Amniotic fluid cathelicidin in PPROM pregnancies: from proteomic discovery to assessing its potential in inflammatory complications diagnosis

Background

Preterm prelabor rupture of membranes (PPROM) complicated by microbial invasion of the amniotic cavity (MIAC) leading to histological chorioamnionitis (HCA) significantly impacts perinatal morbidity. Unfortunately, no well-established tool for identifying PPROM patients threatened by these disorders is available.

Methodology/Principal Findings

We performed an unbiased exploratory analysis of amniotic fluid proteome changes due to MIAC and HCA. From among the top five proteins that showed the most profound and significant change, we sought to confirm results concerning cathelicidin ({"type":"entrez-protein","attrs":{"text":"P49913","term_id":"1706745","term_text":"P49913"}}P49913, CAMP_HUMAN), since an ELISA kit was readily available for this protein. In our exploratory proteomic study, cathelicidin showed a ∼6-fold higher concentration in PPROM patients with confirmed MIAC and HCA. We verified significantly higher levels of cathelicidin in exploratory samples (women without both MIAC and HCA: median 1.4 ng/ml; women with both conditions confirmed: median 3.6 ng/ml; p = 0.0003). A prospective replication cohort was used for independent validation and for assessment of cathelicidin potential to stratify women with MIAC leading to HCA from women in whom at least one of these conditions was ruled out. We confirmed the association of higher amniotic fluid cathelicidin levels with MIAC leading to HCA (the presence of both MIAC and HCA: median 3.1 ng/ml; other women: median 1.4 ng/ml; p<0.0001). A cathelicidin concentration of 4.0 ng/ml was found to be the best cut-off point for identifying PPROM women with both MIAC and HCA. When tested on the validation cohort, a sensitivity of 48%, a specificity of 90%, a likelihood ratio of 5.0, and an area under receiver-operating characteristic curve of 71% were achieved for identification of women with MIAC leading to HCA.

Conclusions

Our multi-stage study suggests cathelicidin as a candidate marker that should be considered for a panel of amniotic fluid proteins permitting identification of PPROM women with MIAC leading to HCA.     

Intra-amniotic inflammatory response in subgroups of women with preterm prelabor rupture of the membranes

Background

To evaluate the influence of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) on the magnitude of intra-amniotic inflammatory response in preterm prelabor rupture of membranes (PPROM).

Methodology/Principal Finding

A prospective cohort study was performed in 107 women with PPROM between 23.0 and 36.6 weeks of gestational age. Twenty-six proteins were assayed by multiple immunoassay in amniotic fluid. The policy for PPROM in Czech Republic is active, and 90% of the women were delivered within 96 hours of membrane rupture. Histopathological placental findings were evaluated based on the Salafia classification. Data were analyzed in four subgroups of population according to the presence of MIAC and/or HCA. Results were stratified by gestational age at PPROM (< or ≥34.0 weeks). The rates of MIAC and HCA were 44% and 57%, respectively. Regardless of gestational age at PPROM, intra-amniotic inflammatory response was higher when MIAC and HCA were both present. There were no differences in the intra-amniotic inflammatory response between women with MIAC or HCA alone and women without infection.

Conclusion

A higher intra-amniotic inflammatory response was identified when both HCA and MIAC were detected.     

Systemic and Local Inflammatory Response in Women with Preterm Prelabor Rupture of Membranes

Objective

To evaluate the inflammatory pattern in maternal circulation, amniotic cavity, cervix and vagina from women with preterm prelabor rupture of membranes (PPROM) considering the occurrence of microbial invasion of the amniotic cavity (MIAC).

Methodology

A prospective study was performed in 58 women with PPROM before 34+0 weeks of gestational age. Twenty-six proteins were analyzed by a multiple immunoassay in samples of amniotic fluid, serum, cervix and vagina. Association of an inflammatory response in the invasive and non-invasive samples with MIAC was investigated.

Results

The rate of MIAC was 36.2% (21/58). Both amniotic fluid IL-6 and cervical C-reactive protein (CRP) showed to be independent predictors of MIAC. A cut-off level of cervical CRP≥1836 pg/mL showed a detection rate of 75%, false positive rate of 19% and positive and negative predictive values to predict MIAC of 67% and 87%, respectively. There were no independent biomarkers of MIAC either in the serum or vaginal compartment.

