Immunoglobulin Replacement Therapy Versus Antibiotic Prophylaxis as Treatment for Incomplete Primary Antibody Deficiency.

BACKGROUND: Patients with an IgG subclass deficiency (IgSD) ± specific polysaccharide antibody deficiency (SPAD) often present with recurrent infections. Previous retrospective studies have shown that prophylactic antibiotics (PA) and immunoglobulin replacement therapy (IRT) can both be effective in preventing these infections; however, this has not been confirmed in a prospective study. OBJECTIVE: To compare the efficacy of PA and IRT in a randomized crossover trial. METHODS: A total of 64 patients (55 adults and 9 children) were randomized (2:2) between two treatment arms. Treatment arm A began with 12 months of PA, and treatment arm B began with 12 months of IRT. After a 3-month bridging period with cotrimoxazole, the treatment was switched to 12 months of IRT and PA, respectively. The efficacy (measured by the incidence of infections) and proportion of related adverse events in the two arms were compared. RESULTS: The overall efficacy of the two regimens did not differ (p = 0.58, two-sided Wilcoxon signed-rank test). A smaller proportion of patients suffered a related adverse event while using PA (26.8% vs. 60.3%, p < 0.0003, chi-squared test). Patients with persistent infections while using PA suffered fewer infections per year after switching to IRT (2.63 vs. 0.64, p < 0.01). CONCLUSION: We found comparable efficacy of IRT and PA in patients with IgSD ± SPAD. Patients with persistent infections during treatment with PA had less infections after switching to IRT. CLINICAL IMPLICATION: Given the costs and associated side-effects of IRT, it should be reserved for patients with persistent infections despite treatment with PA.

Mortality prediction by SOFA score in ICU-patients after cardiac surgery; comparison with traditional prognostic-models.

BACKGROUND: There are many prognostic models and scoring systems in use to predict mortality in ICU patients. The only general ICU scoring system developed and validated for patients after cardiac surgery is the APACHE-IV model. This is, however, a labor-intensive scoring system requiring a lot of data and could therefore be prone to error. The SOFA score on the other hand is a simpler system, has been widely used in ICUs and could be a good alternative. The goal of the study was to compare the SOFA score with the APACHE-IV and other ICU prediction models. METHODS: We investigated, in a large cohort of cardiac surgery patients admitted to Dutch ICUs, how well the SOFA score from the first 24 h after admission, predict hospital and ICU mortality in comparison with other recalibrated general ICU scoring systems. Measures of discrimination, accuracy, and calibration (area under the receiver operating characteristic curve (AUC), Brier score, R2, and C-statistic) were calculated using bootstrapping. The cohort consisted of 36,632 Patients from the Dutch National Intensive Care Evaluation (NICE) registry having had a cardiac surgery procedure for which ICU admission was necessary between January 1st, 2006 and June 31st, 2018. RESULTS: Discrimination of the SOFA-, APACHE-IV-, APACHE-II-, SAPS-II-, MPM24-II - models to predict hospital mortality was good with an AUC of respectively: 0.809, 0.851, 0.830, 0.850, 0.801. Discrimination of the SOFA-, APACHE-IV-, APACHE-II-, SAPS-II-, MPM24-II - models to predict ICU mortality was slightly better with AUCs of respectively: 0.809, 0.906, 0.892, 0.919, 0.862. Calibration of the models was generally poor. CONCLUSION: Although the SOFA score had a good discriminatory power for hospital- and ICU mortality the discriminatory power of the APACHE-IV and SAPS-II was better. The SOFA score should not be preferred as mortality prediction model above traditional prognostic ICU-models.

Non-lytic antibiotic treatment in community-acquired pneumococcal pneumonia does not attenuate inflammation: the PRISTINE trial.

