Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants With Late-Onset Infection.

Importance: Infection in neonates remains a substantial problem. Advances for this population are hindered by the absence of a consensus definition for sepsis. In adults, the Sequential Organ Failure Assessment (SOFA) operationalizes mortality risk with infection and defines sepsis. The generalizability of the neonatal SOFA (nSOFA) for neonatal late-onset infection-related mortality remains unknown. Objective: To determine the generalizability of the nSOFA for neonatal late-onset infection-related mortality across multiple sites. Design, Setting, and Participants: A multicenter retrospective cohort study was conducted at 7 academic neonatal intensive care units between January 1, 2010, and December 31, 2019. Participants included 653 preterm (<33 weeks) very low-birth-weight infants. Exposures: Late-onset (>72 hours of life) infection including bacteremia, fungemia, or surgical peritonitis. Main Outcomes and Measures: The primary outcome was late-onset infection episode mortality. The nSOFA scores from survivors and nonsurvivors with confirmed late-onset infection were compared at 9 time points (T) preceding and following event onset. Results: In the 653 infants who met inclusion criteria, median gestational age was 25.5 weeks (interquartile range, 24-27 weeks) and median birth weight was 780 g (interquartile range, 638-960 g). A total of 366 infants (56%) were male. Late-onset infection episode mortality occurred in 97 infants (15%). Area under the receiver operating characteristic curves for mortality in the total cohort ranged across study centers from 0.71 to 0.95 (T0 hours), 0.77 to 0.96 (T6 hours), and 0.78 to 0.96 (T12 hours), with utility noted at all centers and in aggregate. Using the maximum nSOFA score at T0 or T6, the area under the receiver operating characteristic curve for mortality was 0.88 (95% CI, 0.84-0.91). Analyses stratified by sex or Gram-stain identification of pathogen class or restricted to infants born at less than 25 weeks' completed gestation did not reduce the association of the nSOFA score with infection-related mortality. Conclusions and Relevance: The nSOFA score was associated with late-onset infection mortality in preterm infants at the time of evaluation both in aggregate and in each center. These findings suggest that the nSOFA may serve as the foundation for a consensus definition of sepsis in this population.

Optimal Antibiotic Duration for Bloodstream Infections Secondary to Intraabdominal Infection.

BACKGROUND: Bloodstream infections (BSIs) secondary to intraabdominal infections (IAIs) are common in the intensive care unit (ICU). The Surgical Infection Society guidelines recommend treatment duration after achieving source control in patients with secondary bacteremia; however, literature supporting this recommendation is limited. The purpose of this study was to compare outcomes in patients who received shorter versus extended duration of antibiotics for bacteremia secondary to IAI. MATERIALS AND METHODS: A retrospective cohort analysis was conducted in adult surgical ICU patients (n = 42) with BSIs and source control procedure(s) for IAI. The primary outcome was recurrent IAI. Secondary outcomes included surgical site infections (SSIs), Clostridium difficile infections (CDIs), secondary fungal infections, and in-hospital mortality. RESULTS: Forty-two patients met inclusion criteria and were divided into groups according to antimicrobial duration; 12 patients received <7 d, and 30 patients received >7 d of antibiotics. There were no differences in baseline characteristics between the two cohorts except for the presence of sepsis [4/12 (33.3%) versus 27/30 (90.0%); P = 0.001]. Thirty-one percent (13/42) of all organisms isolated from blood cultures were gram-negative bacteria, 12/42 (28.6%) were MDROs, and 2/42 (4.8%) patients experienced a culture mismatch in which cultured bacteria were not susceptible to empiric antibiotic therapy. Rates of recurrent IAI were similar between the two cohorts [1/12 (8.3%) versus 4/30 (13.3%), P = 0.554]. CONCLUSIONS: Among surgical ICU patients with BSI secondary to IAI, cessation of antibiotic therapy within 7 d of source control was not associated with an increased incidence of recurrent IAI.

Association between Brachyspira and irritable bowel syndrome with diarrhoea.

