A clinical classification system for grading platinum hypersensitivity reactions.

OBJECTIVES: Current grading systems for platinum hypersensitivities (pHSR) rely on subjective features rather than objective clinical signs leading to inconsistencies in grading. To standardize classification of pHSR, a clinical grading system was developed at our institution. We report the clinical outcomes our classification system and evaluate its correlation with the classification systems currently published and used in practice. METHODS: This was a retrospective review of patients with pHSR from 2011 to 2017. Demographics, chemotherapeutic histories (CT), and details of their initial HSR were collected. Mild reactions were defined as local skin manifestations only. Moderate-low reactions included widespread skin, respiratory or GI findings. Moderate-standard reactions were defined as transient cardiovascular compromise (CVC), hypoxia or neurologic changes whereas sustained changes (>10 min) were used to define severe reaction. Fischer Exact Tests (p < .05) and binary logistic regression analyses were performed. Spearman correlation were used to assess relationships between our grading system and the NCCN and CTCAEv4.0 criteria. RESULTS: 87 patients were identified with most having ovarian cancer (n = 55, 63.2%), receiving carboplatin (n = 62, 71.3%), and on second-line CT (n = 34, 42.5%). Chest pain was associated with transient CVC (OR 10.0, 95% CI 1.148-87.133) while nausea/vomiting (OR 8.420, 95% CI 1.263-55.275) was associated with transient hypoxia albeit less closely than transient hypotension (OR 17.010, 95% CI 2.026-142.825). Only presyncope/syncope remained associated with sustained CVC (OR 38.0, 95% CI 2.815-512.912) on logistic regression. The classification system was most strongly correlated with the NCCN grading system (ρ 0.761, p < .001). CONCLUSIONS: This classification system offers an objective means of grading pHSR severity and correlates with currently-used grading systems.

Acute Effects of Interleukin-1 Blockade Using Anakinra in Patients With Acute Pericarditis.

Interleukin-1 (IL-1) receptor antagonist (anakinra) has been shown to be effective in steroid-dependent recurrent pericarditis resistant to nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. We sought to evaluate the acute efficacy of anakinra given early in patients with acute pericarditis. We enrolled patients within 24 hours of presentation of a first or recurrent episode of acute pericarditis who were experiencing severe pain (≥6 in 11-point Likert scale), despite treatment with at least one dose of NSAIDs and of colchicine. The primary outcome was pain relief at 24 hours. Subcutaneous anakinra 100 mg was administered in all patients, whereas NSAIDs and colchicine were suspended for 24 hours. Serum levels of interleukin-6 (IL-6) were measured at baseline and 24 hours. Data are reported as median (interquartile range). We treated 5 patients (4 male and 1 female; 38 [31-54] years old). Anakinra significantly reduced pain from 6.0 (6.0-7.5) to 4.0 (2.5-4.0) at 6 hours (P = 0.012 vs. baseline) and to 2.0 (1.5-2.5) at 24 hours (P = 0.0025 vs. baseline). No patients required rescue pain medication. IL-6 levels were also significantly reduced from 95.3 (24.2-155.1) to 23.9 (4.5-71.9) pg/mL at 24 hours (P = 0.037). The reduction in pain intensity paralleled the reduction in IL-6 serum levels (R = +0.966, P = 0.007). No adverse events related to treatment occurred. The administration of anakinra given early in acute pericarditis treatment course rapidly and significantly improved chest pain from acute pericarditis. The improvement is correlated with a reduction in IL-6 levels.

A case of ANCA associated vasculitis in a patient presenting with chest pain.

Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a group of multisystem autoimmune small vessel diseases. We report here a case of a 68-year-old woman who initially presented with 29-day history of chest pain, malaise and anorexia. Cardiac problems were ruled out and she was considered to have pneumonia. Her symptoms persisted and blood tests showed renal impairment and evidence of an inflammatory response. A kidney biopsy, chest computed tomography (CT) scan and ANCA testing confirmed a diagnosis of AAV renal injury. She was treated with glucocorticoids and cyclophosphamide (CTX) for six months at which time her kidney function had improved and she avoided the need for dialysis. This case study illustrates that the clinical manifestations of AVV are complex, varied, and prone to misdiagnosis.

