The role of obesity in the immune response during sepsis.

BACKGROUND/OBJECTIVES: Sepsis is one of the most important causes of mortality in the developed world, where almost two-thirds of the population suffer from obesity. Therefore, the coexistence of both conditions has become frequent in clinical practice and a growing number of clinical studies attempts to examine the potential effect of obesity on sepsis with controversial results up to now. The present study investigates how obesity influences the immune response of septic patients, by assessing the number and activation state of adipose tissue macrophages, serum and adipose tissue tumor necrosis factor-alpha (TNFα) levels and plasma oxidative stress markers. SUBJECTS/METHODS: The study included 106 patients, divided into four groups (control n=26, obesity n=27, sepsis n=27 and sepsis and obesity n=26). The number of macrophages in subcutaneous and visceral adipose tissue (SAT and VAT) and their subtypes (M1 and M2) were defined with immunohistochemical staining techniques under light microscopy. TNFα mRNA levels were determined in SAT and VAT using real-time reverse transcription-PCR. Serum levels of TNFα were determined with sandwich enzyme-linked immunosorbent assay. Plasma oxidative stress was evaluated using selective biomarkers (thiobarbituric acid-reactive substances (TBARS), protein carbonyls and total antioxidant capacity (TAC)). RESULTS: Sepsis increased the total number of macrophages and their M2 subtype in (VAT), whereas obesity did not seem to affect the concentration of macrophages in fat. Obesity increased TNFα mRNA levels (P<0.05) in VAT as well as the plasma TBARS (P<0.001) and protein carbonyls (P<0.001) in septic patients. The plasma TAC levels were decreased and the serum TNFα levels were increased in sepsis although they were not influenced by obesity. CONCLUSIONS: Obesity is associated with elevated TNFα adipose tissue production and increased oxidative stress biomarkers, promoting the proinflammatory response in septic patients.

Intestinal barrier dysfunction in HIV infection: pathophysiology, clinical implications and potential therapies.

INTRODUCTION: Current pathogenetic aspects on HIV infection highlight the importance of a chronic immune activation ultimately leading to T lymphocyte homeostasis disruption and immune deregulation associated with disease manifestations and progression. It is widely accepted that this continuous immune activation in HIV infection is principally driven by the phenomenon of pathological microbial translocation (MT). METHODS: Review of the literature on the role of intestinal barrier dysfunction in HIV infection, with emphasis on the implicated pathophysiological mechanisms, clinical implications and potentially effective therapeutic interventions. FINDINGS: MT in HIV infection is promoted by a multifactorial disruption of all major levels comprising the intestinal barrier defense. Specifically, HIV infection disrupts the integrity of the intestinal biological (quantitative and qualitative alterations of gut microecology, overgrowth of pathogenic bacteria), immune (depletion of CD4(+) T cells, especially Th17 cells, increased CD4+ FoxP3+ Tregs, decreased mucosal macrophages phagocytic capacity, development of intestinal proinflammatory milieu) and mechanical barrier (enterocytes' apoptosis, disruption of tight junctions). Intestinal barrier dysfunction allows the passage of microbes and immunostimulatory bioproducts from the gut lumen first in the lamina propria and thereafter in the systemic circulation, thus continuously promoting a local and systemic inflammatory response. This chronic immune activation is associated with HIV disease progression, suboptimal response to HAART and development of non-AIDS comorbidities. CONCLUSIONS: We have reached a point where the effective control of HIV viremia by HAART should be combined with emerging pharmacological approaches aiming at the restoration of the intestinal barrier, targeting its diverse levels of structure and function. Elimination of the MT phenomenon would mitigate its effect on immune homeostasis, which might improve the prognosis of the HIV-infected patient in terms of morbidity and mortality.

Good's syndrome and pure white cell aplasia complicated by cryptococcus infection: A case report and review of the literature.