OBJECTIVE: The incidence of IBS increases following enteric infections, suggesting a causative role for microbial imbalance. However, analyses of faecal microbiota have not demonstrated consistent alterations. Here, we used metaproteomics to investigate potential associations between mucus-resident microbiota and IBS symptoms. DESIGN: Mucus samples were prospectively collected from sigmoid colon biopsies from patients with IBS and healthy volunteers, and their microbial protein composition analysed by mass spectrometry. Observations were verified by immunofluorescence, electron microscopy and real-time PCR, further confirmed in a second cohort, and correlated with comprehensive profiling of clinical characteristics and mucosal immune responses. RESULTS: Metaproteomic analysis of colon mucus samples identified peptides from potentially pathogenic Brachyspira species in a subset of patients with IBS. Using multiple diagnostic methods, mucosal Brachyspira colonisation was detected in a total of 19/62 (31%) patients with IBS from two prospective cohorts, versus 0/31 healthy volunteers (p<0.001). The prevalence of Brachyspira colonisation in IBS with diarrhoea (IBS-D) was 40% in both cohorts (p=0.02 and p=0.006 vs controls). Brachyspira attachment to the colonocyte apical membrane was observed in 20% of patients with IBS and associated with accelerated oro-anal transit, mild mucosal inflammation, mast cell activation and alterations of molecular pathways linked to bacterial uptake and ion-fluid homeostasis. Metronidazole treatment paradoxically promoted Brachyspira relocation into goblet cell secretory granules-possibly representing a novel bacterial strategy to evade antibiotics. CONCLUSION: Mucosal Brachyspira colonisation was significantly more common in IBS and associated with distinctive clinical, histological and molecular characteristics. Our observations suggest a role for Brachyspira in the pathogenesis of IBS, particularly IBS-D.

[Master genes and co-expression network analysis in peripheral blood mononuclear cells of patients with gram-positive and gram-negative sepsis].

OBJECTIVE: To investigate the functional pathways enriched and differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of patients with gram-positive and gram-negative sepsis. METHODS: Dataset GSE9960 obtained from NCBI GEO database containing PBMC samples from 16 non-infectious systematic inflammatory response syndrome (SIRS) patients, 17 gram-positive septic patients and 18 gram-negative septic patients were included in the study. Functional pathway annotations were conducted by gene set enrichment analysis and weighted gene co-expression network analysis. DEGs were filtered and master DEGs were then validated in PBMCs of gram-positive septic, gram-negative septic and non-infectious SIRS patients. RESULTS: The enriched gene sets in gram-positive sepsis and gram-negative sepsis were significantly different. The results indicated the opposite co-expression networks in SIRS and gram-negative sepsis, and the entirely different co-expression networks in gram-positive and gram-negative sepsis. Furthermore, we validated that TYMS was up-regulated in gram-positive sepsis (P<0.05), CD3D was down-regulated in gram-negative sepsis (P<0.01), while IRAK3 was up-regulated in gram-negative sepsis (P<0.05). CONCLUSIONS: The results indicate that there are differences in the mechanism and pathogenesis of gram-positive and gram-negative sepsis, which may provide potential markers for sepsis diagnosis and empirical antimicrobial therapy.

Comparisons of clinical features and outcomes between Elizabethkingia meningoseptica and other glucose non-fermenting Gram-negative bacilli bacteremia in adult ICU patients.

BACKGROUND: Clinical information of Elizabethkingia meningoseptica (EM) bacteremia in intensive care unit (ICU) patients is limited and the impact on outcomes uncertain. The aim of this study was to investigate the clinical features and impact of EM bacteremia compared to other glucose non-fermenting Gram-negative bacilli (GNF-GNB) bacteremia in ICU patients. METHODS: This retrospective cohort study enrolled 70 patients who developed GNF-GNB bacteremia after ICU admission, including 19 cases of EM bacteremia (19/70, 27.1%). The main outcome measure was in-hospital mortality. RESULTS: The patients with EM bacteremia had a lower rate of appropriate antibiotic therapy (15.8% vs. 62.7%, p < 0.001) and a longer time to appropriate antibiotic therapy (76.8 ± 46.4 vs. 35.1 ± 38.7 h, p < 0.001), but with a less severity in acute physiology and chronic health evaluation (APACHE) II score and shock status (p < 0.05) at the onset of bacteremia, compared to those with non-EM bacteremia. The in-hospital mortality between those with EM bacteremia and non-EM bacteremia was similar (63.2% vs. 51.0%, p = 0.363). However, primary bacteremia was more frequently noted in EM compared with non-EM group (57.9% vs. 25.5%, p = 0.011), and odds ratio 4.294 (95% confidence interval 1.292-14.277, p = 0.017) in multivariate regression analysis. CONCLUSION: Among the patients with GNF-GNB bacteremia, the numbers of the cases with primary bacteremia and inappropriate therapy were significantly more in EM group than those in non-EM group.