BACKGROUND: The inflammatory response in pneumococcal infection is primarily driven by immunoreactive bacterial cell wall components [lipoteichoic acid (LTA)]. An acute release of these components occurs when pneumococcal infection is treated with ß-lactam antibiotics. OBJECTIVES: We hypothesized that non-lytic rifampicin compared with lytic ß-lactam antibiotic treatment would attenuate the inflammatory response in patients with pneumococcal pneumonia. METHODS: In the PRISTINE (Pneumonia treated with RIfampicin aTtenuates INflammation) trial, a randomized, therapeutic controlled, exploratory study in patients with community-acquired pneumococcal pneumonia, we looked at LTA release and inflammatory and clinical response during treatment with both rifampicin and ß-lactam compared with treatment with ß-lactam antibiotics only. The trial is registered in the Dutch trial registry, number NTR3751 (European Clinical Trials Database number 2012-003067-22). RESULTS: Forty-one patients with community-acquired pneumonia were included; 17 of them had pneumococcal pneumonia. LTA release, LTA-mediated inflammatory responses, clinical outcomes, inflammatory biomarkers and transcription profiles were not different between treatment groups. CONCLUSIONS: The PRISTINE study demonstrated the feasibility of adding rifampicin to ß-lactam antibiotics in the treatment of community-acquired pneumococcal pneumonia, but, despite solid in vitro and experimental animal research evidence, failed to demonstrate a difference in plasma LTA concentrations and subsequent inflammatory and clinical responses. Most likely, an inhibitory effect of human plasma contributes to the low immune response in these patients. In addition, LTA plasma concentration could be too low to mount a response via Toll-like receptor 2 in vitro, but may nonetheless have an effect in vivo.

Intravesical Gentamicin Treatment for Recurrent Urinary Tract Infections Caused by Multidrug Resistant Bacteria.

PURPOSE: Antimicrobial resistance leads to complications in the management of recurrent urinary tract infections. In some patients with recurrent urinary tract infections who have limited treatment options intravenous therapy with reserve antibiotics is often required. In this study we assessed the effectiveness, safety and feasibility of prophylactic treatment with intravesical gentamicin in patients with refractory recurrent urinary tract infections caused by multidrug resistant microorganisms. MATERIALS AND METHODS: This was a prospective trial of 63 adults with recurrent urinary tract infections caused by multidrug resistant pathogens who were enrolled at 1 academic and 1 general hospital in The Netherlands between 2014 and 2017. The intervention was overnight intravesical instillations of gentamicin for 6 months. The primary outcome was the recurrence rate of urinary tract infections compared to that in the preceding 6 months. Secondary objectives included assessment of the safety of intravesical gentamicin instillation and its influence on the development of antibiotic resistance in uropathogens. RESULTS: The mean number of urinary tract infections was reduced from 4.8 to 1.0 during intravesical treatment. The resistance rate of the uropathogens decreased from 78% to 23%. No systemic absorption or clinically relevant side effects were observed. CONCLUSIONS: Intravesical gentamicin instillation reduced the number of urinary tract infection episodes and the degree of antimicrobial resistance.

Long-term Carriage of Extended-Spectrum ß-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae in the General Population in The Netherlands.

Background: This longitudinal study aimed to investigate (risk factors for) persistence of carriage and molecular characteristics of extended-spectrum and plasmid-encoded AmpC ß-lactamase-producing (ESBL/pAmpC) Escherichia coli and Klebsiella pneumoniae (ESBL-E/K) in adults in the Dutch community. Methods: Following a cross-sectional study (ESBL-E/K prevalence, 4.5%), a subset of ESBL-E/K-positive (n = 76) and -negative (n = 249) individuals volunteered to provide 5 monthly fecal samples and questionnaires. ESBL-E/K was cultured using selective enrichment/culture, and multilocus sequence types (MLSTs) were determined. ESBL/pAmpC-genes were analyzed using polymerase chain reaction (PCR) and sequencing. Plasmids were characterized and subtyped by plasmid MLST. Risk factors for persistent carriage were analyzed using logistic regression. Results: Of the initially ESBL-E/K-positive participants, 25 of 76 (32.9%) remained positive in all subsequent samples; 51 of 76 persons (67.1%) tested ESBL-E/K negative at some time point during follow-up, of which 31 (40.8%) stayed negative throughout the longitudinal study. Carriers often carried the same ESBL gene and plasmid, but sometimes in different ESBL-E/K strains, indicative for horizontal transfer of plasmids. Of the 249 initially ESBL-E/K-negative participants, the majority (n = 218 [87.6%]) tested negative during 8 months of follow-up, whereas 31 of 249 (12.4%) participants acquired an ESBL-E/K. Escherichia coli phylogenetic group B2 and D and travel to ESBL high-prevalence countries were associated with prolonged carriage. Conclusions: ESBL-E/K carriage persisted for >8 months in 32.9% of the initially ESBL-positive individuals, while 12.4% of initially negative individuals acquired ESBL-E/K during the study. A single positive test result provides no accurate prediction for prolonged carriage. Acquisition/loss of ESBL-E/K does not seem to be a random process, but differs between bacterial genotypes.

Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases.

IFN-γR1 defects: Mutation update and description of the IFNGR1 variation database.

IFN-γ signaling is essential for the innate immune defense against mycobacterial infections. IFN-γ signals through the IFN-γ receptor, which consists of a tetramer of two IFN-γR1 chains in complex with two IFN-γR2 chains, where IFN-γR1 is the ligand-binding chain of the interferon-γ receptor and IFN-γR2 is the signal-transducing chain of the IFN-γ receptor. Germline mutations in the gene IFNGR1 encoding the IFN-γR1 cause a primary immunodeficiency that mainly leads to mycobacterial infections. Here, we review the molecular basis of this immunodeficiency in the 130 individuals described to date, and report mutations in five new individuals, bringing the total number to 135 individuals from 98 kindreds. Forty unique IFNGR1 mutations have been reported and they exert either an autosomal dominant or an autosomal recessive effect. Mutations resulting in premature stopcodons represent the majority of IFNGR1 mutations (60%; 24 out of 40), followed by amino acid substitutions (28%, 11 out of 40). All known mutations, as well as 287 other variations, have been deposited in the online IFNGR1 variation database (www.LOVD.nl/IFNGR1). In this article, we review the function of IFN-γR1 and molecular genetics of human IFNGR1.

Recurrent respiratory tract infections (RRTI) in the elderly: A late onset mild immunodeficiency?

Elderly with late-onset recurrent respiratory tract infections (RRTI) often have specific anti-polysaccharide antibody deficiency (SPAD). We hypothesized that late-onset RRTI is caused by mild immunodeficiencies, such as SPAD, that remain hidden through adult life. We analyzed seventeen elderly RRTI patients and matched controls. We determined lymphocyte subsets, expression of BAFF receptors, serum immunoglobulins, complement pathways, Pneumovax-23 vaccination response and genetic variations in BAFFR and MBL2. Twelve patients (71%) and ten controls (59%) had SPAD. IgA was lower in patients than in controls, but other parameters did not differ. However, a high percentage of both patients (53%) and controls (65%) were MBL deficient, much more than in the general population. Often, MBL2 secretor genotypes did not match functional deficiency, suggesting that functional MBL deficiency can be an acquired condition. In conclusion, we found SPAD and MBL deficiency in many elderly, and conjecture that at least the latter arises with age.

Treatment duration of febrile urinary tract infection: a pragmatic randomized, double-blind, placebo-controlled non-inferiority trial in men and women.

