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Background: Respiratory-related hospitalization, in particular acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), is common and associated with increasing mortality in patients with IPF. We aimed to evaluate the implications of a newly proposed framework of acute respiratory deterioration (ARD) and AE-IPF in hospitalized patients., Methods: Using the data of an IPF cohort consisting of 225 consecutive patients, we retrospectively studied first hospitalizations from January 2008 to December 2017. We analysed the demographics and 90-day mortality of patients with AE-IPF and those with parenchymal cause of ARD other than AE., Results: Among 122 patients with first hospitalization for ARD, 35 patients were diagnosed with AE-IPF, including 11 patients with triggered AE. Parenchymal cause of ARD other than AE was diagnosed in 71 patients, and extra-parenchymal cause in 16 patients. Almost all hospitalized patients (93%) underwent chest CT, and 83% of patients with AE-IPF underwent bronchoalveolar lavage. There was a significant difference in the anti-inflammatory therapy between the AE-IPF group and parenchymal cause of ARD other than AE group (p < 0.001). AE-IPF was independently associated with poor survival in multivariate Cox proportional regression analysis., Conclusions: AE-IPF accounted for about 30% of first hospitalizations for ARD, and differentiation between AE-IPF and the other categories in ARD is important from a therapeutic and a prognostic point of view., (Copyright © 2018. Published by Elsevier Ltd.)

Unlabelled: Early allograft dysfunction (EAD) after liver transplantation is mostly a reversible event caused by factors related to ischemia/reperfusion (I/R) injury. EAD represents a hepatic injury associated with pre- and early post-transplant inflammatory cytokine responses. Aim of the present study was to evaluate the prognostic and diagnostic value of CRP in liver transplant recipients with EAD., Materials and Methods: Forty-seven patients with EAD were compared with 115 non-EAD patients. Pre- and post-transplant parameters were analyzed. EAD was defined based on postoperative liver function tests such as INR, bilirubin and liver enzymes. Statistical analysis was performed using SPSS version 18.0., Results: Pre-transplant liver enzyme were not significantly different in the two groups. At day 3, 5 and 10 post-transplant CRP was significantly higher in patients with EAD than in non-EAD patients (p⩽0.001 for all investigations) and remained consistently high in patients with EAD and low in non-EAD patients. EAD patients with high CRP at post-transplant days 3 and 5 showed lower survival at 6-month and 12-month post-transplant than patients with low CRP., Conclusion: Our results indicate a prognostic and diagnostic value of CRP in patients with early graft dysfunction and predict 6-month and 12-month mortality in liver transplant recipients., (Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate whether a panel of common biomedical markers can be utilized as trajectories to determine survival in pediatric burn patients., Background: Despite major advances in clinical care, of the more than 1 million people burned in the United States each year, more than 4500 die as a result of their burn injuries. The ability to predict patient outcome or anticipate clinical trajectories using plasma protein expression would allow personalization of clinical care to optimize the potential for patient survival., Methods: A total of 230 severely burned children with burns exceeding 30% of the total body surface, requiring at least 1 surgical procedure were enrolled in this prospective cohort study. Demographics, clinical outcomes, and inflammatory and acute-phase responses (serum cytokines, hormones, and proteins) were determined at admission and at 11 time points for up to 180 days postburn. Statistical analysis was performed using a 1-way analysis of variance, the Student t test, χ test, and Mann-Whitney test where appropriate., Results: Survivors and nonsurvivors exhibited profound differences in critical markers of inflammation and metabolism at each time point. Nonsurvivors had significantly higher serum levels of interleukin (IL)-6, IL-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, C-reactive protein, glucose, insulin, blood urea nitrogen, creatinine, and bilirubin (P < 0.05). Furthermore, nonsurvivors exhibited a vastly increased hypermetabolic response that was associated with increases in organ dysfunction and sepsis when compared with survivors (P < 0.05)., Conclusions: Nonsurvivors have different trajectories in inflammatory, metabolic, and acute phase responses allowing differentiation of nonsurvivors from survivors and now possibly allowing novel predictive models to improve and personalize burn outcomes.

