Non-conventional immunomodulation in the management of sepsis.

Sepsis remains a critical global health issue, demanding novel therapeutic strategies. Traditional immunomodulation treatments such as corticosteroids, specific modifiers of cytokines, complement or coagulation, growth factors or immunoglobulins, have so far fallen short. Meanwhile the number of studies investigating non-conventional immunomodulatory strategies is expanding. This review provides an overview of adjunctive treatments with herbal-based medicine, immunonutrition, vasopressors, sedative treatments and targeted temperature management, used to modulate the immune response in patients with sepsis. Herbal-based medicine, notably within traditional Chinese medicine, shows promise. Xuebijing injection and Shenfu injection exhibit anti-inflammatory and immune-modulatory effects, and the potential to lower 28-day mortality in sepsis. Selenium supplementation has been reported to reduce the occurrence of ventilator-associated pneumonia among sepsis patients, but study results are conflicting. Likewise, the immune-suppressive effects of omega-3 fatty acids have been associated with improved clinical outcomes in sepsis. The immunomodulating properties of supportive treatments also gain interest. Vasopressors like norepinephrine exhibit dual dosage-dependent roles, potentially promoting both pro- and anti-inflammatory effects. Dexmedetomidine, a sedative, demonstrates anti-inflammatory properties, reducing sepsis mortality rates in some studies. Temperature management, particularly maintaining higher body temperature, has also been associated with improved outcomes in small scale human trials. In conclusion, emerging non-conventional immunomodulatory approaches, including herbal medicine, immunonutrition, and targeted supportive therapies, hold potential for sepsis treatment, but their possible implementation into everyday clinical practice necessitates further research and stringent clinical validation in different settings.

[Can artificial intelligence write a medical-scientific article of sufficient quality?] / Kan AI eenNTvG-artikel schrijven?

In this article, we describe the process - from the first draft, through peer revision to a final manuscript - of writing a scientific article only using AI. We discuss the problems and questions that arise and make recommendations for how text-generative AI may be used in the medical-scientific world.

[Covid-19 reinfections: what is the clinical relevance?] / Re-infectie met SARS-CoV-2.

Every day additional confirmed case of SARS-CoV-2 reinfection are being reported across the globe. In the Netherlands more than 50 cases of probable reinfections have been identified. With more than 500 thousand people in the Netherlands who have been infected with SARS-CoV-2 up till now this number does seems to be quite low. Still, important questions have to be asked. How do we define reinfection and how do these reinfections compare to other (corona) viruses? What is the immunological significance? What is the duration of protective immunity? And what does Covid-19 reinfections mean for the prevention and development of a vaccine? The described cases of re-infections do teach us that a SARS-CoV-2 vaccine should also be considered for people with a documented Covid-19 infection in the past and that general precautions, such as the use of face masks and social distancing, still apply to those with a previous SARS-CoV-2 infection.

Recommendations for antibacterial therapy in adults with COVID-19 e an evidence based guideline

The Dutch Working Party on Antibiotic Policy constituted a multidisciplinary expert committee to provide evidence-based recommendation for the use of antibacterial therapy in hospitalized adults with a respiratory infection and suspected or proven 2019 Coronavirus disease (COVID-19). We performed a literature search to answer four key questions. The committee graded the evidence and developed recommendations by using Grading of Recommendations Assessment, Development, and Evaluation methodology. We assessed evidence on the risk of bacterial infections in hospitalized COVID-19 patients, the associated bacterial pathogens, how to diagnose bacterial infections and how to treat bacterial infections. Bacterial co-infection upon admission was reported in 3.5% of COVID-19 patients, while bacterial secondary infections during hospitalization occurred up to 15%. No or very low quality evidence was found to answer the other key clinical questions. Although the evidence base on bacterial infections in COVID-19 is currently limited, available evidence supports restrictive antibiotic use from an antibiotic stewardship perspective, especially upon admission. To support restrictive antibiotic use, maximum efforts should be undertaken to obtain sputum and blood culture samples as well as pneumococcal urinary antigen testing. We suggest to stop antibiotics in patients who started antibiotic treatment upon admission when representative cultures as well as urinary antigen tests show no signs of involvement of bacterial pathogens after 48 hours. For patients with secondary bacterial respiratory infection we recommend to follow other guideline recommendations on antibacterial treatment for patients with hospital-acquired and ventilator-associated pneumonia. An antibiotic treatment duration of five days in patients with COVID-19 and suspected bacterial respiratory infection is recommended upon improvement of signs, symptoms and inflammatory markers. Larger, prospective studies about the epidemiology of bacterial infections in COVID-19 are urgently needed to confirm our conclusions and ultimately prevent unnecessary antibiotic use during the COVID-19 pandemic.