Thymomas can present with a variety of paraneoplastic manifestations, mostly of autoimmune origin, including Good's syndrome when there is associated hypogammaglobulinemia. Although pure red cell aplasia is a recognised complication of thymoma, selective white cell aplasia is very rare, particularly in Good's syndrome. Lethal opportunistic infections are a feature of Good's syndrome, usually occurring in those patients with associated severe T lymphocyte defects. Although the cryptococcus is a recognised fungal pathogen in patients with other causes of CD4+ T cell lymphopenia, surprisingly this complication has not been reported in patients with Good's syndrome. We now describe a 70 year old man with Good's syndrome and pure white cell aplasia who presented with disseminated cryptococcosis, and provide an up-to-date review of the relevant literature. Despite meningeal involvement our patient recovered after combined treatment with intravenous globulin, granulocyte stimulating growth, corticosteroids and antifungal therapy.

Septic Thrombophlebitis Caused by Fusobacterium necrophorum in an Intravenous Drug User.

Septic thrombophlebitis is characterized by venous thrombosis, inflammation and bacteremia, that can lead to fatal complications such as sepsis, septic emboli and even death. Though most commonly caused by indwelling catheters, it is also related to intravenous drug users (IVDU) especially those who attempt to inject drugs into more proximal and central veins. Lemierre's syndrome, also referred to as post-anginal sepsis or necrobacillosis, is a suppurative thrombophlebitis of the internal jugular vein. Primary infection is associated with oropharyngeal and dental infections and the most common causative organism is Fusobacterium necrophorum. We report a case of Lemierre's syndrome in an IVDU, caused by Fusobacterium necrophorum, which was inoculated at the site of injection, without a history of sore throat or pharyngitis.

Red blood cell deformability in patients with human immunodeficiency virus infection.

Red blood cell (RBC) deformability is a major determinant of the ability of the RBC to pass repeatedly through the microcirculation. A decrease in RBC deformability leads to tissue perfusion and organ dysfunction. The purpose of this study was to measure the rigidity of RBCs from human immunodeficiency virus (HIV) seropositive individuals and investigate its relation to immune status and viral load. A filtration method based on the initial flow rate principle was used to determine the index of rigidity (IR) of 53 samples from HIV patients and 53 healthy individuals. The mean IR was significantly increased in patients with HIV compared to healthy individuals (P < 0.01). IR was inversely correlated with current CD4+ T-lymphocyte counts (P < 0.0001). High CD4 cell counts (>200 cells/microl) are related to low IR values, independently of the viral load (VL). No differences in rigidity were noted between the VL groups, although there was a trend towards an increased IR in patients with high VL within the group of CD4<200. RBC deformability is decreased in HIV disease, in a degree mainly related to CD4 depletion. Further studies are needed to elucidate the underlying mechanisms and the role of VL in highly immunocompromised HIV patients.

Prognostic value of phagocytic activity of neutrophils and monocytes in sepsis. Correlation to CD64 and CD14 antigen expression.

The role of the phagocytic function of monocytes and neutrophils in sepsis has been poorly investigated. The present study evaluated the impact of the phagocytic activity of neutrophils and monocytes on the outcome of patients with severe sepsis. Thirty-one patients and 30 healthy individuals were enrolled in the study. The phagocytic activity of monocytes and neutrophils was evaluated during 24 h after admission and the results were correlated to the expression of CD64 on neutrophils and monocytes, CD14 antigen on monocytes, the Simplified Acute Physiology Score II and the patients' survival. A reduced phagocytic activity of neutrophils during the first 24 h after admission was a negative predictor for survival. Increased expression of CD64 antigen on polymorphonuclear cells (PMNs) and monocytes was favourably correlated to the patients' survival. In multivariate analysis the phagocytic activity of PMNs was the only independent predictor factor for survival. Patients with PMN phagocytic activity <37% had lower expression of CD64 on monocytes and PMNs and worse outcome, while those with phagocytic activity >37% had higher expression of CD64 on monocytes and PMNs and better outcome. Reduced phagocytic activity of neutrophils may represent a state of neutrophil inactivation similar to that previously described for monocytes during the compensatory anti-inflammatory response.

