Heparin-binding protein, lysozyme, and inflammatory cytokines in bronchoalveolar lavage fluid as diagnostic tools for pulmonary infection in lung transplanted patients.

Pulmonary infection is a common complication after lung transplantation, and early detection is crucial for outcome. However, the condition can be clinically difficult to diagnose and to distinguish from rejection. The aim of this prospective study was to evaluate heparin-binding protein (HBP), lysozyme, and the cytokines interleukin (IL)-1ß, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF) in bronchoalveolar lavage fluid (BALF) as potential biomarkers for pulmonary infection in lung-transplanted patients. One hundred thirteen BALF samples from 29 lung transplant recipients were collected at routine scheduled bronchoscopies at 3 and 6 months, or on clinical indication. Samples were classified into no, possible, probable, or definite infection at the time of sampling. Rejection was defined by biopsy results. HBP, lysozyme, and cytokines were analyzed in BALF and correlated to likelihood of infection and rejection. All biomarkers were significantly increased in BALF during infection, whereas patients with rejection presented low levels that were comparable to noninfection samples. HBP, IL-1ß, and IL-8 were the best diagnostic markers of infection with area under the receiver-operating characteristic curve values of 0.88, 0.91, and 0.90, respectively. In conclusion, HBP, IL-1ß, and IL-8 could be useful diagnostic markers of pulmonary infection in lung-transplanted patients.

Microbiological findings in bronchoalveolar lavage fluid from lung transplant patients in Sweden.

BACKGROUND: Lung transplant patients experience a high risk of airway infections and microbial colonization of the lung due to constant exposure to the environment through inhaled microorganisms, denervation, reduced ciliary transport, and decreased cough. METHODS: In this nationwide prospective study on Swedish lung transplant patients, we evaluated the microbiological panorama of bacteria, fungi, and virus found in bronchoalveolar lavage fluid (BALF) obtained the first year after lung transplantation (LTx). Differences in microbiological findings depending of concomitant signs of infection and background factors were assessed. RESULTS: A total of 470 bronchoscopies from 126 patients were evaluated. Sixty-two percent (n = 293) of BALF samples had positive microbiological finding(s). Forty-six percent (n = 217) had bacterial growth, 29% (n = 137) fungal growth, and 9% (n = 43) were positive in viral PCR. In 38% of BALF samples (n = 181), a single microbe was found, whereas a combination of bacteria, fungi or virus was found in 24% (n = 112) of bronchoscopies. The most common microbiological findings were Candida albicans, Pseudomonas aeruginosa and coagulase negative Staphylococcus (in 42 (33%), 36 (29%), and 25 (20%) patients, respectively). Microbiological findings were similar in BALF from patients with and without signs of lung infection and the frequency of multidrug resistant (MDR) bacteria was low. No significant association was found between background factors and time to first lung infection. CONCLUSION: This study gives important epidemiologic insights and reinforces that microbiological findings have to be evaluated in the light of clinical symptoms and endobronchial appearance in the assessment of lung infections in lung transplant patients.

Prospective evaluation of a combination of fungal biomarkers for the diagnosis of invasive fungal disease in high-risk haematology patients.

We prospectively evaluated a combination of fungal biomarkers in adult haematology patients with focus on their clinical utility at different time points during the course of infection. In total, 135 patients were monitored once to twice weekly for serum (1-3)-ß-d-glucan (BG), galactomannan (GM), bis-methyl-gliotoxin and urinary d-arabinitol/l-arabinitol ratio. In all, 13 cases with proven or probable invasive fungal disease (IFD) were identified. The sensitivity of BG and GM at the time of diagnosis (TOD) was low, but within 2 weeks from the TOD the sensitivity of BG was 92%. BG >800 pg/mL was highly specific for IFD. At a pre-test probability of 12%, both BG and GM had negative predictive values (NPV) >0.9 but low positive predictive values (PPV). In a subgroup analysis of patients with clinically suspected IFD (pre-test probability of 35%), the NPV was lower, but the PPV for BG was 0.86 at cut-off 160 pg/mL. Among IFD patients, 91% had patterns of consecutively positive and increasing BG levels. Bis-methyl-gliotoxin was undetectable in 15 patients with proven, probable and possible IA. To conclude, BG was the superior fungal marker for IFD diagnosis. Quantification above the limit of detection and graphical evaluation of the pattern of dynamics are warranted in the interpretation of BG results.