Developing a diagnostic understanding of GERD phenotypes through the analysis of levels of mucosal injury, immune activation, and psychological comorbidity.

Patients with gastroesophageal reflux disease (GERD) can present with typical or atypical symptoms. The aim of this study is to explore the underlying physiological and psychological mechanisms that lead to different symptomatic manifestations of GERD. A total of 238 patients diagnosed with GERD underwent gastroscopy, 24 h multichannel intraluminal impedance-pH (MII-pH) monitoring, and psychological assessment with questionnaires. Patient symptoms were used to classify GERD into phenotypes of typical reflux syndrome (TRS, n = 87), reflux chest pain syndrome (RCS, n = 98), and extraesophageal syndromes (EES, n = 53). 38 healthy volunteers served as controls. Reflux parameters and baseline impedance values (BIVs) were acquired from MII-pH monitoring results. A subset of subjects were biopsied from the lower esophagus; certain immune cells were stained with immunohistochemistry. BIVs in GERD patients (TRS, RCS, and EES) were significantly lower than in healthy controls and TRS patients exhibited the lowest BIVs (all P < 0.01). This indicated that the extent of mucosal injury differed across groups. TRS patients had higher acid exposure time (AET) compared to RCS, EES and controls (all P < 0.05). RCS patients had more intraepithelial T lymphocyte (IEL) and mast cell (MC) infiltration, and higher psychometric scores compared to TRS patients and controls (all P < 0.05), suggesting a possible stress-related esophageal hypersensitivity basis. TRS patients are characterized by acid reflux and correlated mucosal injury, which explains their typical reflux symptoms. RCS patients exhibit less acid-related injury but possible psychological stress-related esophageal hypersensitivity, which could be the main cause of their esophageal pain.

Bronchial biopsy and reactivity in patients with chest tightness relieved with bronchodilator.

OBJECTIVE: It has been hypothesized that some patients with chest tightness of unknown origin can be successfully treated with a bronchodilator and that they should be diagnosed with chest pain variant asthma. We conducted a prospective study to characterize newly diagnosed patients with chest tightness relieved with bronchodilator use and without characteristic bronchial asthma attacks. METHODS: Eleven patients were registered following recurrent positive responses of chest tightness to inhalation of a ß2-agonist. These patients underwent assessments of airway responsiveness to methacholine, bronchial biopsy and bronchial lavage under fiber-optic bronchoscopy before receiving treatment. RESULTS: For the patients with chest tightness relieved with bronchodilator use, the bronchial biopsy specimens exhibited significant increases in lymphocyte and macrophage infiltration (p < 0.05) and no significant increase in eosinophils (p = 0.2918) compared with the control subjects. The bronchial responsiveness to methacholine was increased in two of the patients with chest tightness, and it was not increased in seven; in addition, increased percentages of eosinophils were detected in bronchial lavage fluid (5% or more) from two patients, but no increase was detected in eight patients. CONCLUSIONS: We suspect that the chest tightness was induced by airway constriction in these patients, but further study is necessary to validate this hypothesis. We propose that the chest tightness relieved with bronchodilator use was attributed to airway constriction resulting from inflammation with lymphocytes and macrophages and/or that the chest tightness was directly attributed to airway inflammation. This clinical trial is registered at www.umin.ac.jp (UMIN13994 and UMIN 16741).

Impaired circulating CD4+ LAP+ regulatory T cells in patients with acute coronary syndrome and its mechanistic study.