BACKGROUND: In adults with febrile urinary tract infection (fUTI), data on optimal treatment duration in patients other than non-pregnant women without comorbidities are lacking. METHODS: A randomized placebo-controlled, double-blind, non-inferiority trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥ 18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days (the second week being ciprofloxacin 500 mg or placebo orally twice daily). Patients indicated to receive antimicrobial treatment for at least 14 days were excluded from randomization. The primary endpoint was the clinical cure rate through the 10- to 18-day post-treatment visit with preset subgroup analysis including sex. Secondary endpoints were bacteriologic cure rate at 10-18 days post-treatment and clinical cure at 70-84 days post-treatment. RESULTS: Of 357 patients included, 200 were eligible for randomization; 97 patients were randomly assigned to 7 days and 103 patients to 14 days of treatment. Overall, short-term clinical cure occurred in 85 (90%) patients treated for 7 days and in 94 (95%) of those treated for 14 days (difference -4.5%; 90% CI, -10.7 to 1.7; P non-inferiority = 0.072, non-inferiority not confirmed). In women, clinical cure was 94% and 93% in those treated for 7 and 14 days, respectively (difference 0.9; 90% CI, -6.9 to 8.7, P non-inferiority = 0.011, non-inferiority confirmed) and, in men, this was 86% versus 98% (difference -11.2; 90% CI -20.6 to -1.8, P superiority = 0.025, inferiority confirmed). The bacteriologic cure rate was 93% versus 97% (difference -4.3%; 90% CI, -9.7 to 1.2, P non-inferiority = 0.041) and the long-term clinical cure rate was 92% versus 91% (difference 1.6%; 90% CI, -5.3 to 8.4; P non-inferiority = 0.005) for 7 days versus 14 days of treatment, respectively. In the subgroups of men and women, long-term clinical cure rates met the criteria for non-inferiority, indicating there was no difference in the need for antibiotic retreatment for UTI during 70-84 days follow-up post-treatment. CONCLUSIONS: Women with fUTI can be treated successfully with antibiotics for 7 days. In men, 7 days of antibiotic treatment for fUTI is inferior to 14 days during short-term follow-up but it is non-inferior when looking at longer follow-up. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

A 38-year-old woman with necrotising cervical lymphadenitis due to Histoplasma capsulatum.

CASE PRESENTATION: We analysed a 38-year-old woman with disseminated histoplasmosis for primary immunodeficiency. Her blood showed no IFN-γ response while her peripheral blood mononuclear cells (PBMCs) did. We identified IFN-γ autoantibodies of the IgG class in her serum. CONCLUSION: IFN-γ autoantibodies leading to infections were so far mainly detected in people from Asian descent, where it was found to be associated with certain HLA types. This may be the first patient of African descent, and without the typical HLA types that predispose to this problem, that produces IFN-γ autoantibodies.

ICARES: a real-time automated detection tool for clusters of infectious diseases in the Netherlands.

BACKGROUND: Clusters of infectious diseases are frequently detected late. Real-time, detailed information about an evolving cluster and possible associated conditions is essential for local policy makers, travelers planning to visit the area, and the local population. This is currently illustrated in the Zika virus outbreak. METHODS: In the Netherlands, ICARES (Integrated Crisis Alert and Response System) has been developed and tested on three syndromes as an automated, real-time tool for early detection of clusters of infectious diseases. From local general practices, General Practice Out-of-Hours services and a hospital, the numbers of routinely used syndrome codes for three piloted tracts i.e., respiratory tract infection, hepatitis and encephalitis/meningitis, are sent on a daily basis to a central unit of infectious disease control. Historic data combined with information about patients' syndromes, age cohort, gender and postal code area have been used to detect clusters of cases. RESULTS: During the first 2 years, two out of eight alerts appeared to be a real cluster. The first was part of the seasonal increase in Enterovirus encephalitis and the second was a remarkably long lasting influenza season with high peak incidence. CONCLUSIONS: This tool is believed to be the first flexible automated, real-time cluster detection system for infectious diseases, based on physician information from both general practitioners and hospitals. ICARES is able to detect and follow small regional clusters in real time and can handle any diseases entity that is regularly registered by first line physicians. Its value will be improved when more health care institutions agree to link up with ICARES thus improving further the signal-to-noise ratio.

Hospitalization for community-acquired febrile urinary tract infection: validation and impact assessment of a clinical prediction rule.