Severe sepsis and diabetes mellitus have additive effects on red blood cell deformability.

OBJECTIVES: Diabetes mellitus is accompanied by microvascular complications leading to organ dysfunction, while sepsis is a major cause of morbidity and mortality in diabetics. We addressed the hypothesis that red blood cell (RBC) deformability may be additively compromised in septic diabetic patients, leading to a further impairment of microcirculation. METHODS: Forty patients suffering from severe sepsis, 12 patients suffering from diabetes and 24 diabetic patients with severe sepsis were enrolled. A filtration method and a hemorheometer were used to measure the RBCs' index of rigidity (IR). RESULTS: We observed no differences in severity, organ dysfunction and outcome between diabetic and non-diabetic septic patients. Mean SAPS II score was 23.5% vs 26.8% in non-diabetic and diabetic septic patients, respectively. The mortality in non-diabetic septic patients was 22.5% and in septic diabetics was 34.3%, while septic shock occurred in 15.0% and 20.8%, respectively. We detected higher IR (17.72+/-6.31) in septic diabetics than in patients with diabetes and no sepsis (12.26+/-2.28, p< or =0.001) and in patients with sepsis and no diabetes (13.9+/-2.86, p< or =0.01). CONCLUSION: The presence of diabetes mellitus seems to affect the already compromised RBC deformability of septic patients, probably leading to serious microcirculatory functional impairments in septic diabetic patients.

Oxaliplatin-induced acute-onset thrombocytopenia, hemorrhage and hemolysis.

BACKGROUND: Oxaliplatin is a novel platinum derivative with established anti-tumor activity in colorectal cancer. Acute-onset hemolytic anemia and thrombocytopenia associated with this drug have rarely been reported and some of these cases have been severe or even fatal. CASE REPORT: This case report describes a patient who developed fever, chills, abdominal and back pain as well as sudden-onset severe thrombocytopenia, upper gastrointestinal bleeding and hemolysis immediately after treatment with oxaliplatin for metastatic colorectal cancer. The reaction appeared during the 14th cycle of chemotherapy. Corticosteroids and antihistamines were administered together with platelet transfusions. Over the next 2 days platelet count improved and the syndrome abated. The patient was discharged 4 days later. Furthermore, the reaction was accompanied by a strongly positive Coombs test and increased TNF-alpha and IL-10 serum levels which returned to normal following anti-inflammatory drug administration. CONCLUSION: Physicians should be aware of the possibility of acute hematological emergencies following oxaliplatin administration.

Comparative effects of ciprofloxacin and ceftazidime on cytokine production in patients with severe sepsis caused by gram-negative bacteria.

In the present study the effect of ciprofloxacin versus ceftazidime on concentrations of pro- and anti-inflammatory cytokines in the sera of patients with severe sepsis was evaluated. The study included 58 previously healthy patients suffering from severe sepsis caused by gram-negative bacteria, treated with either ciprofloxacin or ceftazidime after thorough clinical and microbiological evaluation and followed up for clinical outcome. Levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1b (IL-1b), IL-6, and IL-8 and of the anti-inflammatory cytokine IL-10, as well as of IL-1 receptor antagonist and soluble TNF receptors I and II, in serum were measured at baseline and 24 and 48 h after the first antimicrobial dose. Mean SAPS-II scores, development of septic shock, and mortality rates were similar in the two groups (43.2 +/- 9.2, 21.4%, and 14.3% in the ceftazidime group versus 49.8 +/- 11.3, 20%, and 13.3% in the ciprofloxacin group). Serum TNF-alpha and IL-6 levels at 24 and 48 h were significantly lower in the ciprofloxacin group, while the IL-10/TNF-alpha ratio was significantly higher, than those for the ceftazidime group. Among patients with high baseline TNF-alpha levels, there were significant increases in the IL-10/TNF-alpha ratio at both 24 and 48 h over that at admission for the ciprofloxacin group, while no differences were noted in the ceftazidime group. These results indicate that ciprofloxacin may have an immunomodulatory effect on septic patients by attenuating the proinflammatory response, while there is no evidence that differences in the cytokines measured have any impact on the final outcome.

