Bacteremia in Patients with Sepsis in the ICU: Does It Make a Difference?

Sepsis (and septic shock) is on of the most common causes of death worldwide. Bacteremia often, but not necessarily, occurs in septic patients, but the impact of true bacteremia on a patient's clinical characteristics and outcome remains unclear. The main aim of this study was to compare the characteristics and outcome of a well-defined cohort of 258 septic patients with and without bacteremia treated in the intensive care unit (ICU) of a tertiary center hospital in Prague, Czech Republic. As expected, more frequently, bacteremia was present in patients without previous antibiotic treatment. A higher proportion of bacteremia was observed in patients with infective endocarditis as well as catheter-related and soft tissue infections in contrast to respiratory sepsis. Multivariant analysis showed increased severity of clinical status and higher Charlson comorbidity index (CCI) as variables with significant influence on mortality. Bacteremia appears to be associated with higher mortality rates and length of ICU stay in comparison with nonbacteremic counterparts, but this difference did not reach statistical significance. The presence of bacteremia, apart from previous antibiotic treatment, may be related to the site of infection.

Sepsis as a Challenge for Personalized Medicine.

Sepsis is a clinical syndrome of systemic inflammation induced by infection, now defined as life-threatening organ dysfunction caused by a dysregulated immune response to infection [...].

Mendelian Susceptibility to Mycobacterial Disease: The First Case of a Diagnosed Adult Patient in the Czech Republic.

We present a case of a 42-year-old woman with Mendelian susceptibility to mycobacterial disease. The disease was diagnosed at an adult age with relatively typical clinical manifestations; the skeleton, joints, and soft tissues were affected by nontuberculous mycobacteria: Mycobacterium lentiflavum, M. kansasii, and M. avium. A previously published loss-of-function and functionally validated variant NM_000416.2:c.819_822delTAAT in IFNGR1 in a heterozygous state was detected using whole-exome sequencing. After interferon-γ therapy was started at a dose of 200 µg/m2 three times a week, there was significant clinical improvement, with the need to continue the macrolide-based combination regimen. In the last 4 months, she has been in this therapy without the need for antibiotic treatment.

Czech Hizentra Noninterventional Study With Rapid Push: Efficacy, Safety, Tolerability, and Convenience of Therapy With 20% Subcutaneous Immunoglobulin.

PURPOSE: Immunoglobulin substitution therapy is an essential therapeutic approach for patients with primary antibody deficiencies. Different methods of administration, including intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) preparations, provide effective and tolerable treatment and enable the adjustment of therapy to patients' needs. A new 20% SCIG represents a new therapeutic option and a new route of administration using rapid-push application. The aim of the Czech Hizentra Noninterventional Study With Rapid Push (CHHINSTRAP) is to evaluate patient satisfaction with as well as the tolerability and efficacy of nonmedical switch to 20% SCIG from previous treatment with IVIG or SCIG and rapid push as a new way to administer SCIG. CHHINSTRAP is the first Phase IV, noninterventional, open-label, prospective, multicentric study of this type conducted in Central and Eastern Europe. METHODS: Primary end points, including efficacy, adverse effects, convenience of use, and overall satisfaction, were evaluated by Treatment Satisfaction Questionnaire for Medication version II. Secondary end points, such as serum IgG trough levels, infusion duration, number of application sites, frequency of infections, related hospital admissions, and antibiotic consumption, were obtained from patients at each follow-up visit. FINDINGS: Together, 50 eligible patients with primary antibody deficiency were switched from SCIG or IVIG to an equivalent dose of 20% SCIG and were followed up for 12 months during 5 consecutive visits. The results indicate that patients switched from previous IVIG or SCIG preparations had significantly higher serum trough IgG levels and a lower incidence of infections and related events, such as hospital admissions or consumption of antibiotics. These findings were also reflected in gradually increasing convenience of use and overall satisfaction reported by patients. Apart from duration of application, no differences were found between patients previously receiving SCIG or IVIG. Moreover, our study found a high level of safety of 20% SCIG rapid push, which was comparable to other preparations and application methods. IMPLICATIONS: On the basis of the results of CHHINSTRAP study, we conclude that 20% SCIG is a tolerable and effective immunoglobulin preparation, representing a new therapeutic approach in patients with primary antibody deficiencies. Its efficacy and tolerability have been found in patients on nonmedical switch from previous treatment with IVIG or SCIG.

Kinetics of Myristic Acid Following Accidentally Induced Septic Response.

