SAA levels.

Hematologic, prostaglandin F2α -metabolite, serum amyloid A, and serum iron changes in horses with experimentally induced endotoxemia.

Endotoxemia is a common and severe disease of horses. Most previous studies have monitored changes caused by a bolus dose of endotoxin over short time periods. We aimed to describe inflammatory responses to endotoxin with inflammatory and hematologic markers monitored over a longer time than has been performed in the past using more prolonged endotoxin exposures. Escherichia coli O55:B5 endotoxin was administered as a 6-hour continuous intravenous infusion of lipopolysaccharide (LPS) to eight horses. Blood cell counts, and prostaglandin F2α -metabolite (PGM), serum amyloid A (SAA), and serum total iron concentrations were monitored for up to 3 or 6days. An immediate and severe decrease in neutrophils and monocytes occurred in all horses, which subsequently changed to a moderate to strong neutrophilia and monocytosis that persisted for more than 78hours postinfusion (PI) of LPS. Lymphocyte and eosinophil numbers decreased gradually and then normalized after 66- and 78-hours PI, respectively. Mild to moderate, biphasic thrombocytopenia occurred. A pronounced, transient increase in PGM occurred between 1 and 7hours, peaking at 2hours. Serum amyloid A began to increase after 6hours PI and remained elevated after 72hours PI. Serum iron was decreased between 6 and 48hours. The clinical signs were most prominent during the first 24hours PI and subsided within 48hours PI. Neutrophilia, monocytoses, and high SAA concentrations were present in horses even after the clinical signs had subsided. Serum iron normalized before SAA. Knowledge of these findings is imperative when interpreting laboratory results in horses with possible endotoxin exposure.

A Clinical Investigation on Serum Amyloid A Concentration in Client-Owned Healthy and Diseased Cats in a Primary Care Animal Hospital.

Although measurement of serum amyloid A (SAA) concentration in client-owned cats has already been shown to be clinically useful, limited data are available on common diseases at primary care hospitals. In this study, we measured the SAA concentration in cats with various diseases and investigated their clinical significance using a primary care hospital as a population. We measured the SAA concentrations in healthy cats (n = 98) and those with various clinical signs (n = 444). The SAA concentrations in healthy cats did not differ significantly by age, breed, sex, and presence/absence of neutering/spaying. The SAA concentrations were significantly higher in the diseased cat group than in the healthy cat group (p < 0.001). We observed significant increases in SAA concentrations in cats with confirmed diagnosis of inflammatory disease such as upper respiratory tract infections (p < 0.001), pneumonia (p < 0.001), pyometra (p = 0.001), and feline infectious peritonitis (p < 0.001), compared with those observed in healthy cats. Conversely, no increase was observed in cardiomyopathy, hyperthyroidism, and diabetes mellitus without systemic inflammation. In univariate analysis, survival at 30 days (p = 0.03) differed significantly between the low and high SAA concentration groups, but not at 180 days. In multivariate analysis, survival at 30 days did not significantly affect SAA concentration. Measurement of SAA concentration is a useful biomarker for detecting the presence or absence of inflammation in diseased cats. However, it may not be useful as a biomarker for determining the prognosis of the disease.

P1.01-69 Blood Serum Amyloid A as Potential Predictor of Response to First-Line Pembrolizumab in Patients with Advanced Non-Small-Cell Lung Cancer

The selection of patients (pts) deriving clinical benefit from immune checkpoint agents represents the modern challenge for clinicians. Tumor-derived Serum Amyloid A (SAA) inhibits the immune response through the expansion of IL-10-secreting neutrophils in pts with melanoma. We investigated the predictive value of blood SAA monitoring in a cohort of Advanced Non-Small-Cell Lung Cancer (ANSCLC) pts receiving up-front Pembrolizumab (P). Pts with ANSCLC (PD-L1≥50%) receiving upfront P, were prospectively evaluated for blood SAA and radiological response at baseline and every 9 weeks during the treatment. The primary endpoint was response rate (RR) according Immune-related Response Evaluation Criteria in Solid Tumors (IrRECIST); the secondary endpoints were progression-free survival (PFS) and overall survival (OS). The most accurate SAA cut-off to predict response was established with a ROC-analysis. Forty-two patients were enrolled. Pts characteristics: male/female (71/29%), number of sites 1/2/3/≥ 4 (5/38/40/17%), ECOG PS 0/≥ 1 (38/62%); never or former/current smokers (12/78%); median age 70.5 (range 35-86) years. The overall RR was 38% (95%CI 25-53%). After a median follow-up of 13.5 months (m), baseline SAA ≤ the ROC-derived cut-off (29.9 mg/L, AUC 0.74, 95% CI 0.59-0.87, p=0.002; 14 [33%] pts) was significantly associated with a higher RR (53.6vs 7.1%, OR 15, 95% CI 1.72-130.7, p<0.01), longer PFS (17.4 vs 2.1 m, HR 0.18, 95%CI 0.06-0.51, p<0.0001) and OS (not reached [NR]vs7.2 m, HR 0.08, 95%CI 0.02-0.39, p<0.0001) compared with SAA >29.9 mg/L. Multivariate analysis confirmed pre-treatment low SAA as independent predictor of longer PFS (p=0.029) and OS (p=0.018). Considering SAA at baseline and the dynamic monitoring (pts=40), the median PFS was 17.4 m (95% CI 10.7-14.7) when SAA remained low (n=14) compared with 2.1 m (95%CI 1.3-5.6) when SAA remained high (n=12) (p<0.0001).The SAA monitoring was also significantly associated with OS (p=0.0002), with a median OS of 7.2 m (95% CI 5.6-13.4) in pts maintaining high SAA versus NR median at 18-m for pts with SAA remained low or changed. No deaths occurred in the permanently low-SAA group at the current data-lock. Baseline low SAA predicts good outcomes of 1stline P and the SAA monitoring throught simple blood test could help to easily identify patients who derived the greatest benefit from immunotherapy. The strong relationship with RR and the known immunosuppressive activity support a potential predictive value of this serum marker. A multi-institutional validation set is currently ongoing to confirm the role of SAA in this setting.