Heparin-Binding Protein Measurement Improves the Prediction of Severe Infection With Organ Dysfunction in the Emergency Department.

OBJECTIVES: Early identification of patients with infection and at risk of developing severe disease with organ dysfunction remains a difficult challenge. We aimed to evaluate and validate the heparin-binding protein, a neutrophil-derived mediator of vascular leakage, as a prognostic biomarker for risk of progression to severe sepsis with circulatory failure in a multicenter setting. DESIGN: A prospective international multicenter cohort study. SETTING: Seven different emergency departments in Sweden, Canada, and the United States. PATIENTS: Adult patients with a suspected infection and at least one of three clinical systemic inflammatory response syndrome criteria (excluding leukocyte count). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Plasma levels of heparin-binding protein, procalcitonin, C-reactive protein, lactate, and leukocyte count were determined at admission and 12-24 hours after admission in 759 emergency department patients with suspected infection. Patients were defined depending on the presence of infection and organ dysfunction. Plasma samples from 104 emergency department patients with suspected sepsis collected at an independent center were used to validate the results. Of the 674 patients diagnosed with an infection, 487 did not have organ dysfunction at enrollment. Of these 487 patients, 141 (29%) developed organ dysfunction within the 72-hour study period; 78.0% of the latter patients had an elevated plasma heparin-binding protein level (>30 ng/mL) prior to development of organ dysfunction (median, 10.5 hr). Compared with other biomarkers, heparin-binding protein was the best predictor of progression to organ dysfunction (area under the receiver operating characteristic curve=0.80). The performance of heparin-binding protein was confirmed in the validation cohort. CONCLUSION: In patients presenting at the emergency department, heparin-binding protein is an early indicator of infection-related organ dysfunction and a strong predictor of disease progression to severe sepsis within 72 hours.

Lactococcus garvieae endocarditis presenting with subdural haematoma.

BACKGROUND: Lactococcus garvieae is a rare cause of infective endocarditis (IE) in humans and the bacterium can easily be misidentified. Intracranial haemorrhage often occurs in conjunction with IE, but subdural haemorrhage (SDH) is very rarely encountered. CASE PRESENTATION: The patient was an 81-year-old male with a history of cardiovascular disease and a prosthetic biologic aortic valve. He presented with fatigue and an acute onset of headache. Computed tomography (CT) revealed a left-sided fronto-temporal subdural haematoma. Low-grade fever was noted and blood cultures yielded growth of L. garvieae. Transesophageal echocardiography (TEE) revealed small vegetations on the native mitral valve and on the prosthetic aortic valve. Treatment with penicillin and tobramycin was initiated and the recovery was slow but uneventful. CONCLUSION: This is the first report of a case where SDH was the sole presenting neurological sign of IE. The case demonstrates that IE should be considered in patients with SDH where a history of trauma is absent, especially if the patient has fever or predisposing conditions such as a prosthetic heart valve.

A case of Mycobacterium goodii prosthetic valve endocarditis in a non-immunocompromised patient: use of 16S rDNA analysis for rapid diagnosis.

BACKGROUND: Mycobacterium goodii is a rare cause of significant infection. M. goodii has mainly been associated with lymphadenitis, cellulitis, osteomyelitis, and wound infection. CASE PRESENTATION: A case of a 76-year-old Caucasian female is presented. The patient developed a prosthetic valve endocarditis caused by M. goodii. She had also suffered from severe neurological symptoms related to a septic emboli that could be demonstrated as an ischemic lesion found on CT of the brain. Transesophageal echocardiography verified a large vegetation attached to the prosthetic valve. Commonly used blood culture bottles showed growth of the bacteria after 3 days. CONCLUSIONS: Although M. goodii is rarely involved in these kinds of severe infections, rapidly growing mycobacteria should be recognized during conventional bacterial investigations and identified by molecular tools such as analysis of 16S rDNA. Species identification of nontuberculous mycobacteria is demanding and is preferably done in collaboration with a mycobacterial laboratory. An early diagnosis provides the opportunity for adequate treatment. In the present case, prolonged antimicrobial treatment and surgery with replacement of the prosthetic valve was successful.