Myristic acid was identified as a metabolite with the highest diagnostic sensitivity and specificity in the metabolome of patients with bacteraemia. Subsequently, its significant decrease was observed in patients in septic shock not responding to treatment. In our study we have captured myristic acid serum level kinetics in 96 hours following accidental intravenous self-administration of eubiotic Hylak forte causing infection-like systemic inflammatory response syndrome (SIRS). To our knowledge, this is the first time the kinetics of myristic acid levels is presented in a septic patient. Myristic acid was evaluated in comparison with other inflammatory biomarkers and with its level in a control group of healthy subjects. Myristic acid levels during septic response were significantly elevated in comparison with the control group. The peak level was recorded almost immediately after the insult with a gradual decrease within 96 hours. Myristic acid appears to be a promising biomarker in sepsis diagnostics, further research by our group into this topic is ongoing.

Sepsis Diagnostics in the Era of "Omics" Technologies.

Sepsis is a multifactorial clinical syndrome with an extremely dynamic clinical course and with high diverse clinical phenotype. Early diagnosis is crucial for the final clinical outcome. Previous studies have not identified a biomarker for the diagnosis of sepsis which would have sufficient sensitivity and specificity. Identification of the infectious agents or the use of molecular biology, next gene sequencing, has not brought significant benefit for the patient in terms of early diagnosis. Therefore, we are currently searching for biomarkers, through "omics" technologies with sufficient diagnostic specificity and sensitivity, able to predict the clinical course of the disease and the patient response to therapy. Current progress in the use of systems biology technologies brings us hope that by using big data from clinical trials such biomarkers will be found.

Evaluation of IFN-γ Enzyme-linked Immunospot Assay (ELISPOT) as a First-line Test in the Diagnosis of Non-Immediate Hypersensitivity to Amoxicillin and Penicillin.

The current diagnostic algorithm for beta-lactam allergy is based on skin and provocation tests, both of which carry a certain risk of inducing hypersensitivity reactions. Thus, non-invasive in vitro tests reliable enough to replace skin and provocation tests at least in a portion of patients are desirable. We aimed to verify the utility of IFN-γ ELISPOT as a first-line test in patients with suspected non-immediate hypersensitivity reaction to amoxicillin (AMX) and penicillin (PNC). The prospective observational study included 24 patients with recent, suspected non-immediate hypersensitivity reaction to AMX or PNC and 6 recently-exposed healthy subjects. In vitro tests were performed in all patients and healthy subjects: a) IFN-γ ELISPOT with PNC, AMX and amoxicillin plus clavulanic acid (AMX-CL); b) penicillin specific IgE; c) basophil activation test (BAT). Skin and provocation tests followed only in certain patients. IFN-γ ELISPOT results with PNC and AMX stimulation did not differ from the unstimulated condition. The highest IFN-γ responses to AMX-CL were close to previously published criteria in three patients; one of which had true hypersensitivity according to drug provocation tests. Five patients with confirmed hypersensitivity by skin tests showed no response to the culprit antibiotic on IFN-γ ELISPOT assay. Our results did not support the utility of IFN-γ ELISPOT in the diagnosis of mild, non-immediate hypersensitivity to amoxicillin and penicillin.

Isolated Arteritis of Both Lower Limbs.

Isolated arteritis of the lower limb vessels is an extremely rare condition. The use of modern vascular imaging techniques substantially facilitates and accelerates the diagnostics. In the isolated lower limb arteritis, it is always necessary to exclude Takayasu's and giant-cell arteritis. We present the case of a female patient with an isolated lower extremity arteritis without any other symptoms of systemic vascular damage or systemic autoimmune disease. Immunosuppressive therapy is obligatory in this case. Interdisciplinary co-operation is required for rapid diagnosis and successful therapy. Our patient has consented to the publication of this report.

IgG4-related Disease - A Patient with Multiple Organ Involvement.

IgG4-related diseases represent a heterogeneous group of conditions characterised by elevated serum IgG4 levels and fibrotic or sclerosing changes in the affected organs or systems accompanied by IgG4-positive plasma cells. A disease associated with IgG4 may affect virtually any organ - salivary glands, periorbital tissue, kidneys, lungs, meninges, aorta, prostate, pericardium or skin. Histopathological findings are uniform, characterised by a major lymphoplasmocytic infiltrate and the presence of IgG4-producing plasma cells, irrespective of the affected site. It can be difficult to establish a correct diagnosis due to the lack of clinical symptoms. Treatment with immunosuppressive drugs provides good results and requires interdisciplinary cooperation.

Immunotherapy of Sepsis: Blind Alley or Call for Personalized Assessment?