Conclusion

A cervical inflammatory response mediated by CRP was observed in PPROM women with MIAC. Evaluation of serum or vaginal samples did not add valuable information regarding the outcome evaluated.     

Umbilical Cord Blood IL-6 as Predictor of Early-Onset Neonatal Sepsis in Women with Preterm Prelabour Rupture of Membranes

Objective

To evaluate umbilical cord interleukin (IL)-6 and funisitis as independent predictors of early-onset neonatal sepsis (EONS) in preterm prelabor rupture of membranes (PPROM).

Design

Prospective cohort study.

Setting

Evaluation of umbilical cord IL-6 and funisitis as predictors of early-onset neonatal sepsis in PPROM.

Population

176 women with PPROM between 23+0−36+6 weeks of gestation.

Methods

Umbilical cord IL-6 was assayed by ELISA. Funisitis was defined according to the Salafia classification. Data was adjusted by gestational age at delivery and prenatal administration of corticosteroids and antibiotics.

Main Outcome Measures

Binary logistic regression was performed to assess the independence of umbilical cord IL-6 and funisitis to predict EONS in women complicated with PPROM.

Results

The rate of EONS was 7%. Funisitis was present in 18% of women. Umbilical cord IL-6 was significantly higher in women complicated with EONS than without [median (range) 389.5 pg/mL (13.9–734.8) vs 5.2 (0.1–801–4), p<0.001]. Umbilical cord IL-6 was the only independent predictor of early-onset neonatal sepsis (odds ratio 13.6, p = 0.004).

Conclusion

Umbilical cord IL-6 was the only predictor of early-onset neonatal sepsis in PPROM. Contrary to what is reported, funisitis was not.     

The Prognostic Value of C-Reactive Protein Serum Levels in Patients with Uterine Leiomyosarcoma

Objective

C-reactive protein (CRP) has previously been shown to serve as a prognostic parameter in women with gynecologic malignancies. Due to the lack of valid prognostic markers for uterine leiomyosarcoma (ULMS) this study set out to investigate the value of pre-treatment CRP serum levels as prognostic parameter.

Methods

Data of women with ULMS were extracted from databases of three Austrian centres for gynaecologic oncology. Pre-treatment CRP serum levels were measured and correlated with clinico-pathological parameters. Univariate and multivariable survival analyses were performed.

Results

In total, 53 patients with ULMS were included into the analysis. Mean (SD) CRP serum level was 3.46 mg/dL (3.96). Solely, an association between pre-treatment CRP serum levels and tumor size (p = 0.04) but no other clinic-pathologic parameter such as tumor stage (p = 0.16), or histological grade (p = 0.07), was observed. Univariate and multivariable survival analyses revealed that CRP serum levels (HR 2.7 [1.1–7.2], p = 0.037) and tumor stage (HR 6.1 [1.9–19.5], p = 0.002) were the only independent prognostic factors for overall survival (OS) in patients with ULMS. Patients with high pre-treatment CRP serum levels showed impaired OS compared to women with low levels (5-year-OS rates: 22.6% and 52.3%, p = 0.007).

Conclusion

High pre-treatment CRP serum levels were independently associated with impaired prognosis in women with ULMS and might serve as a prognostic parameter in these patients.     

The Relationship between Zinc Status and Inflammatory Marker Levels in Rural Korean Adults Aged 40 and Older

Background

Serum cytokines and C-reactive protein (CRP) are known as one of the major risk factors in atherosclerosis. The antioxidant and anti-inflammatory properties of zinc have been suggested, but few data are available on the relationship between zinc status and inflammatory markers in epidemiological studies.

Objective

The present study aims to investigate the cross-sectional relationships of serum cytokines and CRP with dietary zinc intake and serum zinc levels in healthy men and women aged 40 and older in rural areas of South Korea.

Materials and Methods

A group of 1,055 subjects (404 men, 651 women) was included in dietary zinc analysis while another group of 695 subjects (263 men, 432 women) was included in serum zinc analysis. Serum IL-6, TNF-α, and CRP were measured as inflammatory markers.

Results

There was no significant inverse relationship between dietary zinc intake and inflammatory markers. We found a significant inverse relationship between serum zinc levels and all three inflammatory markers in women (P for trend = 0.0236 for IL-6; P for trend = 0.0017 for TNF-α; P for trend = 0.0301 for CRP) and between serum zinc levels and a single inflammatory marker (IL-6) in men (P for trend = 0.0191), although all R2 values by regression were less than 10%.