Role of neuroendocrine modulation and biochemistry in the sepsis in Piaractus mesopotamicus.

Sepsis is a systemic process with multifactorial pathophysiology that affects most animal species. It is responsible for high rates of morbidity and mortality. This work aimed to study the biochemical and neuroendocrine changes of the sepsis process in Piaractus mesopotamicus after Aeromonas hydrophila inoculation analyzing changes in blood leukocyte and differences in neuroendocrine-biochemical modulation using RNA-seq. Fish showed hypercortisolemia, inhibition of glucose absorption, followed by hypocortisolemia and then hyperglycemia. Thyroid hormones (T3 and T4) showed immediate decrease in serum and T4 increased 6 h post-inoculation (HPI). Sepsis-induced hormonal alterations triggered changes in the metabolic pathways increasing protein and lipid catabolism, use of transient anaerobic glycolysis and liver injury. A reference transcriptome was constructed based on blood leukocytes from P. mesopotamicus. The assembly resulted in total 266,272 contigs with a N50 of 2786 bp. There was a reorganization of plasma membrane of leukocytes at the beginning of the septic process with increased expression of neuroendocrine receptors and with continuous flow of neurotransmitters, hormones and solutes with compensatory regulation at 6 HPI. Three and nine HPI seemed to be critical, the expression of a number of transcription factors was increased, including the modulatory DEGs related to glucocorticoid and thyroid hormones induced and suppressed (FDR < 0.05). Neuroendocrine modulation can regulate leukocytes and biochemical parameters of peripheral blood, being important sources for the study of the pathophysiology of sepsis. These finding highlights the importance of further studies focusing on biochemical-neuroendocrine changes in blood leukocytes and systemic sepsis.

Impairment of electroneutral Na+ transport and associated downregulation of NHE3 contributes to the development of diarrhea following in vivo challenge with Brachyspira spp.

The effect of Brachyspira hyodysenteriae and Brachyspira hampsonii spirochetosis on Na+ transport was assessed in the colon to determine its contribution to diarrheal disease in pigs following experimental infection. Electrogenic and electroneutral Na+ absorption was assessed in Ussing chambers by radiolabeled 22Na flux and pharmacological inhibitory studies. Basal radiolabeled 22Na flux experiments revealed that mucosal-to-serosal flux (Jms) was significantly impaired in B. hyodysenteriae and B. hampsonii-diseased pigs. Inhibition of epithelial sodium channel via amiloride did not significantly reduce electrogenic short-circuit current (Isc) in the proximal, apex, and distal colonic segments of diseased pigs over control pigs, suggesting that a loss of electroneutral Na+ absorption is responsible for diarrheal development. These findings were further supported by significant downregulation of Na+/H+ exchanger (NHE1, NHE2, and NHE3) mRNA expression in the proximal, apex, and distal colonic segments paired with decreased protein expression of the critical NHE3 isoform. The decrease in NHE3 mRNA expression appears not to be attributed to the host's cytokine response as human IL-1α did not modify NHE3 mRNA expression in Caco-2 cells. However, a whole cell B. hampsonii lysate significantly downregulated NHE3 mRNA expression and significantly increased p38 phosphorylation in Caco-2 cells. Together these findings provide a likely mechanism for the spirochete-induced malabsorptive diarrhea, indicated by a decrease in electroneutral Na+ absorption in the porcine colon due to Brachyspira's ability to inhibit NHE3 transcription, resulting in diarrheal disease.NEW & NOTEWORTHY This research demonstrates that diarrheal disease caused by two infectious spirochete spp. is a result of impaired electroneutral Na+ absorption via Na+/H+ exchanger 3 (NHE3) in the porcine colon. Our findings suggest that the decrease in NHE3 mRNA and protein is not likely a result of the host's cytokine response. Rather, it appears that these two Brachyspira spp. directly inhibit the transcription and translation of NHE3, resulting in the development of diarrhea.