BACKGROUND: There is a lack of severity assessment tools to identify adults presenting with febrile urinary tract infection (FUTI) at risk for complicated outcome and guide admission policy. We aimed to validate the Prediction Rule for Admission policy in Complicated urinary Tract InfeCtion LEiden (PRACTICE), a modified form of the pneumonia severity index, and to subsequentially assess its use in clinical practice. METHODS: A prospective observational multicenter study for model validation (2004-2009), followed by a multicenter controlled clinical trial with stepped wedge cluster-randomization for impact assessment (2010-2014), with a follow up of 3 months. Paricipants were 1157 consecutive patients with a presumptive diagnosis of acute febrile UTI (787 in validation cohort and 370 in the randomized trial), enrolled at emergency departments of 7 hospitals and 35 primary care centers in the Netherlands. The clinical prediction rule contained 12 predictors of complicated course. In the randomized trial the PRACTICE included guidance on hospitalization for high risk (>100 points) and home discharge for low risk patients (<75 points), in the control period the standard policy regarding hospital admission was applied. Main outcomes were effectiveness of the clinical prediction rule, as measured by primary hospital admission rate, and its safety, as measured by the rate of low-risk patients who needed to be hospitalized for FUTI after initial home-based treatment, and 30-day mortality. RESULTS: A total of 370 patients were included in the randomized trial, 237 in the control period and 133 in the intervention period. Use of PRACTICE significantly reduced the primary hospitalization rate (from 219/237, 92%, in the control group to 96/133, 72%, in the intervention group, p < 0.01). The secondary hospital admission rate after initial outpatient treatment was 6% in control patients and 27% in intervention patients (1/17 and 10/37; p < 0.001). CONCLUSIONS: Although the proposed PRACTICE prediction rule is associated with a lower number of hospital admissions of patients presenting to the ED with presumptive febrile urinary tract infection, futher improvement is necessary to reduce the occurrence of secondary hospital admissions. TRIAL REGISTRATION: NTR4480 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4480 , registered retrospectively 25 mrt 2014 (during enrollment of subjects).

Febrile urinary tract infection in the emergency room.

PURPOSE OF REVIEW: To review the recent advances in the diagnostic and therapeutic approach to adults presenting with febrile urinary tract infection (UTI) in the emergency department (ED). RECENT FINDINGS: Recent research suggests overdiagnosis and therefore overtreatment of UTI in the ED, especially in the elderly. Antimicrobial pretreatment, an indwelling catheter, and malignancy are independent risk factors for bacteremia with uropathogens that cannot be cultured from urine. A simple clinical prediction rule can predict clinically relevant radiologic findings in patients with invasive UTI. Procalcitonin is a marker for bacteremia; pro-adrenomedullin predicts a complicated course and 30-day mortality in complicated UTI. Several reports have identified the risk factors for resistant uropathogens in community-acquired febrile UTI. Adherence to the guidelines and early culture-guided intravenous-to-oral switch reduces the length of hospitalization. SUMMARY: An effective strategy is needed to improve the diagnosis of UTIs in acute care. Further research regarding biomarker-guided triage might improve the management of patients with febrile UTI. Future efforts should be directed toward the improvement of adherence to UTI treatment guidelines.

Postoperative pro-adrenomedullin levels predict mortality in thoracic surgery patients: comparison with Acute Physiology and Chronic Health Evaluation IV Score*.

OBJECTIVES: Risk assessment in ICU patients using commonly used prognostic models may be influenced using different data definitions and by errors in data collection. We investigated whether a set of biomarkers (procalcitonin, MR-pro-adrenomedullin, CT-pro-endothelin-1, CT-pro-arginine vasopressin, and MR-pro-atrial natriuretic peptide), alone or as a panel, could be useful in postoperative risk assessment for hospital mortality in comparison with the Acute Physiology and Chronic Health Evaluation IV score. DESIGN: In a prospective observational cohort study, we analyzed 800 consecutive patients undergoing elective cardiac surgery. We assessed biomarker levels on admission to the ICU and every 6 hours thereafter for 24 hours. For every postoperative time point and for every biomarker, we determined the predictive value for hospital mortality and made a comparison with the Acute Physiology and Chronic Health Evaluation IV score. SETTING: Intensive care of an academic referral hospital. PATIENTS: A total of 800 consecutive patients undergoing elective cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: MR-pro-adrenomedullin is a good predictor of mortality (c-statistic at time point 6 hr after admission to the ICU, 0.940; 95% CI, 0.918-0.956) and performed better than the Acute Physiology and Chronic Health Evaluation IV score (c-statistic, 0.842; 95% CI, 0.811-0.868). The c-statistic did not change significantly on the time points 6, 12, and 18 hours after admission. Using a cutoff value for proadrenomedullin taken 6 hours after admission on ICU (time point 2) of 3.2 nmol/L sensitivity was 81.8% and specificity 93.9%, the positive likelihood ratio was 13.3, positive predictive value was 31.0%, and negative predictive value was 99.4%. Patients with a MR-pro-adrenomedullin above this cutoff level had an odds ratio of 68.9 (95% CI, 22.2-213.1) for not surviving their hospital stay. The other biomarkers had less predictive power. CONCLUSIONS: In elective cardiac surgery, MR-pro-adrenomedullin measured between 6 and 18 hours after admission to the ICU is a better predictor of hospital mortality in comparison with the Acute Physiology and Chronic Health Evaluation IV score.