OBJECTIVE: CD4(+) latency-associated peptide (LAP)(+) regulatory T cells (Tregs) are a newly discovered T cell subset in humans and the role of these cells in patients with acute coronary syndrome (ACS) has not been explored. We designed to investigate whether circulating frequency and function of CD4(+)LAP(+) Tregs are defective in ACS. METHODS: One hundred eleven ACS patients (acute myocardial infarction and unstable angina) and 117 control patients were enrolled in the study. The control patients consisted of chronic stable angina (CSA) and chest pain syndrome (CPS). The frequencies of circulating CD4(+)LAP(+) Tregs and the expression of the transmembrane protein glycoprotein-A repetitions predominant (GARP) on CD4(+) T cells were determined by flow cytometry. The function of CD4(+)LAP(+) Tregs was detected using thymidine uptake. Serum interleukin-10 (IL-10) and transforming growth factor-ß protein (TGF-ß) levels were detected using ELISA and expression of GARP mRNA in peripheral blood mononuclear cells (PBMCs) was measured by real time-polymerase chain reaction. RESULTS: We found ACS patients had a significantly lower frequency of circulating CD4(+)LAP(+) Tregs, and the function of these cells was reduced compared to controls. The expression of GARP in CD4(+) T cells and the serum levels of TGF-ß in ACS patients were lower than those of control patients. The serum levels of IL-10 were similar between the two cohorts. CONCLUSIONS: A novel regulatory T cell subset, defined as CD4(+)LAP(+) T cells is defective in ACS patients.

The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome.

MicroRNAs (miRNAs) are a novel class of small, non-coding RNAs that play a significant role in both inflammatory and cardiovascular diseases. Immune cells, especially T helper (Th) cells, are critical in the development of atherosclerosis and the onset of acute coronary syndrome (ACS). To assess whether inflammation-related miRNAs (such as miR-155, 146a, 21, 125a-5p, 125b, 31) are involved in the imbalance of Th cell subsets in patients with ACS, we measured the expression of related miRNAs in patients with acute myocardial infarction (AMI), unstable angina (UA), stable angina (SA) and chest pain syndrome (CPS); analyzed the relationship between miRNA expression and the frequency of Th cell subsets; and observed the co-expression of miR-155 and IL-17A in peripheral blood mononuclear cells (PBMCs) of patients with ACS. The results showed that the expression of miR-155 in the PBMCs of patients with ACS was decreased by approximately 60%, while the expression of both miR-21 and miR-146a was increased by approximately twofold. The expression patterns of miRNAs in plasma correlated with those in PBMCs, except for miR-21, which was increased by approximately sixfold in the AMI group and showed no significant difference between the UA group and the CPS group. We also found that the expression of miR-155 inversely correlated with the frequency of Th17 cells (r=-0.896, P<0.01) and that miR-155 was co-expressed with IL-17A in patients with ACS. In conclusion, our study revealed the expression patterns of inflammation-related miRNAs in patients with ACS and found that miR-155 may be associated with Th17 cell differentiation.

[Periodic fever with increased IgD]. / Fièvre périodique avec élévation des immunoglobulines D.

Periodic fever or hereditary inflammatory fevers are characterized by intermittent inflammatory attacks. Many entities are well recognized today such as familial mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). We report on the case of a 6-year-old boy referred for evaluation of a recurrent fever associated with chest pain, pneumonitis, or pleuritis since the age of 5 years. Laboratory data showed leukocytosis, a high erythrocyte sedimentation rate, and C-reactive protein; however, a permanent high serum level IgD was noted. Stereotypical episodes of fever appeared every 4-6 weeks, while infectious, malignant, and auto-immune causes were eliminated. A search for the most common mutations of the FMF gene in Tunisian patients (M694V, M680I, V726A, E148Q, M694I, and A744S) were negative. Likewise, urinary leukotriene E(4), which may be increased in HIDS, was normal in this patient. Mevalonate kinase activity in lymphocytes was not assayed. Ethnic origin and clinical presentation suggest FMF with an increased IgD rather than authentic HIDS, in spite of the lack of improvement under colchicine treatment and the negativity of the main mutations involved in FMF.

Smoking is associated with epicardial coronary endothelial dysfunction and elevated white blood cell count in patients with chest pain and early coronary artery disease.