Five-day moxifloxacin therapy compared with 7-day co-amoxiclav therapy for the treatment of acute exacerbation of chronic bronchitis.

In this randomized, non-blinded study, the efficacy and safety of a 5-day course of moxifloxacin (one 400 mg tablet daily) was compared with that of co-amoxiclav (one 625 mg tablet every 8h) for 7 days, for the treatment of acute exacerbations of chronic bronchitis (AECB). A total of 162 patients with clear signs of an acute exacerbation of chronic bronchitis were enrolled. Of these, 153 could be studied. Seventy-nine patients were randomized in the moxifloxacin arm and 74 in the co-amoxiclav arm of the study. The primary efficacy parameter was clinical response at 14 days in the evaluable population. A clinical success was classified as resolution or improvement of symptoms. Variables used to assess clinical response included wheeze, cough, dyspnoea, sputum volume, rales and ronchi. The success rate in the moxifloxacin group was 88.6% (70 of 79) and that for co-amoxiclav group was 89.2% (66 of 74). At follow-up (28-35 days post-treatment), the continued clinical cure rates were 90.0% (63 of 70) for moxifloxacin and 89.4% (59 of 66) for co-amoxiclav. No significant differences were detected between the two groups. A total of 78 pathogenic bacteria were isolated from the sputum samples of the patients, with Moraxella catarrhalis, Haemophilus influenzae and Streptococcus pneumoniae being the most frequently isolated pathogens. The eradication rate at 14 days in the valid patients was similar for both groups, 90.9% (20 of 22) for the moxifloxacin group and 90.0% (18 of 20) for the co-amoxiclav group. Both drugs were well tolerated with no differences in the drug-related adverse effects or the patients withdrawing because of an adverse event. These results and the good spectrum of antibacterial activity make moxifloxacin a promising and also safe alternative for the empirical treatment of AECB.

Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections.

This study was performed to evaluate the impact of pro- and anti-inflammatory molecules and human leukocyte antigen DR (HLA-DR) expression as markers of immune status for the final outcome of septic patients. The study included 30 patients with severe sepsis due to community-acquired infections. Concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-8, IL-10, and transforming growth factor beta1 (TGF-beta1) in serum, as well as monocyte HLA-DR expression, were determined on admission and on days 3, 10, 13, and 17 during hospitalization. Of the 30 patients enrolled, 13 survived, while 17 died during their hospital stay. All patients had significantly lower HLA-DR expression and higher pro- and anti-inflammatory cytokine levels than healthy individuals. HLA-DR expression was significantly decreased in nonsurvivors at almost all time points. In nonsurvivors, higher levels in serum of TNF-alpha on days 13 and 17; IL-6 levels on day 3; and IL-10 on days 3, 10, and 13 were found. Baseline levels of TGF-beta1 were significantly higher in survivors. Independent risk factors of mortality were IL-10 levels on days 3 and 10, while monocyte HLA-DR expression on admission was a good predictor for survival. Several pro- and anti-inflammatory cytokines are oversynthesized during severe infections, especially in patients with a poor outcome. Monocyte HLA-DR expression is an early and constant predictive marker for survival in severe sepsis, while serum IL-10 levels on days 3 and 10 have negative prognostic value for the final outcome.

Prevalence of hepatitis B and C virus infection in the general population and selected groups in South-Western Greece.