Limited role for ASC and NLRP3 during in vivo Salmonella Typhimurium infection.

BACKGROUND: The inflammasome is an intracellular protein complex triggered by exposure to intracellular pathogens, its components or other endogenous proteins. It leads to the activation of and subsequent release of proinflammatory cytokines such as IL-1ß and IL-18. S. Typhimurium is a Gram-negative intracellular bacterium, which is known to trigger inflammasome assembly via recognition by the cytosolic receptors, NLRP3 and NLRC4 (which act via the adaptor protein, ASC) to induce cell death and cytokine release. We sought to characterize the role of ASC and NLRP3 in two different murine models (typhoid and colitis) of systemic Salmonella infection. RESULTS: Release of the inflammasome cytokine IL-18 was hampered in Asc-/- but not Nlrp3-/- mice (background C57BL/6) during S. Typhimurium infection. Unexpectedly, neither ASC nor NLRP3 played a significant role in host defense against S. Typhimurium infection, as reflected by equal bacterial counts in WT, Asc-/- and Nlrp3-/- mice at all time points, in both the typhoid and colitis models. Proinflammatory cytokine levels (TNF-α, IL-6) and the extent of hepatic and splenic pathology did not differ between groups in the typhoid model. In the colitis model small differences were seen with regard to splenic and hepatic inflammation, although this was IL-18 independent. CONCLUSIONS: IL-18 release was reduced in Asc-/- but not Nlrp3-/- mice during S. Typhimurium infection. Despite this reduction, bacterial counts, cytokine levels and histological inflammation did not differ between wild-type and knockout mice in either model. Our results reveal a limited role for ASC and NLRP3 during in vivo S. Typhimurium infection despite its role in cytokine maturation.

LL-37-derived peptides eradicate multidrug-resistant Staphylococcus aureus from thermally wounded human skin equivalents.

Burn wound infections are often difficult to treat due to the presence of multidrug-resistant bacterial strains and biofilms. Currently, mupirocin is used to eradicate methicillin-resistant Staphylococcus aureus (MRSA) from colonized persons; however, mupirocin resistance is also emerging. Since we consider antimicrobial peptides to be promising candidates for the development of novel anti-infective agents, we studied the antibacterial activities of a set of synthetic peptides against different strains of S. aureus, including mupirocin-resistant MRSA strains. The peptides were derived from P60.4Ac, a peptide based on the human cathelicidin LL-37. The results showed that peptide 10 (P10) was the only peptide more efficient than P60.4Ac, which is better than LL-37, in killing MRSA strain LUH14616. All three peptides displayed good antibiofilm activities. However, both P10 and P60.4Ac were more efficient than LL-37 in eliminating biofilm-associated bacteria. No toxic effects of these three peptides on human epidermal models were detected, as observed morphologically and by staining for mitochondrial activity. In addition, P60.4Ac and P10, but not LL-37, eradicated MRSA LUH14616 and the mupirocin-resistant MRSA strain LUH15051 from thermally wounded human skin equivalents (HSE). Interestingly, P60.4Ac and P10, but not mupirocin, eradicated LUH15051 from the HSEs. None of the peptides affected the excretion of interleukin 8 (IL-8) by thermally wounded HSEs upon MRSA exposure. In conclusion, the synthetic peptides P60.4Ac and P10 appear to be attractive candidates for the development of novel local therapies to treat patients with burn wounds infected with multidrug-resistant bacteria.

Induction of A. fumigatus-specific CD4-positive T cells in patients recovering from invasive aspergillosis.