Master genes and co-expression network analysis in peripheral blood mononuclear cells of patients with gram-positive and gram-negative sepsis / 浙江大学学报·医学版

OBJECTIVE@#To investigate the functional pathways enriched and differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of patients with gram-positive and gram-negative sepsis.@*METHODS@#Dataset GSE9960 obtained from NCBI GEO database containing PBMC samples from 16 non-infectious systematic inflammatory response syndrome (SIRS) patients, 17 gram-positive septic patients and 18 gram-negative septic patients were included in the study. Functional pathway annotations were conducted by gene set enrichment analysis and weighted gene co-expression network analysis. DEGs were filtered and master DEGs were then validated in PBMCs of gram-positive septic, gram-negative septic and non-infectious SIRS patients.@*RESULTS@#The enriched gene sets in gram-positive sepsis and gram-negative sepsis were significantly different. The results indicated the opposite co-expression networks in SIRS and gram-negative sepsis, and the entirely different co-expression networks in gram-positive and gram-negative sepsis. Furthermore, we validated that @*CONCLUSIONS@#The results indicate that there are differences in the mechanism and pathogenesis of gram-positive and gram-negative sepsis, which may provide potential markers for sepsis diagnosis and empirical antimicrobial therapy.

Successful application of CytoSorb® hemadsorption in an immunocompromised teenager with collapsing glomerulopathy, acute respiratory distress syndrome, and sepsis.

OBJECTIVE: CytoSorb® hemadsorption is an adjunctive therapy in order to reduce elevated cytokine levels of interleukin-6, interleukin-1, and tumor necrosis factor alpha. Here we present a successful administration of CytoSorb® hemadsorption in an immunocompromised pediatric patient with collapsing glomerulopathy, acute respiratory distress syndrome, and sepsis. DATA SOURCES: Clinical observations of one patient. STUDY SELECTION: Case report. DATA EXTRACTION: Data sources are clinical observation during patient management and patient's medical records if needed. The patient's consent was obtained prior to the study. DATA SYNTHESIS: A 17-year-old male with diarrhea was admitted to the hospital and was later found to have elevated creatinine levels and proteinuria. The renal biopsy was consistent with collapsing glomerulopathy and treatment with multi immunosuppressive agents including corticosteroids, mycophenolate mofetil, and rituximab coupled with several courses of hemodialysis and plasmapheresis were administered. During the hospital stay, Stenotrophomonas maltophilia bacteremia from the blood and the catheter cultures were identified. No clinical response was achieved, and patient developed severe sepsis despite antibiotics, intravenous immunoglobulin, and supportive management including albumin, platelet and erythrocyte concentrations, and fresh frozen plasma. CytoSorb® hemadsorption was then added to the ongoing treatment for three consecutive days. Subsequent to CytoSorb® hemadsorption, immediate laboratory and clinical response were observed. CONCLUSION: This is the successful clinical report of an immunocompromised teenager with collapsing nephropathy, sepsis, and multi-organ dysfunction syndrome treated with a combination of renal replacement therapy and CytoSorb® hemadsorption. The usage of CytoSorb® hemadsorption represents a novel approach to improve survival of the patients with multiple organ dysfunction and sepsis.

Fulminant gas-forming breast abscess associated with synergistic Veillonella infection.

We present a rare case of a rapidly fulminant and destructive breast abscess with gas production by the synergistic infection of Veillonella and Streptococcus species. To our knowledge, this is the first reported case of Veillonella infection in the breast. Early recognition, empiric antibiotic cover, aggressive surgical debridement, and drainage are necessary to avoid systemic septicemia. Staged reconstructive breast surgery allows for correction any resultant breast deformity.

Aeromonas hydrophila infection in silver catfish causes hyperlocomotion related to stress.