The Value of Serum Amyloid A Levels in Familial Mediterranean Fever to Identify Occult Inflammation During Asymptomatic Periods.

The aim of this observational study was to evaluate whether there was any correlation between the acute phase reactants in children with familial Mediterranean fever (FMF) during attack and attack-free periods. The study was conducted between June 2016 and January 2018. Clinical features and laboratory parameters of children with FMF during attack and attack-free periods were recorded longitudinally. The cohort consisted of 168 children with FMF (84 boys, 84 girls). Median values of acute phase reactants during FMF attacks were 433.5 mg/L (34.0-1780.0 mg/L) for serum amyloid A (SAA), 56.7 mg/L (7.6-379.0 mg/L) for C-reactive protein (CRP), and 37.5 mm/h (5-100 mm/h) for erythrocyte sedimentation rate (ESR). Median values for the same tests in attack-free periods were 3.2 mg/L (0.1-25.0 mg/L), 1.7 mg/L (0.1-12.7 mg/L), and 8 mm/h (1-30 mm/h), respectively. Correlation analyses showed that SAA and CRP were highly correlated in FMF attack (r = 0.67, p < 0.01), but no correlation was found between SAA and ESR levels. C-reactive protein was elevated in 13.6%, ESR in 20.8%, and SAA in 28.5% of the patients during attack-free period. Age at onset, sex of the patients, and characteristics of attacks were found to be not associated with elevated SAA in attack-free period. On the other hand, having homozygous exon 10 mutation and having elevated CRP were found to be associated with high SAA in attack-free period. C-reactive protein and SAA correlate well with FMF attacks. Therefore, checking for SAA during a FMF attack is not required. However, SAA seems to be the most sensitive method for demonstrating subclinical inflammation in attack-free period. Thus, checking SAA levels might be a valuable tool in selected FMF patients.

Diagnostic Criteria for Obesity Disease in Cats.

Accumulated visceral and subcutaneous fat masses were measured with computed tomography (CT) in cats with various body condition scores (BCS) from 5/9 to 9/9. BCS does not always reflect visceral fat accumulation which induces pro-inflammatory reactions. Obese cats with accumulated visceral fat showed low plasma adiponectin and high serum amyloid A (SAA) concentrations, an inflammatory marker. Based on the above results, new diagnostic criteria for obesity disease were established as follows. For overweight cats with high BCS of >7/9, showing two or more of the following three symptoms, low adiponectin concentrations, hyperlipidemia, and high SAA concentrations, categorizes them as having obesity disease. Cats with BCS 6/9–9/9, without inflammatory reactions, were classified as simple obesity, which is similar to metabolically healthy obesity (MHO) defined in human medicine. Simple obesity group showed significantly higher adiponectin concentrations than those in control group. The obesity disease group showed significantly higher plasma triglyceride (TG) and SAA concentrations and lower concentrations of adiponectin than the control group. Moreover, plasma glucose and malondialdehyde (MDA) concentrations in the obesity disease group were higher than those in healthy control group, although the differences were not statistically significant. Establishing criteria for obesity disease based on visceral fat accumulation and inflammation markers levels contributes to early and correct diagnosis of obesity in cats.

Dysfunctional high-density lipoprotein activates toll-like receptors via serum amyloid A in vascular smooth muscle cells

Serum amyloid A (SAA) is an uremic toxin and acute phase protein. It accumulates under inflammatory conditions associated with high cardiovascular morbidity and mortality in patients with sepsis or end-stage renal disease (ESRD). SAA is an apolipoprotein of the high-density lipoprotein (HDL). SAA accumulation turns HDL from an anti-inflammatory to a pro-inflammatory particle. SAA activates monocyte chemoattractant protein-1 (MCP-1) in vascular smooth muscle cells. However, the SAA receptor-mediated signaling pathway in vascular cells is poorly understood. Therefore, the SAA-mediated signaling pathway for MCP-1 production was investigated in this study. The SAA-induced MCP-1 production is dependent on the activation of TLR2 and TLR4 as determined by studies with specific receptor antagonists and agonists or siRNA approach. Experiments were confirmed in tissues from TLR2 knockout, TLR4 deficient and TLR2 knock-out/TLR4 deficient mice. The intracellular signaling pathway is IκBα and subsequently NFκB dependent. The MCP-1 production induced by SAA-enriched HDL and HDL isolated from septic patients with high SAA content is also TLR2 and TLR4 dependent. Taken together, the TLR2 and TLR4 receptors are functional SAA receptors mediating MCP-1 release. Furthermore, the TLR2 and TLR4 are receptors for dysfunctional HDL. These results give a further inside in SAA as uremic toxin involved in uremia-related pro-inflammatory response in the vascular wall.