Sepsis is the most frequent cause of death in noncoronary intensive care units. In the past 10 years, progress has been made in the early identification of septic patients and their treatment. These improvements in support and therapy mean that mortality is gradually decreasing, however, the rate of death from sepsis remains unacceptably high. Immunotherapy is not currently part of the routine treatment of sepsis. Despite experimental successes, the administration of agents to block the effect of sepsis mediators failed to show evidence for improved outcome in a multitude of clinical trials. The following survey summarizes the current knowledge and results of clinical trials on the immunotherapy of sepsis and describes the limitations of our knowledge of the pathogenesis of sepsis. Administration of immunomodulatory drugs should be linked to the current immune status assessed by both clinical and molecular patterns. Thus, a careful daily review of the patient's immune status needs to be introduced into routine clinical practice giving the opportunity for effective and tailored use of immunomodulatory therapy.

IgG4-related Diseases - A Rare Polycystic Form of Ormond's Disease.

Currently, Ormond's disease is classified among IgG4-associated diseases. Its clinical manifestation varies and is characterized by the presence of fibrous retroperitoneal tissue that often affects the ureters or abdominal aorta and iliac arteries. We present a unique case of the polycystic form of Ormond's disease, imitating tumour in the retroperitoneal space. At the time of diagnosis, the disease was not metabolically active and did not require immunosuppressive therapy. The polycystic mass was removed surgically. There has been no exacerbation of the disease during the last 12 months.

Combination of Steroids and Azathioprine in the Treatment of Ormond's Disease--A Single Centre Retrospective Analysis.

We present a retrospective analysis of patients treated in our Department of Clinical Biochemistry, Haematology and Immunology, Na Homolce Hospital, during 1997-2013 for Ormond's disease. We analyse the clinical history, diagnostic approaches, surgical, and immunosuppressive therapies and their subsequent effect on our patients. 28 patients treated for Ormond's disease were included. Patients with established disease activity (26 patients) were given immunosuppressive treatment, using corticosteroids in combination with azathioprine. Treatment response was evaluated using clinical symptomatology, inflammatory parameters and imaging methods. In the cohort as a whole, immunosuppressive therapy was applied in 26 patients; in two patients it was not used as no inflammatory activity was found with the disease. In all 26 patients, computed tomography showed that immunosuppressive treatment resulted in partial or complete regression of inflammatory infiltrate. Out of the total number of 26 patients, two patients experienced disease exacerbation 7 and 16 months after the immunosuppressive treatment was discontinued. The longest follow-up period was 16 years; the shortest one was 21 months. Idiopathic retroperitoneal fibrosis--Ormond's disease--is a disease with serious complications. Standard treatment involves a combination of surgery and immunosuppressive treatment. The combination of corticosteroids and azathioprine represents a potentially safe and useful method of treatment.

Ormond's Disease--IgG4-related Disease.

Ormond's disease is a relatively rare disease with unclear etiology, characterized by chronic periaortitis and retroperitoneal fibrosis. The inflammatory process affects the infrarenal part of the abdominal aorta and the iliac arteries, and the presence of infiltrates encasing the ureters and inferior vena cava. This disease is currently classed as an IgG4-related disease. In our review we analyse the clinical history, diagnostic approaches, surgical and immunosuppressive therapies.

Sepsis biomarkers.

Sepsis is the most frequent cause of death in non-coronary intensive care units (ICUs). In the past 10 years, progress has been made in the early identification of septic patients and in their treatment and these improvements in support and therapy mean that the mortality is gradually decreasing but it still remains unacceptably high. Leaving clinical diagnosis aside, the laboratory diagnostics represent a complex range of investigations that can place significant demands on the system given the speed of response required. There are hundreds of biomarkers which could be potentially used for diagnosis and prognosis in septic patients. The main attributes of successful markers would be high sensitivity, specificity, possibility of bed-side monitoring, and financial accessibility. Only a fraction is used in routine clinical practice because many lack sufficient sensitivity or specificity. The following review gives a short overview of the current epidemiology of sepsis, its pathogenesis and state-of-the-art knowledge on the use of specific biochemical, hematological and immunological parameters in its diagnostics. Prospective approaches towards discovery of new diagnostic biomarkers have been shortly mentioned.

Differences between the spectra of respiratory illnesses in children living in urban and rural environments.