Conclusion

In conclusion, serum zinc levels may be inversely related to inflammatory markers (IL-6, TNF-α, and CRP), particularly in women.     

Inflammatory and Haematological Markers in the Maternal,Umbilical Cord and Infant Circulation in Histological Chorioamnionitis

Background

The relationship between histological chorioamnionitis and haematological and biochemical markers in mothers and infants at delivery, and in infants postnatally, is incompletely characterised. These markers are widely used in the diagnosis of maternal and neonatal infection. Our objective was to investigate the effects of histological chorioamnionitis (HCA) on haematological and biochemical inflammatory markers in mothers and infants at delivery, and in infants post-delivery.

Methods

Two hundred and forty seven mothers, delivering 325 infants, were recruited at the only tertiary perinatal centre in Western Australia. Placentae were assessed for evidence of HCA using a semi-quantitative scoring system. Maternal high sensitivity C-reactive protein (hsCRP), procalcitonin, and umbilical cord hsCRP, procalcitonin, white cell count and absolute neutrophil count were measured at delivery. In infants where sepsis was clinically suspected, postnatal CRP, white cell count and absolute neutrophil count were measured up to 48 hours of age. The effect of HCA on maternal, cord and neonatal markers was evaluated by multivariable regression analysis.

Results

The median gestational age was 34 weeks and HCA was present in 26 of 247 (10.5%) placentae. Mothers whose pregnancies were complicated by HCA had higher hsCRP (median 26 (range 2–107) versus 5.6 (0–108) mg/L; P<0.001). Histological chorioamnionitis was associated with higher umbilical cord hsCRP (75^th percentile 2.91 mg/L (range 0–63.9) versus 75^th percentile 0 mg/L (0–45.6); P<0.001) and procalcitonin (median 0.293 (range 0.05–27.37) versus median 0.064 (range 0.01–5.24) ug/L; P<0.001), with a sustained increase in neonatal absolute neutrophil count (median 4.5 (0.1–26.4)×10⁹/L versus 3.0 (0.1–17.8)×10⁹/L), and CRP up to 48 hours post-partum (median 10 versus 6.5 mg/L) (P<0.05 for each).

Conclusion

Histological chorioamnionitis is associated with modest systemic inflammation in maternal and cord blood. These systemic changes may increase postnatally, potentially undermining their utility in the diagnosis of early-onset neonatal infection.     

Preterm Prelabor Rupture of Membranes and Outcome of Very-Low-Birth-Weight Infants in the German Neonatal Network

Objective

It was the aim of our study to evaluate the independent effect of preterm prelabor rupture of membranes (PPROM) as a cause of preterm delivery on mortality during primary hospital stay and significant morbidities in very-low-birth-weight (VLBW) infants < 32 weeks of gestation.

Design

Observational, epidemiological study design.

Setting

Population-based cohort, German Neonatal Network (GNN).

Population

6102 VLBW infants were enrolled in GNN from 2009-2012, n=4120 fulfilled criteria for primary analysis (< 32 gestational weeks, no pre-eclampsia, HELLP (highly elevated liver enzymes and low platelets syndrome) or placental abruption as cause of preterm birth).

Methods

Multivariable logistic regression analyses included PPROM as potential risk factors for adverse outcomes and well established items such as gestational age in weeks, birth weight, antenatal steroids, center, inborn delivery, multiple birth, gender and being small-for-gestational-age.

Results

PPROM as cause of preterm delivery had no independent effect on the risk of early-onset sepsis, clinical sepsis and blood-culture proven sepsis, while gestational age proved to be the most important contributor to sepsis risk. The diagnosis of PPROM was associated with an increased risk for bronchopulmonary dysplasia (BPD; OR: 1.25, 95% CI: 1.02-1.55, p=0.03) but not with other major outcomes.

Conclusions

The diagnosis of PPROM per se is not associated with adverse outcome in VLBW infants < 32 weeks apart from a moderately increased risk for BPD. Randomized controlled trials with primary neonatal outcomes are needed to determine which subgroup of VLBW infants benefit from expectant or intentional management of PPROM.     

Does AMH Reflect Follicle Number Similarly in Women with and without PCOS?

Context

Increased Anti-Mullerian Hormone in polycystic ovary syndrome, may be due to overactive follicles rather than reflect antral follicle count.

Objective

Does Anti-Mullerian Hormone reflect antral follicle count similarly in women with or without polycystic ovary syndrome or polycystic ovarian morphology?