Background: Inflammation plays a crucial role in the pathogenesis and prognosis of stroke. We studied the behavior of lipoprotein(a) [Lp(a)], ferritin, and albumin as acute phase reactants and their roles in the severity and mortality of stroke., Methods: We recruited 100 consecutive patients with acute ischemic stroke and 120 controls. Blood samples were drawn on days 1 and 7 and at both 3 and 6 months. Stroke was classified using Trial of Org 10172 in Acute Stroke Treatment classification. Stroke severity was assessed using the National Institutes of Health Stroke Scale. Prognosis at 6 months was assessed using the modified Rankin Scale, and mortality was assessed using the Kaplan-Meier analysis. Serum levels of interleukin-6 (IL-6), Lp(a), ferritin, and albumin were measured using enzyme-linked immunosorbent assay, immunoturbidimetry, and chemiluminescence commercial kits, respectively., Results: Levels of IL-6, Lp(a), and ferritin were consistently higher among cases than controls (P < .0001). Serum Lp(a) levels peaked at day 7 after stroke and tapered thereafter. Albumin levels were lower than controls on admission day and increased subsequently. In our study, Lp(a) acted as an acute phase reactant while albumin acted as a negative acute phase reactant. There was no association between Trial of Org 10172 in Acute Stroke Treatment subtype and elevated serum levels of Lp(a), albumin, and ferritin. Lp(a) and ferritin were high in patients with severe stroke. Albumin was negatively correlated with stroke severity. Serum levels of Lp(a) ≥ 77 mg/dL, albumin ≤ 3.5 g/dL, and ferritin ≥ 370 ng/dL is associated with a significantly increased risk of having a poorer outcome in stroke. Serum levels of Lp(a) >77 mg/dL and albumin <3.5 g/dL were also associated with increased mortality., Conclusions: High levels of Lp(a) and ferritin and low levels of albumin are associated with increased severity and poorer long term prognosis of stroke. Patients with admission levels of Lp(a) >77 mg/dL and albumin <3.5 g/dL had increased mortality., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The paradigm of systemic inflammatory response syndrome-to-compensatory anti-inflammatory response syndrome transition implies that hyperinflammation triggers acute sepsis mortality, whereas hypoinflammation (release of anti-inflammatory cytokines) in late sepsis induces chronic deaths. However, the exact humoral inflammatory mechanisms attributable to sepsis outcomes remain elusive. In the first part of this study, we characterized the systemic dynamics of the chronic inflammation in dying (DIE) and surviving (SUR) mice suffering from cecal ligation and puncture sepsis (days 6-28). In the second part, we combined the current chronic and previous acute/chronic sepsis data to compare the outcome-dependent inflammatory signatures between these two phases. A composite cytokine score (CCS) was calculated to compare global inflammatory responses. Mice were never sacrificed but were sampled daily (20 μl) for blood. In the first part of the study, parameters from chronic DIE mice were clustered into the 72, 48, and 24 h before death time points and compared with SUR of the same post-cecal ligation and puncture day. Cytokine increases were mixed and never preceded chronic deaths earlier than 48 h (3- to 180-fold increase). CCS demonstrated simultaneous and similar upregulation of proinflammatory and anti-inflammatory compartments at 24 h before chronic death (DIE 80- and 50-fold higher versus SUR). In the second part of the study, cytokine ratios across sepsis phases/outcomes indicated steady proinflammatory versus anti-inflammatory balance. CCS showed the inflammatory response in chronic DIE was 5-fold lower than acute DIE mice, but identical to acute SUR. The systemic mixed anti-inflammatory response syndrome-like pattern (concurrent release of proinflammatory and anti-inflammatory cytokines) occurs irrespective of the sepsis phase, response magnitude, and/or outcome. Although different in magnitude, neither acute nor chronic septic mortality is associated with a predominating proinflammatory and/or anti-inflammatory signature in the blood.

Background: High score of model for end-stage liver diseases (MELD) before liver transplantation (LT) indicates poor prognosis. Artificial liver support system (ALSS) has been proved to effectively improve liver and kidney functions, and thus reduce the MELD score. We aim to evaluate whether downgrading MELD score could improve patient survival after LT., Methodology/principal Findings: One hundred and twenty-six LT candidates with acute-on-chronic hepatitis B liver failure and MELD score ≥30 were included in this prospective study. Of the 126 patients, 42 received emergency LT within 72 h (ELT group) and the other 84 were given ALSS as salvage treatment. Of the 84 patients, 33 were found to have reduced MELD score (<30) on the day of LT (DGM group), 51 underwent LT with persistent high MELD score (N-DGM group). The median waiting time for a donor was 10 for DGM group and 9.5 days for N-DGM group. In N-DGM group there is a significantly higher overall mortality (43.1%) than that in ELT group (16.7%) and DGM group (15.2%). N-DGM (vs. ECT and DGM) was the only independent risk factor of overall mortality (P = 0.003). Age >40 years and the interval from last ALSS to LT >48 h were independent negative influence factors of downgrading MELD., Conclusions/significance: Downgrading MELD for liver transplant candidates with MELD score ≥30 was effective in improving patient prognosis. An appropriate ALSS treatment within 48 h prior to LT is potentially beneficial.