A longitudinal study launched in 1994 within the framework of the Teplice Programme aimed at comparing the respiratory morbidity in children born (1994-1998) and living in the districts of Teplice (TE) and Prachatice (PRA) in the Czech Republic. Lists of all illnesses of 960 children from birth to 10 years of age were obtained from paediatric medical records. From 26,471 diagnoses (in ICD-10 codes), 34.7% were diagnoses of upper respiratory infections (URI, J00-02, J06), 11.3% of tonsillitis, 10.2% of influenza, 9.4% of bronchitis, 8.9% of laryngitis/tracheitis (J04), 2.7% of otitis media, and 0.5% of pneumonia. The more polluted district of Teplice was divided into two parts: the town itself (TE-town) and the rest of the district (TE-district). The cumulative incidence rates of the above respiratory illnesses per 100 children per 10 years were 2,212 in TE-town, 2,192 in PRA and 1,985 in TE-district. In the first two years of life, the children from TE-town had a significantly higher incidence of laryngitis/tracheitis, influenza, otitis media, and pneumonia and significantly lower incidence of bronchitis and tonsillitis than children living in PRA. The incidence rates of laryngitis/tracheitis and influenza in TE-town persisted as the highest among the three regions till the age of 10 years. The incidence rates of bronchitis (from the 1st to 5th year) and URI (from 4th to 10th year) were highest in children living in PRA. When compared to TE-town, children in TE-district had a higher incidence of upper respiratory infections (1-8 years) and lower incidence of bronchitis (6-8 years). Children in the district of Prachatice had a significantly higher prevalence of allergic rhinitis and a lower prevalence of wheezing than children in the district of Teplice. Thus, the three regions differed by the spectra of respiratory illnesses rather than by overall morbidity and, hypothetically, the effects of air pollution were obscurred by differences in the degree of urbanization.

Alteration in lipoprotein-associated phospholipase A2 levels during acute coronary syndrome and its relationship to standard biomarkers.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) probably plays an important role in the development of acute coronary syndrome (ACS); elevated levels of Lp-PLA2 are associated with a poorer prognosis in patients with ischemic heart disease. Alterations of Lp-PLA2 levels during ACS and its relationship to standard biomarkers are, however, unclear. FINDINGS: Fifty-one consecutive ACS patients were enrolled in the study. All were managed with early invasive strategy and according to the current guidelines for pharmacotherapy; intensive statin therapy was started in all patients at admission. Serum levels of Lp-PLA2, LDL-cholesterol (LDL), troponin l (Tnl), and C-reactive protein (CRP) were assessed at admission (D0), on the first morning (D1), and on the second morning of hospitalization (D2). Mean serum levels of Lp-PLA2 (ng/mL) decreased from 264.6±19.1 at D0, to 193.2±14.4 at D1 (P < 0.001 vs. D0) and 189.8±22.6 at D2 (P = 0.002 vs. D0; P = not significant vs. D1). Alterations in Lp-PLA2 levels significantly correlated with changes in LDL (r = 0.43; P = 0.008). On the other hand, no relationship between Lp-PLA2 and Tnl or CRP was found. CONCLUSIONS: Initially, serum levels of Lp-PLA2 were significantly elevated in ACS patients, but decreased within the first 24 hours after admission and subsequently remained stable. Lp-PLA2 levels correlated with LDL levels but not with Tnl or CRP levels. Our results demonstrated dynamic alterations in Lp-PLA2 levels during the early stages of ACS and, therefore, indirectly support the hypothesis of an active role for Lp-PLA2 in the pathogenesis of ACS.

Blood levels of copeptin on admission predict outcomes in out-of-hospital cardiac arrest survivors treated with therapeutic hypothermia.

INTRODUCTION: Prognostic stratification of cardiac arrest survivors is essential for the selection of the most appropriate therapeutic strategy. However, accurate early outcome predictions for this patient population remain challenging. At present, there is a lack of data examining the prognostic value of C-terminal provasopressin (copeptin) in cardiac arrest survivors. METHODS: A group of 40 out-of-hospital cardiac arrest survivors who were treated with endovascular hypothermia was analyzed. Copeptin levels were measured in blood samples taken at admission using a commercially available immunoassay. Neurological outcome was assessed at 30 days post admission according to the Cerebral Performance Category (CPC): CPC 1, no neurological deficit; CPC 2, mild to moderate dysfunction; CPC 3, severe dysfunction; CPC 4, coma; and CPC 5, death. RESULTS: Copeptin levels were significantly lower in patients with CPC 1 compared with CPC 2 or CPC 3 to CPC 5 (74.3 ± 14.4 pmol/l, 219.8 ± 33.9 pmol/l and 302.7 ± 52.1 pmol/l, respectively; P < 0.0001). Using an optimal cutoff value ≤ 217.9 pmol/l calculated from the receiver operating characteristic curve (area under curve = 0.801, 95% confidence interval = 0.644 to 0.910; P = 0.0001), the sensitivity of predicting survival with good neurological outcome was 78.6% and the specificity was 75.0%. Multiple logistic regression analysis revealed that a copeptin level > 217.9 pmol/l was an independent predictor of severe neurological dysfunction or death, with an adjusted odds ratio of 27.00 (95% confidence interval = 2.27 to 321.68; P = 0.009). CONCLUSION: The present study found that copeptin levels have a significant prognostic value at the time of hospital admission, and are a promising diagnostic tool for predicting outcomes in out-of-hospital cardiac arrest survivors.