Design

Cross-sectional, case-control.

Setting

Women who delivered preterm in 1999–2006. For each index woman, a woman with a term delivery was identified.

Patients

Participation rate was 69%. Between 2006–2008, 262 women were included, and diagnosed to have polycystic ovary syndrome, polycystic ovarian morphology or to be normal controls.

Intervention(s)

Blood tests, a clinical examination and vaginal ultrasound.

Main Outcome Measure(s)

Anti-Mullerian Hormone / antral follicle count -ratio, SHBG, androstenedione and insulin, to test potential influence on the Anti-Mullerian Hormone / antral follicle count -ratio.

Results

Mean Anti-Mullerian Hormone / antral follicle count ratio in women with polycystic ovary syndrome or polycystic ovarian morphology was similar to that of the controls (polycystic ovary syndrome: 1,2 p = 0,10 polycystic ovarian morphology: 1,2, p = 0,27 Controls 1,3). Anti-Mullerian Hormone showed a positive linear correlation to antral follicle count in all groups. Multivariate analysis did not change the results.

Conclusions

We confirmed the positive correlation between AMH and follicle count. Anti-Mullerian Hormone seems to be a reliable predictor of antral follicle count, independent of polycystic ovary syndrome diagnosis or ovarian morphology.     

Exploratory Cohort Study of Associations between Serum C - Reactive Protein and Fatigue after Stroke

Background and Aim

Post-stroke fatigue is a common and distressing problem but little is known about its biological mechanisms. This cohort study was to investigate associations between C-reactive protein (CRP) and fatigue after stroke.

Methods

Patients were assessed at one, six and 12 months after their stroke onset, with the Fatigue Assessment Scale, a case definition of post-stroke fatigue, Hospital Anxiety and Depression Scale, and daily step counts. Blood samples were collected at each assessment and the CRP level was determined by a standard CRP immunoassay. Cross-sectional associations between CRP and fatigue at each time point were determined by Pearson correlation coefficient and independent-samples t-test. Whether CRP levels at one month predict fatigue scores at six and 12 months was explored by multiple linear regression, with anxiety, depression, and daily step counts as covariates.

Results

Sixty-five patients (mean age 67 years, 65% men) were included: 61 at one month, 49 at six months, and 41 at 12 months. CRP levels and fatigue scores were not associated at one month (p = 0.88) or 12 months (p = 0.56), but weakly associated at six months (r = 0.27, p = 0.04); however, this association was no longer significant (p = 0.14) after controlling for the effects of covariates. The CRP level was not associated with the fulfilment of case definition of post-stroke fatigue at any time points (all p > 0.05). The CRP level at one month was not a significant predictor for fatigue levels at either six months (p = 0.93) or 12 months (p = 0.78).

Conclusions

There is insufficient evidence for the association between CRP and PSF in stroke patients. Future studies with larger sample sizes and controlling for potential confounders are needed to investigate whether this association exists.     

Accuracy and Feasibility of Point-Of-Care White Blood Cell Count and C-Reactive Protein Measurements at the Pediatric Emergency Department

Background

Several point-of-care (POC) tests are available for evaluation of febrile patients, but the data about their performance in acute care setting is sparse. We investigated the analytical accuracy and feasibility of POC tests for white blood cell (WBC) count and C-reactive protein (CRP) at the pediatric emergency department (ED).

Methods

In the first part of the study, HemoCue WBC and Afinion AS100 CRP POC analyzers were compared with laboratory’s routine WBC (Sysmex XE-2100) and CRP (Modular P) analyzers in the hospital central laboratory in 77 and 48 clinical blood samples, respectively. The POC tests were then adopted in use at the pediatric ED. In the second part of the study, we compared WBC and CRP levels measured by POC and routine methods during 171 ED patient visits by 168 febrile children and adolescents. Attending physicians performed POC tests in capillary fingerprick samples.

Results

In parallel measurements in the laboratory both WBC and CRP POC analyzers showed good agreement with the reference methods. In febrile children at the emergency department (median age 2.4 years), physician performed POC determinations in capillary blood gave comparable results with those in venous blood analyzed in the laboratory. The mean difference between POC and reference test result was 1.1 E9/L (95% limits of agreement from -6.5 to 8.8 E9/L) for WBC and -1.2 mg/L (95% limits of agreement from -29.6 to 27.2 mg/L) for CRP.