Therapeutic plasma exchange (PE) is the accepted therapy for thrombotic thrombocytopenic purpura (TTP). Because not all patients achieve remission, other treatment modalities have been used in addition to PE, but no randomized clinical trial evaluated their efficacy. The aim of this multicentric study was to compare the effectiveness of standard- versus high-dose methylprednisolone as an adjunctive treatment to PE in the acute phase of TTP. Sixty patients with idiopathic TTP were randomized to receive methylprednisolone 1 mg/kg/die intravenous or 10 mg/kg/die for 3 days, thereafter, 2.5 mg/kg/die in addition to PE. Both dosages of steroids were well tolerated. At the end of induction therapy (day 23), the percentage of patients failing to achieve complete remission was significantly higher in the standard dose (16 of 30) than in the high-dose group (seven of 30). Also, the number of cases without a good response at day 9 and the number of deaths were higher in the standard-dose arm, but the differences did not reach the statistical significance. Results of present study indicate that the association of PE with high-dose instead of standard-dose steroids reduces the percentage of TTP patients that fail to achieve complete remission.

DAP12 (KARAP) is a transmembrane signaling adaptor for a family of innate immunoreceptors that have been shown to activate granulocytes and monocytes/macrophages, amplifying production of inflammatory cytokines. Contrasting with these data, recent studies suggest that DAP12 signaling has an inhibitory role in the macrophage response to microbial products (Hamerman, J.A., N.K. Tchao, C.A. Lowell, and L.L. Lanier. 2005. Nat. Immunol. 6:579-586). To determine the in vivo role for DAP12 signaling in inflammation, we measured the response of wild-type (WT) and DAP12-/- mice to septic shock. We show that DAP12-/- mice have improved survival from both endotoxemia and cecal ligation and puncture-induced septic shock. As compared with WT mice, DAP12-/- mice have decreased plasma cytokine levels and a decreased acute phase response during sepsis, but no defect in the recruitment of cells or bacterial control. In cells isolated after sepsis and stimulated ex vivo, DAP12 signaling augments lipopolysaccharide-mediated cytokine production. These data demonstrate that, during sepsis, DAP12 signaling augments the response to microbial products, amplifying inflammation and contributing to mortality.

The physiological and pathophysiological functions of C-reactive protein (CRP), the classical acute-phase protein, are not well established, despite many reports of biological effects of CRP in vitro and in model systems in vivo. Limited, small scale experiments have suggested that rabbit and human CRP may both protect mice against lethal toxicity of Gram-negative bacterial LPS. However, in substantial well-controlled studies in C57BL/6 mice challenged with Escherichia coli O111:B4 LPS, we show in this work that significant protection against lethality was conferred neither by an autologous acute-phase response to sterile inflammatory stimuli given to wild-type mice 24 h before LPS challenge, nor by human CRP, whether passively administered or expressed transgenically. Male mice transgenic for human CRP, which mount a major acute-phase response of human CRP after LPS injection, were also not protected against the lethality of LPS from either E. coli O55:B5 or Salmonella typhimurium. Even when the acute-phase human CRP response was actively stimulated in transgenic mice before LPS challenge, no protection against LPS toxicity was observed. Indeed, male mice transgenic for human CRP that were pretreated with casein to stimulate an acute-phase response 24 h before LPS challenge suffered significantly greater mortality than unstimulated human CRP transgenic controls. Rather than being protective in this situation, human CRP may thus have pathogenic proinflammatory effects in vivo.