Heparin-binding protein: a diagnostic marker of acute bacterial meningitis.

BACKGROUND: The early detection of bacterial meningitis is crucial for successful outcome. Heparin-binding protein, a potent inducer of increased vascular permeability, is released from activated neutrophils in severe sepsis. OBJECTIVE: In this study we investigated whether heparin-binding protein levels in cerebrospinal fluid could be used as a diagnostic marker for acute bacterial meningitis. DESIGN: One prospective and one retrospective patient cohort from two university hospitals in Sweden were analyzed. SETTING AND PATIENTS: Cerebrospinal fluid samples were collected from 174 patients with suspected central nervous system infection. Thirty-seven patients with acute community-acquired bacterial meningitis, four patients with neurosurgical bacterial meningitis, 29 patients with viral meningitis or encephalitis, seven patients with neuroborreliosis, and 97 control patients were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cerebrospinal fluid samples were analyzed for the concentrations of heparin-binding protein, lactate, protein, glucose, neutrophils, and mononuclear cells. Heparin-binding protein levels were significantly higher (p < .01) in patients with acute bacterial meningitis (median 376 ng/mL, range 12-858 ng/mL) than in patients with viral central nervous system infection (median 4.7 ng/mL, range 3.0-41 ng/mL) or neuroborreliosis (median 3.6 ng/mL, range 3.2-10 ng/mL) or in control patients with a normal cerebrospinal fluid cell count (median 3.5 ng/mL, range 2.4-8.7 ng/mL). In the prospectively studied group, a heparin-binding protein concentration exceeding 20 ng/mL gave a sensitivity of 100%, a specificity of 99.2%, and positive and negative predictive values of 96.2% and 100%, respectively, in diagnosing acute bacterial meningitis. The area under the receiver-operating characteristic curve for heparin-binding protein was 0.994, which was higher than for the other investigated parameters. CONCLUSION: Elevated cerebrospinal fluid levels of heparin-binding protein distinguish between patients with acute bacterial meningitis and patients with other central nervous system infections.

Bacteremic sepsis leads to higher mortality when adjusting for confounders with propensity score matching.

One can falsely assume that it is well known that bacteremia is associated with higher mortality in sepsis. Only a handful of studies specifically focus on the comparison of culture-negative and culture-positive sepsis with different conclusions depending on study design. The aim of this study was to describe outcome for critically ill patients with either culture-positive or -negative sepsis in a clinical review. We also aimed to identify subphenotypes of sepsis with culture status included as candidate clinical variables. Out of 784 patients treated in intensive care with a sepsis diagnosis, blood cultures were missing in 140 excluded patients and 95 excluded patients did not fulfill a sepsis diagnosis. Of 549 included patients, 295 (54%) had bacteremia, 90 (16%) were non-bacteremic but with relevant pathogens detected and in 164 (30%) no relevant pathogen was detected. After adjusting for confounders, 90-day mortality was higher in bacteremic patients, 47%, than in non-bacteremic patients, 36%, p = 0.04. We identified 8 subphenotypes, with different mortality rates, where pathogen detection in microbial samples were important for subphenotype distinction and outcome. In conclusion, bacteremic patients had higher mortality than their non-bacteremic counter-parts and bacteremia is more common in sepsis when studied in a clinical review. For reducing population heterogeneity and improve the outcome of trials and treatment for sepsis, distinction of subphenotypes might be useful and pathogen detection an important factor.

Axillary abscess complicated by venous thrombosis: identification of Streptococcus pyogenes by 16S PCR.

We report a case of an axillary abscess with Streptococcus pyogenes complicated by venous thrombosis. Bacterial etiology and typing were obtained by PCR and sequencing of the 16S rRNA and M-protein genes from abscess material. The bacterium was of serotype M41, and serology indicated that it had expressed procoagulant factors.

Scores for sepsis detection and risk stratification - construction of a novel score using a statistical approach and validation of RETTS.