Aeromonosis is a fish disease that leads to haemorrhagic septicaemia and high mortality. The detection of early behavioural changes associated to this disease could be helpful in anticipating the initiation of treatment, increasing the probability of success. The influence of this disease on the hypothalamic-pituitary-interrenal (HPI) axis and on the brain expression of heat shock proteins (HSP) is little known. Therefore, the aim of this study was to evaluate the effect of Aeromonas hydrophila infection on individual behaviour and brain expression of genes related to stress (slc6a2, hsp90, hspa12a, hsd20b, hsd11b2, crh) in silver catfish (Rhamdia quelen). Thirty fish were divided into healthy and infected groups. The fish of the infected group were inoculated intramuscularly with 50 µL of bacterial suspension (6.4 × 108 CFU/mL), while control animals received 50 µL of saline. On day five post-infection, animals were submitted to the novel tank test, euthanized, and the brain was collected for molecular analysis. Infected fish swam more in the unknown aquarium and presented an increase in brain expression of genes related to HSP (hspa12a) and the route of cortisol synthesis (crh) when compared to uninfected fish. Therefore, this disease causes hyperlocomotion related to stress.

Multi-Omics Strategies Uncover Host-Pathogen Interactions.

With the success of the Human Genome Project, large-scale systemic projects became a reality that enabled rapid development of the systems biology field. Systems biology approaches to host-pathogen interactions have been instrumental in the discovery of some specifics of Gram-negative bacterial recognition, host signal transduction, and immune tolerance. However, further research, particularly using multi-omics approaches, is essential to untangle the genetic, immunologic, (post)transcriptional, (post)translational, and metabolic mechanisms underlying progression from infection to clearance of microbes. The key to understanding host-pathogen interactions lies in acquiring, analyzing, and modeling multimodal data obtained through integrative multi-omics experiments. In this article, we will discuss how multi-omics analyses are adding to our understanding of the molecular basis of host-pathogen interactions and systemic maladaptive immune response of the host to microbes and microbial products.

Mitral Annular Plane Systolic Excursion as a Predictor of Mortality in Children With Septic Shock.

OBJECTIVES: Myocardial dysfunction is well recognized in severe sepsis and septic shock. Echocardiography provides rapid, noninvasive, and bedside evaluation of cardiac function in patients with hemodynamic instability. Mitral annular plane systolic excursion is an M-mode-derived echocardiographic variable used to assess longitudinal left ventricular systolic function. No data are available about the uses of mitral annular plane systolic excursion in children with septic shock. Therefore, we aimed to assess the prognostic significance of mitral annular plane systolic excursion in children with septic shock and to correlate it with the most commonly used measures of left ventricular systolic function and myocardial injury. DESIGN: A prospective cohort study. SETTING: The study carried out at the PICU of Menoufia University Hospital in the period from March 2015 to September 2016. PATIENTS: We serially enrolled 50 children with septic shock. INTERVENTIONS: Complete diagnostic workup was performed for each patient including calculation of Pediatric Risk of Mortality III score. Transthoracic echocardiography was done to obtain mitral annular plane systolic excursion and the left ventricular ejection fraction measurement within 24 hours of inclusion then repeated on third and fifth days. Patients were followed up until hospital discharge or death. The predictive power of mitral annular plane systolic excursion was determined using the receiver operating characteristic curve. MEASUREMENTS AND MAIN RESULTS: Mitral annular plane systolic excursion was significantly lower in nonsurvivors compared with survivors (p < 0.001). Receiver operating characteristic curve analysis showed an area under the curve of 0.892 for mitral annular plane systolic excursion on day 1. The cut-off point was 7.9 mm with 82.76% sensitivity and 80.95% specificity. Furthermore, follow-up of the patient's systolic function showed that mitral annular plane systolic excursion was significantly lower in nonsurvivors compared with survivors on days of follow-up, whereas left ventricular ejection fraction was not significantly different between survivors and nonsurvivors at any day. Mitral annular plane systolic excursion was positively correlated with left ventricular ejection fraction (p = 0.044) and duration of hospital stay (p < 0.001) and negatively correlated with Pediatric Risk of Mortality III score (p < 0.001) and cardiac troponin I level (p < 0.001). CONCLUSIONS: Measurement of mitral annular plane systolic excursion at admission added a prognostic value in septic shock children. Compared with the left ventricular ejection fraction, longitudinal systolic function might be more sensitive in the detection of myocardial dysfunction in critically ill children and should receive more attention.