Conclusions

POC tests are feasible and relatively accurate methods to assess CRP level and WBC count among febrile children at the ED.     

Norwegian PUQE (Pregnancy-Unique Quantification of Emesis and Nausea) Identifies Patients with Hyperemesis Gravidarum and Poor Nutritional Intake: A Prospective Cohort Validation Study

Objective

The English questionnaire Pregnancy-Unique Quantification of Emesis and nausea (PUQE) identifies women with severe Hyperemesis Gravidarum. Our aim was to investigate whether scores from the translated Norwegian version; SUKK (SvangerskapsUtløst Kvalme Kvantifisering) was associated with severity of hyperemesis and nutritional intake.

Design

A prospective cohort validation study.

Setting

Hospital cohort of Hyperemesis Gravidarum (HG) patients from western Norway and healthy pregnant women from Bergen, Norway.

Sample

38 women hospitalized due to HG and 31 healthy pregnant controls attending routine antenatal check-up at health centers.

Methods

Data were collected May 2013-January 2014. The study participants answered the Norwegian PUQE-questionnaire (scores ranging from 3 to15) and registered prospectively 24-hours nutritional intake by a food list form.

Main outcome measures

Differences of PUQE-scores, QOL-score and nutritional intake between hyperemesis patients and controls.

Results

Hyperemesis patients had shorter gestational age compared to controls (median 9.7 weeks; 95% CI 8.6-10.6 versus 11.9; 95% CI 10.1-12.9, p=0.004), and larger weight-change from pre-pregnant weight (loss of median 3 kg; 95% CI 3-4 versus gain of 2 kg; 95% CI 0.5-2, p<0.001) otherwise groups were similar regarding pre-pregnant BMI, age, gravidity, and inclusion weight. Compared to controls, hyperemesis patients had significant higher PUQE-score (median 13; 95% CI 11-14 vs. 7; 95% CI 4-8), lower QOL (median score 3; 95% CI 2-4 vs. 6; 95% CI 4.5-8) and lower nutritional intake (energy intake median 990 kcal/24 hours; 95% CI 709-1233 vs. 1652; 95% CI 1558-1880 all p<0.001). PUQE-score was inversely correlated to nutritional intake (-0.5, p<0.001). At discharge PUQE-score had fallen to median 6 (95% CI 5-8) and QOL score risen to 7 (95% CI 6-8) in the HG group, (both p<0.001 compared to admission values).

Conclusion

PUQE-scoring has been validated as a robust indicator of severe hyperemesis gravidarum and insufficient nutritional intake in a Norwegian setting.     

Baseline Plasma C-Reactive Protein Concentrations and Motor Prognosis in Parkinson Disease

Background

C-reactive protein (CRP), a blood inflammatory biomarker, is associated with the development of Alzheimer disease. In animal models of Parkinson disease (PD), systemic inflammatory stimuli can promote neuroinflammation and accelerate dopaminergic neurodegeneration. However, the association between long-term systemic inflammations and neurodegeneration has not been assessed in PD patients.

Objective

To investigate the longitudinal effects of baseline CRP concentrations on motor prognosis in PD.

Design, Setting, and Participants

Retrospective analysis of 375 patients (mean age, 69.3 years; mean PD duration, 6.6 years). Plasma concentrations of high-sensitivity CRP were measured in the absence of infections, and the Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) scores were measured at five follow-up intervals (Days 1–90, 91–270, 271–450, 451–630, and 631–900).

Main Outcome Measure

Change of UPDRS-III scores from baseline to each of the five follow-up periods.

Results

Change in UPDRS-III scores was significantly greater in PD patients with CRP concentrations ≥0.7 mg/L than in those with CRP concentrations <0.7 mg/L, as determined by a generalized estimation equation model (P = 0.021) for the entire follow-up period and by a generalized regression model (P = 0.030) for the last follow-up interval (Days 631–900). The regression coefficients of baseline CRP for the two periods were 1.41 (95% confidence interval [CI] 0.21–2.61) and 2.62 (95% CI 0.25–4.98), respectively, after adjusting for sex, age, baseline UPDRS-III score, dementia, and incremental L-dopa equivalent dose.

Conclusion

Baseline plasma CRP levels were associated with motor deterioration and predicted motor prognosis in patients with PD. These associations were independent of sex, age, PD severity, dementia, and anti-Parkinsonian agents, suggesting that subclinical systemic inflammations could accelerate neurodegeneration in PD.     