Objective: Recombinant human growth hormone (rHGH) has been shown to increase mortality in adult trauma patients; however, little has been reported on its side effects in children. The acute phase response has been suggested to be a contributing factor to trauma mortality. Therefore, the purpose of this study was to examine the effects of exogenous rHGH on the acute phase response in pediatric bum patients., Design: Prospective, randomized, double-blind study., Setting: Shriners Hospital for Children., Patients: Thermally injured pediatric patients, ranging in age from 0.1 to 16 yrs., Interventions: Twenty-eight thermally injured children received either 0.2 mg/kg/day of rHGH or saline (placebo) within 3 days of admission and for at least 25 days., Measurements and Main Results: Measurements were patient demographics, incidence of sepsis, inhalation injury, mortality, serum constitutive proteins, acute phase proteins, proinflammatory cytokines and insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3. No differences could be demonstrated in age, gender, burn size, incidence in sepsis (20% vs. 26%), inhalation injury (46% vs. 27%), or mortality (8% vs. 7%) between those receiving rHGH or placebo. Serum IGF-I and IGFBP-3 increased with rHGH treatment, whereas serum IGFBP-1 decreased compared with placebo (p < .05). Burned children treated with rHGH required significantly less albumin substitution to maintain normal levels compared with placebo (p < .05). Those receiving rHGH demonstrated a decrease in serum C-reactive protein and serum amyloid-A and an increase in serum retinol-binding protein compared with placebo (p < .05). rHGH decreased serum tumor necrosis factor-alpha and interleukin (IL)-1beta, whereas no changes were found for serum IL-1alpha, IL-6, and IL-10 compared with placebo (p < .05). Free fatty acids were elevated in burned children who received rHGH (p < .05)., Conclusion: Data indicate that rHGH does not increase mortality. rHGH decreased acute phase proteins, tumor necrosis factor-alpha, and IL-1beta, which is associated with increases in constitutive hepatic proteins and IGF-I.

There are few reports on factors that determine survival in advanced gastrointestinal cancer with weight loss. In these patients (n = 91, median weight loss 16.6%), we prospectively examined the importance of metastatic spread, anthropometry, blood parameters, Karnofsky performance status, appetite, and the acute-phase response as predictors of survival. Survival was calculated from date of assessment to the most recent clinic attendance (> or = 30 mo) or until death. On multivariate analysis, metastatic spread (p < 0.05), Karnofsky performance status (p < 0.01), and C-reactive protein concentration (p < 0.001) had independent prognostic value. In locally advanced disease (n = 64), Karnofsky performance status and C-reactive protein concentration remained significant. There was a significantly lower survival in patients with an acute-phase response (median 136 days) than in patients with no response (median 466 days; p < 0.01). Performance status and the acute-phase response are associated, independent of weight loss, with survival duration in advanced gastrointestinal cancer patients.

Aim: to study the clinical significance and potential utility of measuring serum amyloid A protein (SAA) compared with the classical acute phase protein, C-reactive protein (CRP)., Method: a 3 month prospective study on 66 women, mean age 83 years (range 69-106) and 33 men, mean age 84 years (range 69-95), admitted to the geriatric medicine unit at Hammersmith Hospital. CRP and SAA were determined on admission and at intervals throughout hospital stay; outcome end-points were death during the study, detection of infection, duration of admission and early re-admission to hospital after discharge., Results: CRP and SAA responses were highly correlated (r = 0.75, P = 0.0001). However, the SAA response was greater than that of CRP in most individuals, with a median ratio of initial SAA to CRP of 2.2 in patients with infective pathology and 1.6 in those with inflammatory pathology. Median (range) SAA on admission was 98 (0.1-940) mg/ml in patients with infection and was twice that observed in patients with other causes of inflammation, median value 50 (0.6-699) mg/l. There was no difference between median CRP on admission in patients with infection or inflammation, median value 53 (0.1-235) and 51.5 (5-246) mg/l respectively. Initial and peak levels of CRP, but not of SAA, were significantly greater in patients who subsequently died, whereas high levels of both proteins predicted length of admission and early re-admission., Conclusion: major elevations of the serum concentrations of CRP and SAA indicated serious disease and predicted poor outcome. Measurement of SAA as well as CRP enhanced the clinical utility of monitoring the acute phase response in 7% of patients with a diagnosis of infection.