BACKGROUND: Smoking is a major risk factor for cardiovascular events. One of the potential mechanisms may be related to both coronary endothelial dysfunction and increased inflammatory response. The present study was designed to test the hypothesis that smoking is associated with epicardial coronary endothelial dysfunction and inflammation. METHODS AND RESULTS: Coronary endothelial function in response to acetylcholine was assessed in 881 patients (115 current smokers and 766 nonsmokers, including 314 previous smokers). Smokers were significantly younger than nonsmokers (43+/-1 versus 51+/-1 years, P<0.0001), had more epicardial vasoconstriction in response to intracoronary acetylcholine (-19+/-2% versus -14+/-1% change in coronary artery diameter, P=0.03), and were more likely than nonsmokers to have epicardial endothelial dysfunction (46% versus 35%, P=0.005), but their microvascular endothelial function was intact. Smokers had higher white blood cell counts than nonsmokers (7.7+/-0.2 versus 6.6+/-0.1x10(9)/L, P<0.0001), higher myeloperoxidase (156+/-19 versus 89+/-8 ng/mL), higher lipoprotein-associated phospholipase A2 (242+/-12 versus 215+/-5 ng/mL), and higher levels of intracellular adhesion molecule (283+/-14 versus 252+/-5 ng/mL). There were no differences in the levels of C-reactive protein, fibrinogen, or vascular cell adhesion molecule between the groups. CONCLUSIONS: Young smokers are characterized by epicardial coronary endothelial dysfunction, preserved microvascular endothelial function, and increased levels of inflammatory biomarkers and oxidative stress. The present study provides further information regarding the potential mechanisms by which smoking contributes to cardiovascular events.

Inflammation, endothelial cell activation, and coronary microvascular dysfunction in women with chest pain and no obstructive coronary artery disease.

BACKGROUND: Coronary artery microvascular dysfunction is prevalent in women with chest pain in the absence of obstructive coronary artery disease (CAD) and is manifested by attenuated coronary flow reserve (CFR). Markers of inflammation and endothelial cell activation have been found to be elevated in patients with chest pain but without CAD. The relationship between inflammation, endothelial activation, and CFR is not known. METHODS: Ninety-four women with chest pain in the absence of obstructive angiographic CAD underwent catheterization-based assessment of CFR and measurement of levels of inflammatory markers (n = 78) and endothelial cell activation in the NHLBI WISE study. RESULTS: Coronary flow reserve did not correlate with levels of C-reactive protein (high-sensitivity C-reactive protein) (rs = -0.07, P = .53), interleukin (IL)-6 (rs = -0.12, P = .31), IL-18 (rs = 0.14, P = .23), tumor necrosis factor alpha (rs = -0.09, P = .43), transforming growth factor beta1 (rs = 0.02, P = .84), and soluble intracellular adhesion molecule-1 (rs = 0.04, P = .68). Median levels of markers of inflammation and endothelial cell activation did not differ between the 57 women with abnormal CFR (< 2.5) and the 37 women with normal coronary microvascular function (high-sensitivity C-reactive protein 0.32 vs 0.25 mg/dL, P = .80; IL-6 2.89 vs 2.39 pg/mL, P = .63; IL-18 218 vs 227 pg/mL, P = .59; tumor necrosis factor alpha 2.7 vs 2.4 pg/mL, P = .43; transforming growth factor beta1 9928 vs 12436 pg/mL, P = .76; soluble intracellular adhesion molecule-1 286 vs 287 pg/mL, P = .95). Multivariable models demonstrated no evidence of associations between markers of inflammation and of endothelial cell activation and CFR. CONCLUSIONS: Coronary microvascular dysfunction is not associated with markers of inflammation and endothelial cell activation in women with chest pain in the absence of obstructive CAD. These results suggest that inflammation and endothelial cell activation may not play a pathophysiological role in coronary microvascular dysfunction.

[Influence of Helicobacter pylori infection on the results of 24-hour gastric pH-metry in patients diagnosed because of atypical chest pain]. / Wplyw zakazenia Helicobacter pylori na wyniki 24-godzinnej pH-metrii zoladkowej u pacjentów diagnozowanych z powodu nietypowego bólu w klatce piersiowej.