Oligohydramnios in Women with Preterm Prelabor Rupture of Membranes and Adverse Pregnancy and Neonatal Outcomes

Objective

To determine the association between the presence of oligohydramnios, determined as an amniotic fluid index ≤ 5 cm and the intra-amniotic inflammatory response, fetal inflammatory response and neonatal outcomes in actively managed preterm prelabor rupture of membranes (PPROM).

Methods

Women with singleton pregnancies complicated by PPROM at a gestational age of between 24+0 and 36+6 weeks were included in the study. Ultrasound assessments of the amniotic fluid index and evaluation of the amniotic fluid interleukin (IL)-6 levels were performed at admission. The umbilical cord blood IL-6 levels were evaluated after delivery.

Results

In total, 74 women were included. The women with oligohydramnios did not have different amniotic fluid IL-6 levels [with oligohydramnios: median 342 pg/mL, interquartile range (IQR) 110-1809 vs. without oligohydramnios: median 256 pg/mL, IQR 122–748; p = 0.71] or umbilical cord blood IL-6 levels (with oligohydramnios: median 8.2 pg/mL, IQR 3.8–146.9 vs. without oligohydramnios: median 5.9 pg/mL, IQR 2.1–27.9; p = 0.14) than those without oligohydramnios. No association between oligohydramnios and neonatal morbidity was found. A correlation between the amniotic fluid index and the interval from rupture of membranes to amniocentesis was observed (rho = −0.34; p = 0.003).

Conclusion

The presence of oligohydramnios is not associated with an adverse outcome in actively managed PPROM in singleton pregnancies in the absence of other complications.     

Iron,Hepcidin and Inflammatory Status of Young Healthy Overweight and Obese Women in Australia

Background and Aims

Evidence suggests obesity-related inflammation alters iron metabolism potentially increasing the risk of iron deficiency. This cross-sectional study aimed to investigate iron, hepcidin and inflammatory status in young, healthy overweight and obese women.

Methods

114 young (18–25 years), healthy comorbidity-free women with a body mass index (BMI) ≥27.5 kg/m² were recruited. Biochemical data were analysed using mean ± standard deviation or median (interquartile range) and multivariate modelling. Biochemical markers were also stratified according to varying degrees of overweight and obesity.

Results

Anaemia (haemoglobin <120 g/l) and iron deficiency (serum ferritin <15.0 µg/l) were prevalent in 10% and 17% of participants respectively. Mean/median soluble transferrin receptor was 1.61±0.44 mg/l; hepcidin 6.40 (7.85) ng/ml and C-reactive protein (CRP) 3.58 (5.81) mg/l. Multivariate modelling showed that BMI was a significant predictor of serum iron (coefficient = -0.379; standard error = 0.139; p = 0.008), transferrin saturation (coefficient = -0.588; standard error = 0.222; p = 0.009) and CRP (coefficient = 0.127; standard error = 0.024; p<0.001). Stratification of participants according to BMI showed those with ≥35.0 kg/m² had significantly higher CRP (p<0.001) than those in lower BMI categories.

Conclusions

Increasing obesity was associated with minor disturbances in iron metabolism. However, overall outcomes indicated simple iron deficiency (hypoferritinaemia) was the primary iron-related abnormality with no apparent contribution of inflammation or hepcidin, even in those with BMI >35.0 kg/m². This indicates that obesity alone may not be sufficient to induce clinically significant disturbances to iron metabolism as previously described. This may be attributed to the lack of comorbidity in this cohort.     

Early Diagnosis of Pneumonia in Severe Stroke: Clinical Features and the Diagnostic Role of C-Reactive Protein

Background

Accurate diagnosis of pneumonia complicating severe stroke is challenging due to difficulties in physical examination, altered immune responses and delayed manifestations of radiological changes. The aims of this study were to describe early clinical features and to examine C-reactive protein (CRP) as a diagnostic marker of post-stroke pneumonia.

Methods

Patients who required nasogastric feeding and had no evidence of pneumonia within 7 days of stroke onset were included in the study and followed-up for 21 days with a daily clinical examination. Pneumonia was diagnosed using modified British Thoracic Society criteria.