Evaluation of aspirin's effect on platelet function early after coronary artery bypass grafting.

OBJECTIVE: Aspirin therapy decreases mortality and ischemic complication rates after coronary artery bypass grafting (CABG). However, platelet inhibition after oral aspirin seems to be insufficient in the early postoperative period. There are incomplete data reporting aspirin efficacy early after CABG. The aim of this study was to assess the pharmacologic effect of aspirin on platelets in the first postoperative days using the most specific laboratory tests for the evaluation of aspirin efficacy. DESIGN: A prospective study. SETTING: A clinical study in one cardiac surgery center and measurements in two pharmacologic institutions. PARTICIPANTS: Thirty patients. INTERVENTIONS: Postoperative aspirin efficacy (200 mg/d) was assessed by the suppression of serum thromboxane B(2) (TxB(2)) and by arachidonic acid-induced aggregometry using the MULTIPLATE analyzer. Samples were collected before surgery and on postoperative days 1-5. METHODS AND MAIN RESULTS: The median baseline value (range) of serum TxB(2) was 1.6 ng/mL (1.4-1.9). The median TxB(2) inhibition >90% (the value required for full platelet inhibition) was not achieved until day 5 (-91%, 0.13 ng/mL [0.08-0.22], p < 0.001) and in only 55% of patients. The median baseline ASPI value was 805 (640-975) aggregation units (AU)*min. A significant decrease in aspirin insufficiency was not seen before postoperative day 5 (390 [243-621], p < 0.003) and only 34% of patients reached an effective platelet inhibition on day 5 (cutoff < 300 AU*min). CONCLUSIONS: The effect of aspirin on inhibition of TxB(2) production and arachidonic acid-induced platelet aggregation is impaired during the first postoperative days after CABG. A more effective antiplatelet strategy presumably could increase early graft patency and improve clinical outcomes after CABG.

Valganciclovir prophylaxis against cytomegalovirus impairs lymphocyte proliferation and activation in renal transplant recipients.

BACKGROUND: Antiviral prophylaxis against cytomegalovirus has been associated with reduced risk of allograft rejection and improved allograft survival after renal transplantation. This phenomenon might not be fully explained by preventing the indirect effects of cytomegalovirus. The effect of antiviral agents on lymphocyte function in patients treated with modern immunosuppression has not been studied to date. METHODS: Adult renal transplant recipients were assigned to 3-month prophylaxis with either valganciclovir (900 mg once daily; n=19) or valacyclovir (2 g four times daily; n=17) as part of an ongoing randomized trial. Subsets of lymphocytes, lymphocyte proliferation and/or cytokine production after in vitro mitogen stimulation were evaluated at the end of prophylaxis and 1 month after withdrawal of antiviral drugs. RESULTS: Lymphocyte proliferation was significantly decreased both after phytohemagglutinine (25% ±15% versus 32% ±18%; P=0.025) and concanavalin A stimulation (17% ±9% versus 25% ±16%; P=0.011) during valganciclovir, but not valacyclovir therapy. Moreover, a lower activated T-cell count (CD3(+)HLA-DR(+) cells) was noted in valganciclovir-treated patients (13% ±10% versus 17% ±12% of total CD3(+) T-cells; P=0.005). CONCLUSIONS: Valganciclovir suppresses lymphocyte proliferation and activation in patients after renal transplantation.

[Diagnostics of sepsis]. / Diagnostika sepse.

Sepsis is a serious high mortality disease. As regards pathophysiology, it is a systemic inflammatory response to infection. Its timely diagnosis strongly influences mortality. The identification of biomarkers is used for diagnosing, monitoring, and prognosis in septic patients. The methods for their measurement cover a range of disciplines such as clinical biochemistry, haematology, immunology, and clinical microbiology. The most frequently used sepsis markers in routine clinical diagnostics are C-reactive protein and procalcitonin. The detection of selected cytokines, mediators, and surface markers in immunocompetent cells gives us further chance for improvement of this diagnostics. The methods of calculating gene expression represent a technology with a potential for the discovery of new biomarkers which would improve both diagnostics and therapy in the sense of personalized medicine.