BACKGROUND: To allow early identification of patients at risk of sepsis in the emergency department (ED), a variety of risk stratification scores and/or triage systems are used. The first aim of this study was to develop a risk stratification score for sepsis based upon vital signs and biomarkers using a statistical approach. Second, we aimed to validate the Rapid Emergency Triage and Treatment System (RETTS) for sepsis. RETTS combines vital signs with symptoms for risk stratification. METHODS: We retrospectively analysed data from two prospective, observational, multicentre cohorts of patients from studies of biomarkers in ED. A candidate risk stratification score called Sepsis Heparin-binding protein-based Early Warning Score (SHEWS) was constructed using the Least Absolute Shrinkage and Selector Operator (LASSO) method. SHEWS and RETTS were compared to National Early Warning Score 2 (NEWS2) for infection-related organ dysfunction, intensive care or death within the first 72h after admission (i.e. sepsis). RESULTS: 506 patients with a diagnosed infection constituted cohort A, in which SHEWS was derived and RETTS was validated. 435 patients constituted cohort B of whom 184 had a diagnosed infection where both scores were validated. In both cohorts (A and B), AUC for infection-related organ dysfunction, intensive care or death was higher for NEWS2, 0.80 (95% CI 0.76-0.84) and 0.69 (95% CI 0.63-0.74), than RETTS, 0.74 (95% CI 0.70-0.79) and 0.55 (95% CI 0.49-0.60), p = 0.05 and p <0.01, respectively. SHEWS had the highest AUC, 0.73 (95% CI 0.68-0.79) p = 0.32 in cohort B. CONCLUSIONS: Even with a statistical approach, we could not construct better risk stratification scores for sepsis than NEWS2. RETTS was inferior to NEWS2 for screening for sepsis.

Heparin-binding protein: an early marker of circulatory failure in sepsis.

BACKGROUND: The early detection of circulatory failure in patients with sepsis is important for successful treatment. Heparin-binding protein (HBP), released from activated neutrophils, is a potent inducer of vascular leakage. In this study, we investigated whether plasma levels of HBP could be used as an early diagnostic marker for severe sepsis with hypotension. METHODS: A prospective study of 233 febrile adult patients with a suspected infection was conducted. Patients were classified into 5 groups on the basis of systemic inflammatory response syndrome criteria, organ failure, and the final diagnosis. Blood samples obtained at enrollment were analyzed for the concentrations of HBP, procalcitonin, interleukin-6, lactate, C-reactive protein, and the number of white blood cells. RESULTS: Twenty-six patients were diagnosed with severe sepsis and septic shock, 44 patients had severe sepsis without septic shock, 100 patients had sepsis, 43 patients had an infection without sepsis, and 20 patients had an inflammatory response caused by a noninfectious disease. A plasma HBP level > or = 15 ng/mL was a better indicator of severe sepsis (with or without septic shock) than any other laboratory parameter investigated (sensitivity, 87.1%; specificity, 95.1%; positive predictive value, 88.4%; negative predictive value, 94.5%). Thirty-two of the 70 patients with severe sepsis were sampled for up to 12 h before signs of circulatory failure appeared, and in 29 of these patients, HBP plasma concentrations were already elevated. CONCLUSION: In febrile patients, high plasma levels of HBP help to identify patients with an imminent risk of developing sepsis with circulatory failure.

A population-based study on the treatment and outcome of enterococcal prosthetic joint infections. A consecutive series of 55 cases.

AIM: Enterococci cause 2-11% of all prosthetic joint infections (PJI) and are generally considered difficult to treat. However, study-results are not consistent. In this study we present a population-based case series of 55 cases with enterococcal PJI, investigating treatment and outcome, as well as describing the affected patient population regarding demography and co-morbidities. METHODS: We identified all enterococcal PJIs in the Region of Skåne, Sweden, during a five-year period (2011-2015) and reviewed the patients' medical records. RESULTS: Fifty-five enterococcal PJIs were found. Enterococcus faecalis was the most frequently isolated species (84%), and poly-microbial infections were common (64%). Treatment with intention to cure was given to 43 (78%) cases. Debridement with retention of the implant and antibiotics (DAIR) was the most common surgical treatment strategy (71%), with a cure-rate of 72%. Overall cure-rate was 67%, and in cases where cure was intended, this was achieved in 80%. CONCLUSIONS: When cure is aimed for, the prognosis for enterococcal PJI is not so poor, and DAIR treatment can provide adequate results in many cases.