Potential pathogenicity of Inquilinus limosus in a pediatric patient with cystic fibrosis.

PRESENTATION: Patient is a 6-year-old male with CF, MRSA colonization, and pancreatic insufficiency that presented with worsening ppFEV1 and systemic symptoms despite multiple interventions. BAL grew NTM, Stenotrophomonas maltophilia, and Inquilinus limosus, a rare organism found in patients with CF. COURSE: I. limosus treatment was deferred. Despite treatment of other pathogens, symptoms worsened. I. limosus was targeted with meropenem, amikacin, and ciprofloxacin along with clindamycin for MRSA colonization. Within weeks, symptoms had resolved with ppFEV1 improvement. DISCUSSION: This case discusses the importance of a rare organism in the CF population. Targeting I. limosus was key to recovery, revealing its potential pathogenicity.

Effect of respiratory Achromobacter spp. infection on pulmonary function in patients with cystic fibrosis.

PURPOSE: Cystic fibrosis (CF) patients are susceptible to infection with Achromobacter spp., although its clinical significance remains controversial. The aim of this study was to investigate the clinical impact of infection with Achromobacter spp. in CF patients. METHODS: CF outpatients with multiple sputum cultures and follow-up lung function tests were assigned to the case group (infected with Achromobacter spp.) or the control group (never infected with Achromobacter spp.) according to the isolation of Achromobacter spp. The Achromobacter spp. group included two subgroups, taking into consideration whether the isolation of Achromobacter spp. was intermittent or chronic. Baseline lung function tests and longitudinal behaviour were examined in relation to Achromobacter spp. status. RESULTS: A total of 190 CF patients were treated from January 2003 to December 2015 in the CF unit and 21 (11 %) had at least one positive culture for Achromobacter spp. Of these, 11/21 (52.4 %) patients were chronically infected with Achromobacter spp. An analysis of changes during follow-up showed the annual rate of FEV1 decline: -2.3±1.6 % in the Achromobacter spp. group compared to -1.1±0.9 % (P=0.02) in the control group. The chronically infected group also had a significantly greater decline in FEV1 compared to the control group (-2.9±1.9 vs -1.1±0.9; P=0.04). The mean number of annual pulmonary exacerbations during the study period was significantly higher in the case group (1.9±0.9 vs 1.1±0.8; P=0.03). CONCLUSIONS: The Achromobacter spp. status in CF shows a trend towards more severe airflow obstruction and an association with accelerated decline in lung function parameters.

Mixed pneumonic plague and nosocomial MDR-bacterial infection of lung: a rare case report.

BACKGROUND: Plague is a life-threatening disease caused by the bacterium, Yersinia pestis. Madagascar is the leading country for human plague cases worldwide. Human plague is a serious disease, particularly in its septicaemic and pneumonic forms. We report a case of pneumonic plague co-infected by a MDR-Stenotrophomonas maltophilia. CASE PRESENTATION: A 24 year-old man originated from Soavinandriana, a plague focus, felt uneasy and developed high fever with chills. He started treatment by himself, by private medical care and by a traditional healer for nine days moving several times from place to place. His condition had deteriorated when he presented to a district hospital with a syndrome of dyspnea, bronchial rale and altered state of consciousness. Two days later, plague diagnosis, performed as a last resort, revealed a positive F1 antigen on rapid diagnostic test. Additional tests (pla PCR and plague serology) evidenced a Y. pestis infection. However, streptomycin treatment did not achieve a complete recovery as the course of disease was complicated by the presence of MDR-S. maltophilia in his lung. This opportunistic infection could have been favored by an immunosuppression due to Y. pestis pulmonary infection and probably been acquired during his stay at a District Hospital. He was treated with a combination of ciprofloxacin and gentamycin and recovered fully. CONCLUSIONS: Pneumonic plague infection may promote another virulent or avirulent bacterial infection particularly when it is not initially suspected. However, coinfection is rarely described and its occurrence frequency is unknown. In middle or low resources areas, which is the case of most plague endemic countries, control and prevention of infections in health facilities is not optimal. Co-infection with an opportunistic pathogen agent, such as S. maltophilia, is a risk which must not be disregarded as demonstrated by this case report. When deciding of a national control strategy, it should be taken into account in the choice of the first line treatment.