Results

60 patients were recruited (mean age 77 years, mean National Institutes of Health Stroke Scale Score 19.47). Forty-four episodes of pneumonia were identified. Common manifestations on the day of the diagnosis were new onset crackles (43/44, 98%), tachypnoea>25/min (42/44, 95%), and oxygen saturation <90% (41/44, 93%). Cough, purulent sputum, and pyrexia >38°C were observed in 27 (61%), 25 (57%) and 15 (34%) episodes respectively. Leucocytosis (WBC>11,000/ml) and raised CRP (>10 mg/l) were observed in 38 (86%) and 43 (97%) cases of pneumonia respectively. The area under the ROC curve for CRP was 0.827 (95% CI 0.720, 0.933). The diagnostic cut-off for CRP with an acceptable sensitivity (>0.8) was 25.60 mg/L (Youden index (J) 0.515; sensitivity 0.848; specificity 0.667). A cut-off of 64.65 mg/L had the highest diagnostic accuracy (J 0.562; sensitivity 0.636; specificity 0.926).

Conclusion

Patients with severe stroke frequently do not manifest key diagnostic features of pneumonia such as pyrexia, cough and purulent sputum early in their illness. The most common signs in this group are new-onset crackles, tachypnoea and hypoxia. Our results suggest that a CRP >25 mg/L should prompt investigations for pneumonia while values >65 mg/L have the highest diagnostic accuracy to justify consideration of this threshold as a diagnostic marker of post-stroke pneumonia.     

The Effects of Intravenous Immunoglobulins in Women with Recurrent Miscarriages: A Systematic Review of Randomised Trials with Meta-Analyses and Trial Sequential Analyses Including Individual Patient Data

Background

Immunological disturbances are hypothesised to play a role in recurrent miscarriage (RM) and therefore intravenous immunoglubulins (IVIg) have been tested in RM patients.

Objectives

The objectives were to investigate the benefits and harms of IVIg versus placebo, no intervention, or treatment as usual in women with RM.

Search Strategy

We searched the published literature in all relevant databases.

Selection Criteria

Randomised trials investigating IVIg versus placebo, no intervention, or treatment as usual in women with RM.

Data Collection and Analysis

We undertook meta-analyses of aggregated data and individual patient data using a two-step approach, and we conducted bias domain assessments and trial sequential analyses to assess the risks of systematic and random errors.

Main Results

We identified 11 randomised clinical trials. No significant difference in the frequency of no live birth was found when IVIg was compared with placebo or treatment as usual (RR 0.92, 95% CI 0.75–1.12, p = 0.42). Trial sequential analysis showed that the required information size of 1,008 participants was not obtained. IVIg compared with placebo seems to increase the risk of adverse events. Subgroup analysis suggests that women with RM after a birth (secondary RM) seemed most likely to obtain a potential beneficial effect of IVIg (RR for no live birth 0.77, 95%CI 0.58–1.02, p = 0.06), however, trial sequential analysis showed that insufficient information is presently accrued.

Conclusion

We cannot recommend or refute IVIg in women with RM. IVIg should therefore be assessed in further randomised clinical trials with positive outcomes before any clinical use is considered.     

Response to Therapeutic Plasma Exchange as a Rescue Treatment in Clinically Isolated Syndromes and Acute Worsening of Multiple Sclerosis: A Retrospective Analysis of 90 Patients

Objectives

Experience with therapeutic plasma exchange (TPE) for acute relapses in clinically isolated syndrome (CIS) or multiple sclerosis (MS) patients has been derived from small and inhomogeneous patient populations so far. In the present study, we retrospectively evaluated features associated with TPE response in a larger cohort of CIS and MS patients with acute worsening of disease.

Participants

Ninety CIS and MS patients with acute relapses or acute worsening of symptoms were firstly treated with TPE. The population consisted of 62 women and 28 men with a median age of 38 years (range 18–69 years).

Outcome Measures

Primary endpoint was the clinical response to TPE, focused on the functional improvement of the target neurologic deficit. Secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring.

Results

A clinical response to TPE was observed in 65 out of 90 patients (72.2%), with marked improvement in 18 (20.0%) and moderate improvement in 47 out of 90 patients (52.2%). The median EDSS was reduced from 3.75 before to 3.0 after TPE (p = 0.001). Response to TPE was significantly more frequent in patients with relapsing courses of disease (CIS, RR-MS, p = 0.001), no disease modifying drugs (p = 0.017), gadolinium-positive (Gd⁺) MRI lesions (p = 0.001) and EDSS ≤ 5.0 before TPE (p = 0.014). In the multiple logistic regression analysis only the detection of Gd⁺ MRI lesions was significantly altered (p = 0.004).