Greece is a country of intermediate endemicity for hepatitis B and low endemecity for hepatitis C with a downward trend during the last years. In the present study we investigated the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in the region of South-Western Greece and tried to identify the most important risk factors of transmission. This is a unique epidemiological study, as it is the first community based study in the general population of Greece, with a methodological approach based on multi-staged random sampling. The prevalence of HBV infection seems to be decreasing with a 22.6% rate of HBV markers and a 2.1% rate of chronic HBV carriers. We found male sex, old age and intrafamiliar exposure as the major independent risk factors of HBV transmission, while sexual contact, absence of condom prophylaxis and living in rural areas seem to have also a significant impact for HBV infection. No relation was found between HBV transmission and working in health care facilities, pre-existing hospital admissions and history of transfusion. The prevalence of anti-bodies to the HCV was found 0.5%, even lower than the rate reported in the Mediterranean region. Parenteral exposure was the main risk factor for the transmission of HCV infection.

Remote abscess formation during interferon-alpha therapy for viral hepatitis.

Abscess formation at the injection site is an unusual infectious complication of interferon-alpha (IFN-alpha) treatment of chronic hepatitis C virus (HCV) infection, but remote abscess formation during IFN-alpha therapy is very rare. In the present communication, we report three cases of remote abscess formation detected among 68 patients with chronic viral hepatitis treated with IFN-alpha, and review the pertinent English literature. We believe that, as fever and constitutional symptoms are common side effects of IFN-alpha treatment, a high index of suspicion is indicated to exclude abscess formation in cases of unexplained fever during IFN-alpha therapy.

Keratoconjunctivitis sicca and chronic HCV infection.

BACKGROUND: The aim of this study was to determine the prevalence of keratoconjunctivitis sicca (KCS) in Greek patients with chronic hepatitis C virus (HCV) infection and its association with HCV genotypes and liver histology. PATIENTS AND METHODS: 93 HCVAb (+) patients underwent lacrimal function testing (Schirmer-1 test, break-up time test and Rose-Bengal staining test) and estimation of serum cryoglobulins and autoantibodies. 80 healthy volunteers were included in the study as controls. RESULTS: 34 out of 93 HCV patients (36.6%) and eight out of 80 healthy subjects (10%) had at least two abnormal lacrimal function tests suggestive of KCS (p < 0.001), cryoglobulinemia was evident in 20 patients (21.5%), rheumatoid factor (RF) in 43 (46.2%), antinuclear antibodies (ANA) in 19 (20.4%), antinuclear antigens (anti-SS-A and anti-SS-B) in one (1.1%) and two (2.2%) patients, respectively. Reduced prevalence of KCS was found in patients with genotype 3a compared to those with other genotypes (5/30, 16.7% vs 20/42, 47.6%, p = 0.007), probably because of their younger age. In patients with KCS a higher staging score was noted in liver biopsy compared to those without KCS (4.50 +/- 1.65 vs 3.06 +/- 1.88, p = 0.005). CONCLUSION: Greek patients with chronic HCV infection have a high prevalence of KCS (36.6%). The low frequency of anti-SS-A and anti-SS-B antibodies in these patients denotes different pathogenetic associations from primary Sjogren's syndrome.

Interleukin-6 and C-reactive protein as early markers of sepsis in patients with diabetic ketoacidosis or hyperosmosis.

AIMS/HYPOTHESIS: An early diagnosis of sepsis in patients with diabetic ketoacidosis and hyperosmolar non-ketotic coma is crucial and could save lives. We studied serum C-reactive protein and interleukin-6 to find out how useful these might be for identifying sepsis. METHODS: Sixty one diabetic patients with ketoacidosis or hyperosmolar non-ketotic coma were enrolled. Patients with signs and symptoms of systemic inflammatory response syndrome were identified. Acute-phase reactants, including C-reactive protein and interleukin-6, the main cytokine responsible for the induction of acute-phase proteins, were measured on admission and when patients had clinically improved and were euglycaemic. RESULTS: A total of 49 out of 61 patients with diabetic ketoacidosis or hyperosmosis had signs of systemic inflammatory response syndrome. Another 27 patients had systemic inflammatory response syndrome and no signs of infection and 22 patients had systemic inflammatory response syndrome due to proven infection. We detected a significant increase in serum C-reactive protein and interleukin-6 values in patients infected compared with patients not infected with systemic inflammatory response syndrome SIRS. Patients who finally died had much higher levels of these proteins, while there was a prompt reduction of serum C-reactive protein and interleukin-6 early during remission. CONCLUSION/INTERPRETATION: Diabetic ketoacidosis and hyperosmolar non-ketotic coma can often cause a clinical syndrome resembling systemic inflammatory response syndrome. Determination of serum C-reactive protein and interleukin-6 levels is a useful way of excluding an underlying infection early on as well as confirming and monitoring sepsis.