[Treatment of orthopedic implant-associated infections]. / Handläggning av infektioner vid ortopediska implantat en utmaning för vården.

The Swedish National Guidelines for Bone and Joint Infections were revised during 2018. The work was carried out on behalf of the Swedish Society for Infectious Diseases. The study group consists of senior consultants in infectious diseases, supported by specialists in orthopedic surgery, clinical microbiology and allergology when needed. The study group emphasizes that implant associated infections are challenging and requires multidisciplinary cooperation, including, but not limited to, specialists in orthopedic surgery, infectious diseases, clinical microbiology and radiology for optimal treatment results. All aspects of the clinical management are equally important; selecting the optimal antibiotic prophylaxis in arthroplasty as well as fracture surgery, early diagnosis of infection, adequate treatment, follow-up, and finally a structured evaluation of outcome. Profound and updated knowledge of treatment of biofilm related infection is necessary to achieve optimal results in patients with implant-associated infections. Future challenges include improved decision support for combining surgical treatment with selection of proper antibiotics, as well as management of antibiotic resistance, drug-drug interactions and adverse effects of antibiotic treatment.

NEWS2 is Superior to qSOFA in Detecting Sepsis with Organ Dysfunction in the Emergency Department.

Early administration of antibiotics is associated with better survival in sepsis, thus screening and early detection for sepsis is of clinical importance. Current risk stratification scores used for bedside detection of sepsis, for example Quick Sequential Organ Failure Assessment (qSOFA) and National Early Warning Score 2 (NEWS2), are primarily validated for death and intensive care. The primary aim of this study was to compare the diagnostic accuracy of qSOFA and NEWS2 for a composite outcome of sepsis with organ dysfunction, infection-related mortality within <72 h, or intensive care due to an infection. Retrospective analysis of data from two prospective, observational, multicentre, convenience trials of sepsis biomarkers at emergency departments were performed. Cohort A consisted of 526 patients with a diagnosed infection, 288 with the composite outcome. Cohort B consisted of 645 patients, of whom 269 had a diagnosed infection and 191 experienced the composite outcome. In Cohort A and B, NEWS2 had significantly higher area under receiver operating characteristic curve (AUC), 0.80 (95% CI 0.75-0.83) and 0.70 (95% CI 0.65-0.74), than qSOFA, AUC 0.70 (95% CI 0.66-0.75) and 0.62 (95% CI 0.57-0.67) p < 0.01 and, p = 0.02, respectively for the composite outcome. NEWS2 was superior to qSOFA for screening for sepsis with organ dysfunction, infection-related mortality or intensive care due to an infection both among infected patients and among undifferentiated patients at emergency departments.

Heparin-Binding Protein as a Prognostic Biomarker of Sepsis and Disease Severity at the Emergency Department.

OBJECTIVE: Rapid and early detection of patients at risk to develop sepsis remains demanding. Heparin-binding protein (HBP) has previously demonstrated good prognostic properties in detecting organ dysfunction among patients with suspected infections. This study aimed to evaluate the plasma levels of HBP as a prognostic biomarker for infection-induced organ dysfunction among patients seeking medical attention at the emergency department. DESIGN: Prospective, international multicenter, convenience sample study. SETTING: Four general emergency departments at academic centers in Sweden, Switzerland, and Canada. PATIENTS: All emergency encounters among adults where one of the following criteria were fulfilled: respiratory rate >25 breaths per minute; heart rate >120 beats per minute; altered mental status; systolic blood pressure <100 mm Hg; oxygen saturation <90% without oxygen; oxygen saturation <93% with oxygen; reported oxygen saturation <90%. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A total of 524 emergency department patients were prospectively enrolled, of these 236 (45%) were eventually adjudicated to have a noninfectious disease. Three hundred forty-seven patients (66%) had or developed organ dysfunction within 72 h, 54 patients (10%) were admitted to an intensive care unit, and 23 patients (4%) died within 72 h. For the primary outcome, detection of infected-related organ dysfunction within 72 h, the area under the receiver operating curve (AUC) for HBP was 0.73 (95% CI 0.68-0.78) among all patients and 0.82 (95% CI 0.76-0.87) among patients confidently adjudicated to either infection or no infection. Against the secondary outcome, infection leading to admittance to the ICU, death or a persistent high SOFA-score due to an infection (SOFA-score ≥5 at 12-24 h) HBP had an AUC of 0.87 (95% CI 0.79-0.95) among all patients and 0.88 (95% CI 0.77-0.99) among patients confidently adjudicated to either infection or noninfection. CONCLUSIONS: Among patients at the emergency department, HBP demonstrated good prognostic and discriminatory properties in detecting the most severely ill patients with infection.