UNLABELLED: Changes in gastric acidity induced by Helicobacter pylori (Hp) infection, may influence intensity of symptoms in patients diagnosed because of chest pain. The aim of this study was to compare the results of 24-hours gastric pH-metry in patients suffering from atypical chest pain infected and not-infected by Hp. PATIENTS AND METHODS: In 99 men diagnosed because of atypical chest pain performed were: interview, physical examination, gastroduodenoscopy with musoca biopsy from gastric corpus and antrum, as well as 24-hour gastric pH-metry. Hp infection was diagnosed on the basis of positive urease test or/and histologic examination. RESULTS: 78% of subjects were infected by Hp. Hp positive patients had lower total and night-time percentage of monitoring time with gastric pH<4 and greater with pH > 6. Patients with isolated antral Hp colonization and subjects with pangastritis didn't differ in respect to gastric pH-metry parameters values. However in patients, with Hp colonization only in gastric corpus the time with gastric pH < 4 was shorter and with pH > 6 longer than in other groups. CONCLUSIONS: Hp-positive patients with atypical chest pain had lower gastric acidity than Hp-negative subjects. In patients with corporal Hp gastric mucosa colonization higher intra-gastric pH was observed than in the rest of patients.

Elevated serum and bronchoalveolar lavage fluid levels of interleukin 8 and granulocyte colony-stimulating factor associated with the acute chest syndrome in patients with sickle cell disease.

The role of cytokines in the development of acute chest syndrome (ACS) in patients with sickle cell disease (SCD) was studied. Serum interleukin 8 (IL-8) levels were elevated in 14 episodes and undetectable in six out of 20 episodes of ACS in 19 patients with SCD. In contrast, IL-8 levels were undetectable in the sera of 29 control patients with SCD studied during routine clinic visits or hospitalization for vaso-occlusive crises. The differences in mean IL-8 levels and the proportion of patients with detectable levels between the two groups were highly significant (P < 0.0001 and 0.04 respectively). The mean IL-8 level in bronchial fluid samples from children with ACS was also significantly higher than that in sickle cell patients undergoing elective surgery (5500 +/- 1400 pg/ml vs. 1900 +/- 470 pg/ml, P = 0.03). Granulocyte colony-stimulating factor (G-CSF) (2000 +/- 1700 pg/ml) was present in five out of six samples of bronchial fluid, but not serum, from children with ACS. All but one of the patients with ACS studied were negative for the Duffy red cell antigen, which is a receptor that binds and inactivates IL-8 and other chemokines. These findings suggest that IL-8 and G-CSF may play a role in the development of the ACS and the complications associated with it.

Detection of aggregated leukocytes in the circulating pool during stress-demargination is not necessarily a result of decreased leukocyte adhesiveness.

Leukocyte endothelial interactions are essential for a normal immune response. It is known that this response is influenced by stress and that the latter induces demargination. We examined the question of whether stress demargination results from a decreased state of leukocyte adhesiveness. Included were various volunteers and patients under different degrees of stress. 66 young athletes before beginning their daily exercises, 67 middle-aged healthy volunteers, 25 patients before ergometry for evaluation of chest pain, 75 patients who were referred to the emergency room with chest pain without ischemia/infarction, 78 patients with ischemia/infarction, 65 patients with minor trauma, 25 with a fracture and 12 with polytrauma. The leukocyte adhesiveness/aggregation (LAA) values were measured with a direct slide test. The respective LAA values were 7.4 +/- 4.7, 6.3 +/- 4.4, 5.8 +/- 3.6, 5.2 +/- 3.5, 10.8 +/- 8.5, 9.1 +/- 5.8, 12.2 +/- 6.6 and 19 +/- 12.6% of aggregated leukocytes. We conclude that an increase in aggregated white blood cells can be detected in the circulating pool during major stress. It is therefore suggested that stress demargination is not necessarily a result of diminished leukocyte adhesiveness.