Fatty liver in obesity: relation to Doppler perfusion index measurement of the liver.

BACKGROUND: The correlation of clinical and laboratory findings with various imaging techniques in obese patients is difficult. Colour duplex Doppler is of particularly limited value in fat individuals. The Doppler Perfusion Index (DPI) measures the ratio of hepatic arterial to total liver blood flow and seems to be more accurate in the study of hepatic hemodynamics. The aim of the present study was to investigate the clinical use of DPI measurement of the liver in obesity. METHODS: In the present prospective, open study we evaluated the DPI in 41 obese patients (body mass index (BMI) > 30 kg/m2) and 18 volunteers with normal or slightly increased weight. Thirty patients of the study group underwent liver biopsy during bariatric surgery. In these patients liver histology was assessed and age, BMI, waist to hip ratio (WHR), DPI, liver function tests and serum triglycerides were measured. RESULTS: Obese patients had significantly (P = 0.0036) higher DPI values (0.25 +/- 0.138) than the healthy volunteers (0.15 +/- 0.04). Multivariate analysis revealed that grade of fatty liver in the study group was inversely associated with DPI and positively depended on serum triglyceride and aspartate aminotransferase (ASAT) levels (fatty liver index = 1.03 x ASAT (IU/l) + 0.152 x triglyceride (mg%) - 49.75*DPI, with P < 0.0001 and r2 = 0.80). CONCLUSION: Grade of fatty liver in obese patients may be predicted from DPI, serum triglyceride and AST levels. The proposed index may be useful as a non-invasive diagnostic tool during the follow-up of patients with obesity-related fatty liver.

Effect of cytokines and colony-stimulating factors on passive polymorphonuclear leukocyte deformability in vitro.

Cytokines are potent polymorphonuclear leukocyte (PMN) activators and can decrease their deformability. We evaluated passive PMN deformability using the micropipette method after incubation with different concentrations of lipopolysaccharide (LPS), interleukins (IL-) 1, 6, 8 and 10, tumour necrosis factor (TNF), granulocyte (G) and granulocyte-macrophage (GM) colony-stimulating factors (CSF). TNF, IL-1, G-CSF, GM-CSF and, to a lesser degree, IL-6 significantly and in a dose-dependent fashion decrease PMN deformability. LPS had no direct effect on PMN deformability. When cytokines at concentrations with no effect on deformability were combined they increased PMN rigidity. The findings suggest that several cytokines and CSF impair directly, and not by activation alone, PMN deformability.

The effects of lipids on the immune response of patients with cancer.

The role of diet and certain nutritional factors in the etiology or promotion of various malignant diseases has widely been studied. A link between dietary fat and cancer has long been proposed through various human epidemiologic and experimental data. High fat diets are associated with a high incidence and accelerated development of certain tumors, while there is evidence that dietary w-3 fatty acids have beneficial effects in cancer growth and metastasis. The relation between the different lipid formulations and cancer appears to be mainly related to the influence of specific fatty acids on the synthesis of the immunosuppressive prostaglandin E2. Omega-3 polyunsaturated fatty acids seem to have an anti-tumor effect through their immunomodulating, anti-inflammatory action and direct inhibition of tumor cell proliferation via alteration in prostaglandin E2 production.