After allogeneic stem cell transplantation patients are at risk of invasive aspergillosis, especially during the period of neutropenia. Recent data suggest that impaired T-cell immune reconstitution after transplantation plays an important role in this increased risk. In this study we investigated whether Aspergillus-specific T cells are involved in the recovery from invasive aspergillosis by analyzing the Aspergillus-specific T-cell response in patients with invasive aspergillosis. In nine patients whose Aspergillus infection improved, we identified Crf1- or Catalase1-specific T cells on the basis of CD154 expression and interferon-γ production following stimulation with overlapping peptides of the A. fumigatus proteins Crf1 and Catalase1. These Aspergillus-specific T cells were induced at the moment of regression of the aspergillus lesions. Crf1- and Catalase1-specific T cells, sorted on the basis of CD154 expression at the peak of the immune response, had a T helper-1 phenotype and recognized a variety of T-cell epitopes. In contrast, in two patients with progressive invasive aspergillosis, no Crf1- or Catalase1-specific T cells were identified. These data indicate that the presence of Aspergillus-specific T cells with a T helper-1 phenotype correlates with the clearance of aspergillus infection.

Emerging infectious colitis.

PURPOSE OF REVIEW: The present review will highlight recent advances in the knowledge of emerging pathogens causing infectious colitis and provide a description of the most important food-borne outbreaks. RECENT FINDINGS: Outbreaks of enteric disease caused by Salmonella spp., Campylobacter spp., and Shiga toxin-producing Escherichia coli (STEC) continue to surprise with new epidemiological findings or changing virulence characteristics. These pathogens evolve to exploit novel opportunities for spread and transmission, such as fresh produce within the food chain, and generate new public health challenges. Organic sprouts were recently considered as the source responsible for a large German disease outbreak comprising 3842 patients. The outbreak strain was identified as an enteroaggregative STEC O104:H4 (EAggC), a rare hybrid pathogen that harbours the phage encoded Shiga toxin gene and antibiotic resistance in an EAggEC background. Clostridium difficile PCR ribotype 078 is emerging across Europe, causing severe disease outside healthcare facilities as well as disease in farm animals, indicating that the species border has been crossed. Although the global impact of cryptosporidiosis is less pronounced, these organisms have been responsible for large outbreaks of infectious diarrhoea, often not reported. Invasive listeriosis is a serious food-borne illness and was found recently in 28 US states affecting 147 patients, associated with eating contaminated cantaloupe. Outbreaks of gastroenteritis caused by Listeria monocytogenes are most likely severely underestimated. Centralized surveillance of food-borne enteropathogens is essential for the early detection of disease outbreaks and for the organization of an immediate and appropriate response. SUMMARY: An improved understanding of the pathogenesis, pathology and epidemiology of emerging enteropathogens causing infectious colitis will provide new approaches for disease prevention and control.

The human lactoferrin-derived peptide hLF1-11 exerts immunomodulatory effects by specific inhibition of myeloperoxidase activity.

Because of their ability to eliminate pathogens and to modulate various host immune responses, antimicrobial peptides are considered as candidate agents to fight infections by (antibiotic-resistant) pathogens. We recently reported that hLF1-11 (GRRRRSVQWCA), an antimicrobial peptide derived from the N terminus of human lactoferrin, displays diverse modulatory activities on monocytes, thereby enhancing their actions in innate immune responses. The aim of this study was to identify the cellular target of hLF1-11 that mediates these effects. Results revealed that hLF1-11 binds and subsequently penetrates human monocytes, after which it inhibits the enzymatic activities of myeloperoxidase (MPO). Moreover, a chemical inhibitor of MPO (aminobenzoic acid hydrazide) mimicked the effects of hLF1-11 on the inflammatory response by monocytes and on monocyte-macrophage differentiation. Computer-assisted molecular modeling predicted that hLF1-11 can bind to the edge of and within the crevice of the active site of MPO. Experiments with a set of hLF1-11 peptides with amino acid substitutions identified the stretch of arginines and the cysteine at position 10 as pivotal in these immunomodulatory properties of hLF1-11. We conclude that hLF1-11 may exert its modulatory effects on human monocytes by specific inhibition of MPO activity.