Conclusion

Clinical response to TPE was achieved in the majority of our patients. We identified clinical and diagnostic features in CIS and MS relapses that might be helpful to identify patients responding to TPE. Gd⁺ MRI lesions before treatment were the best predictor of the response to TPE in our cohort.     

The Use of Delta Neutrophil Index and Myeloperoxidase Index for Predicting Acute Complicated Appendicitis in Children

Background

In children with acute appendicitis, 30% to 75% present with a complication, such as perforation, and the early diagnosis of complications is known to improve outcomes. Serum delta neutrophil index (DNI) and myeloperoxidase index (MPXI) are new inflammatory markers, and thus, in the present study, the authors evaluated the predictive values of these two markers for the presence of a complication in children with acute appendicitis.

Methods

This retrospective observational study was conducted on 105 consecutive children (<12 years old) with acute appendicitis treated over a 31-month period. DNI, MPXI, C-reactive protein (CRP), and white blood cells (WBCs) were measured in an emergency department and investigated with respect to their abilities to predict the presence of acute complicated appendicitis.

Results

Twenty-nine of the 105 patients (median age, 9 years) were allocated to the complicated group (27.6%) and 76 to the non-complicated group (72.4%). Median serum DNI and CRP were significantly higher in the complicated group [0% vs. 2.2%, p<0.001 and 0.65 mg/dL vs. 8.0 mg/dL, p<0.001], but median MPXI was not (p = 0.316). Area under curve (AUC) for the ability of serum DNI and CRP to predict the presence of acute complicated appendicitis were 0.738 and 0.840, respectively. Multiple logistic regression analyses showed initial CRP [odds ratio 1.301, 95% confidence interval (1.092–1.549), p = 0.003] significantly predicted the presence of a complication. The optimal cutoff for serum CRP was 4.0 mg/dL (sensitivity 69%, specificity 83%, AUC 0.840).

Conclusions

Although serum DNI values were significantly higher in children with acute complicated appendicitis, no evidence was obtained to support the notion that serum DNI or serum MPXI aid the differentiation of acute complicated and non-complicated appendicitis in the ED setting.     

Adipocytokines,C-Reactive Protein,and Cardiovascular Disease: A Population-Based Prospective Study

Background

Being overweight or obese is associated with a greater risk of coronary heart disease and stroke compared with normal weight. The role of the specific adipose tissue-derived substances, called adipocytokines, in overweight- and obesity-related cardiovascular disease (CVD) is still unclear.

Objective

To investigate the associations of three adipose tissue-derived substances: adiponectin, leptin, and interleukin-6 with incident CVD in a longitudinal population-based study, including extensive adjustments for traditional and metabolic risk factors closely associated with overweight and obesity. C-reactive protein (CRP) was used as a proxy for interleukin-6.

Methods

Prospective population-based study of 6.502 participants, 51.9% women, aged 30–60 years, free of CVD at baseline, with a mean follow-up time of 11.4 years, equivalent to 74,123 person-years of follow-up. As outcome, we defined a composite outcome comprising of the first event of fatal and nonfatal coronary heart disease and fatal and nonfatal stroke.

Results

During the follow-up period, 453 composite CV outcomes occurred among participants with complete datasets. In models, including gender, age, smoking status, systolic blood pressure, treatment for hypertension, diabetes, body mass index (BMI), total cholesterol, high-density-lipoprotein cholesterol, homeostasis model assessment of insulin resistance, estimated glomerular filtration rate, adiponectin, leptin, and CRP, neither adiponectin (hazard ratio [HR] with 95% confidence interval [CI]: 0.97 [0.87–1.08] per SD increase, P = 0.60) nor leptin (0.97 [0.85–1.12] per SD increase, P = 0.70) predicted the composite outcome, whereas CRP was significantly associated with the composite outcome (1.19 [1.07–1.35] per SD increase, P = 0.002). Furthermore, in mediation analysis, adjusted for age and sex, CRP decreased the BMI-associated CV risk by 43% (95%CI 29–72).

Conclusions

In this study, neither adiponectin nor leptin were independently associated with CVD, raising questions over their role in CVD. The finding that CRP was significantly associated with an increased risk of CVD and decreased the BMI-associated CVD risk substantially, could imply that interleukin-6-related pathways may play a role in mediating overweight- and obesity-related CVD.