A possible role for tumor necrosis factor (TNF) alpha during Trypanosoma cruzi infection was explored by using transgenic mice expressing in blood high levels of a soluble TNFR1-FcIgG3 fusion protein, which neutralizes the effects of TNF in vivo. Nontransgenic littermates were used as controls. The transgenic mice showed high susceptibility to T. cruzi infection. Inocula sublethal for control mice resulted in over 80% mortality associated with higher levels of parasites in the blood. In histological sections of the hearts of transgenic mice, large parasitic clusters without inflammatory cell infiltrates around the parasites were seen, while smaller parasitic clusters associated with leukocytes were seen in control mice. No difference in specific antibody response or lymphocyte composition of the spleen was found between transgenic and control mice, although the unresponsiveness of spleen cells to concanavalin A stimulation in vitro, typical of the acute phase of T. cruzi infection, was less pronounced in transgenic mice. Infected transgenic mice produced higher levels of gamma interferon than did control mice. These results confirm that TNF is involved in mechanisms leading to parasite clearance and protection from death in the acute phase of T. cruzi infection. More importantly, the data reveal that TNF is necessary for the establishment of effective tissue inflammation and parasite load control in acute experimental Chagas' disease myocarditis.

Septic shock remains a serious disorder associated with high mortality. Accumulating evidence indicates that TNF is a major and essential mediator of endotoxin shock. We report here that administration of an antibody against CD18 dramatically reduced endotoxin-induced shock in rabbits as revealed by prevention of severe hypotension, metabolic acidosis and a pathological change suggestive of disseminated intravascular coagulation with concomitant inhibition of elevation of plasma TNF activity. The anti-CD18 antibody also inhibited the hypotension induced by administering recombinant TNF. Furthermore, an antibody against a ligand for CD18 complexes, intercellular adhesion molecule-1, also prevented TNF-induced shock as well as endotoxin shock in rabbits. These observations suggest that adhesion of leukocytes to endothelium may be of primary importance in the action of TNF as well as in the production of TNF in vivo and that the antibody against adhesion molecules could be of therapeutic benefit in life-threatening septic shock in humans.

A prospective study of 135 secondary operations (> 24 h after trauma) in patients with multiple injuries (ISS 40.6 pts) was performed to determine specific and unspecific indicators of the inflammatory response that may indicate the degree of risk of postoperative organ failure in these patients. On the morning of the operation each patients' data were recorded and blood samples were collected. Patients were divided in those in whom respiratory, renal and/or hepatic failure developed or preexisting organ failure worsened by more than 20% from baseline within 2 days after the operation and those who had no complications. In 29 patients who were operated upon between 24 and 72 h after trauma only the pO2/FiO2 ratio allowed discrimination between the two groups. The overall accuracy of this parameter as a predictor of postoperative organ failure was 83%, with a sensitivity of 78% and a specificity of 85%. In 106 patients with secondary operations later than 72 h after trauma, neutrophil elastase, C-reactive protein and platelet count revealed the highest predictive accuracy, with cut-off values of 250 ng/ml, 11 mg/dl and 180 x 10(6)/ml, respectively. The combined accuracy of these three parameters in prediction of postoperative organ failure was 79% (sensitivity 73%, specificity 83%). In this group of patients the pO2/FiO2 ratio was of less value and blood pressure, heart rate, renal function parameters, lactate and coagulation parameters were of no value.(ABSTRACT TRUNCATED AT 250 WORDS)

One hundred patients with multiple injuries (mean ISS 37 patients) were prospectively evaluated over a period of 14 days following trauma. Significant differences in the blood levels of PMN elastase, cathepsin B, lactate, neopterin, C-reactive protein (CRP) and antithrombin III (ATIII) were found in non-survivors and in survivors with and without organ failure. On admission, a prediction of organ failure was possible with an accuracy of 63% to 69% (PMN elastase, cathepsin B, ATIII). Death was predictable with an 80% to 90% accuracy within the first 4 days (PMN elastase, lactate, CRP, neopterin). The prognostic value of these factors was comparable to trauma scores regarding organ failure and better with respect to death. Biochemical parameters may be helpful in estimating the severity of the injury and prognosis and in monitoring the ICU course of such patients.

Despite the wide-spread opinion, that early stabilisation of femur fractures in multiply injured patients is of advantage, there are no publications that unambiguously prove this statement. In contrast, primary fracture stabilisation of the femur with concomitant thoracic trauma seems to increase the rate of complications. The biochemical data of the prospective study presented here suggest, that operative stabilisation of femoral fractures imposes an additional trauma on the already compromised organism. The period between days 2 to 4, when the primary activation of humoral and cellular mediators has returned to normal levels, seems to be the best time for osteosyntheses of these fractures. The operation in this period allows intramedullary fixation--the biologically and biomechanically best fixation procedure--with low risk.