Sepsis Incidence: A Population-Based Study.

BACKGROUND: Although sepsis is a major health problem, data on sepsis epidemiology are scarce. The aim of this study was to assess the incidence of sepsis, based on clinical findings in all adult patients treated with intravenous antibiotic in all parts of all hospitals in an entire population. METHODS: This is a retrospective chart review of patients ≥18 years, living in 2 regions in Sweden, who were started on an intravenous antibiotic therapy on 4 dates, evenly distributed over the year of 2015. The main outcome was the incidence of sepsis with organ dysfunction. The mean population ≥18 years at 2015 in the regions was 1275753. Five hundred sixty-three patients living in the regions were started on intravenous antibiotic treatment on the dates of the survey. Patients who had ongoing intravenous antibiotic therapy preceding the inclusion dates were excluded, if sepsis was already present. RESULTS: Four hundred eighty-two patients were included in the study; 339 had a diagnosed infection, of those, 96 had severe sepsis according to the 1991/2001 sepsis definitions, and 109 had sepsis according to the sepsis-3. This is equivalent to an annual incidence of traditional severe sepsis of 687/100000 persons (95% confidence interval [CI], 549-824) or according to the sepsis-3 definition of 780/100000 persons (95% CI, 633-926). Seventy-four patients had sepsis according to both definitions. CONCLUSIONS: The incidence of sepsis with organ dysfunction is higher than most previous estimates independent of definition. The inclusion of all inpatients started on intravenous antibiotic treatment of sepsis in a population makes an accurate assessment of sepsis incidence possible.

Public Awareness of Sepsis Is Low in Sweden.

Background. Sepsis is a serious and common condition with high mortality and morbidity. The public awareness, knowledge, and perception of sepsis in Sweden are unknown. Methods. A survey was performed using an online interview distributed to adults, aged 18-74, between March 6 and 9, 2015. Results. A total of 1001 people responded to the survey. Twenty-one percent of participants had heard of sepsis, whereas more than 86% had heard of each of the other conditions listed; for example, stroke (95%), chronic obstructive pulmonary disease (COPD) (95%), and leukemia (92%). Of those who had heard of sepsis, 93% responded that it is an infection or blood poisoning in an open question. The respondents who had heard of each disease estimated its mortality. For sepsis, the mortality was estimated at an average of 30%, which was at the same level as estimated mortalities for prostate and breast cancer but lower than for stroke, COPD, and leukemia. Conclusions. The awareness and knowledge of sepsis is low. The mortality for sepsis is not as overestimated as for many other diseases. The lack of awareness of sepsis might be a target to improve the outcome for sepsis patients by reducing the prehospital delay and hence enable early interventions. An increased general awareness might also raise interest for funding for research in this area and for its priority in healthcare support.

Urine D-arabinitol/L-arabinitol ratio in diagnosing Candida infection in patients with haematological malignancy and HIV infection.

Adult patients with hematologic malignancies along with HIV infected patients were prospectively studied to determine the performance of urine D-arabinitol/L-arabinitol (DA/LA) ratio in diagnosing invasive candidiasis. Ten evaluable febrile neutropenic patients had proven invasive candidiasis and elevated DA/LA ratios were found in 5. Invasive candidiasis with normal DA/LA ratios was most frequently due to Candida krusei infection. This Candida species is a non-producer of arabinitol. Only 4 of 81 febrile neutropenic patients given either antifungal prophylaxis or empiric antifungal treatment had elevated DA/LA ratios. Only 1 of 15 HIV positive patients with either oropharyngeal or esophageal candidiasis had elevated DA/LA ratios. Widespread use of fluconazole prophylaxis in bone marrow transplantation patients at the study hospital has led to an increased prevalence of C. krusei infection. This is the likely reason for the low sensitivity of the test in proven and suspected invasive Candida infections reported here.