[Clinical Characteristics of Coronavirus Disease 2019 in the Netherlands]. / SARS-CoV-2 in Nederland: de kliniek van een nieuw virus.

Since February, 27 2019, when the first patient with coronavirus disease 2019 (Covid-19) was identified in the Netherlands it has rapidly spread throughout the country. Exactly one month later 8603 people had been tested positive for SARS-CoV-2, 2500 patients were or had been admitted to the hospital and 456 patients died. Here the clinical data are summarized of the first 236 patients that have been admitted to hospitals in Uden, Breda and Tilburg which were all at the centre of the initial outbreak in the Netherlands. This commentary focusses on the clinical characteristics of the patients that are currently being treated on the Dutch clinical corona units, their medical management and the first clinical outcomes. Data is compared to current cohort studies from China, Italy and the United States.

[Rise and threat of infectious diseases]. / Opkomst en dreiging van infectieziekten.

In 2019, 1 in 4 deaths was caused by infectious diseases. In addition to the big 3 - HIV, malaria and tuberculosis - these diseases are mainly respiratory infections, infectious diarrhoea and sepsis. The burden of disease caused by infections also remains high in the Netherlands. This could still get worse because of several factors: ageing, 'vaccination doubts', increased use of immunosuppressive drugs, increased mobility of people and globalisation of food chains. Global warming also affects the spread of pathogens and disease vectors. Pathogens have an impressive ability to adapt and, for example, to develop resistance to antimicrobial agents. In order to cope with these threats, we would do well to consider the emergence of new infectious diseases as well as the threat of old ones. What can we learn from decades past? Why do new infections keep emerging? What does the future look like?

Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomized, double-blind, placebo-controlled, non-inferiority trial.

OBJECTIVES: To investigate whether antibiotic treatment of 6 days' duration is non-inferior to treatment for 12 days in patients hospitalized for cellulitis. METHODS: This multicentre, randomized, double-blind, placebo-controlled, non-inferiority trial enrolled adult patients hospitalized for severe cellulitis who were treated with intravenous flucloxacillin. At day 6 participants with symptom improvement who were afebrile were randomized between an additional 6 days of oral flucloxacillin or placebo in a 1:1 ratio, stratified for diabetes and hospital. The primary outcome was cure by day 14, without relapse by day 28. Secondary outcomes included a modified cure assessment and relapse rate by day 90. RESULTS: Between August 2014 and June 2017, 151 of 248 included participants were randomized. The intention-to-treat population consisted of 76 and 73 participants allocated to 12 and 6 days of antibiotic therapy, respectively (mean age 62 years, 67% males, 24% diabetics); 38/76 (50.0%) and 36/73 (49.3%) were cured in the 12- and 6-day groups respectively (ARR 0.7 percentage points, 95%CI: -15.0 to 16.3). Cure rates were 56/76 (73.7%) and 49/73 (67.1%) with the modified cure assessment (ARR 6.6, 95%CI: -8.0 to 20.8). After initial cure without relapse, day 90 relapse rates were higher in the 6-day group (6% versus 24%, p < 0.05). CONCLUSIONS: Given the wide confidence intervals, we can neither confirm nor refute our hypothesis that 6 days of therapy is non-inferior to 12 days of therapy. However, a 6-day course resulted in significantly more frequent relapses by day 90. These findings require confirmation in future studies.

Microbiological diagnostics of bloodstream infections in Europe-an ESGBIES survey.

OBJECTIVES: High-quality diagnosis of bloodstream infections (BSI) is important for successful patient management. As knowledge on current practices of microbiological BSI diagnostics is limited, this project aimed to assess its current state in European microbiological laboratories. METHODS: We performed an online questionnaire-based cross-sectional survey comprising 34 questions on practices of microbiological BSI diagnostics. The ESCMID Study Group for Bloodstream Infections, Endocarditis and Sepsis (ESGBIES) was the primary platform to engage national coordinators who recruited laboratories within their countries. RESULTS: Responses were received from 209 laboratories in 25 European countries. Although 32.5% (68/209) of laboratories only used the classical processing of positive blood cultures (BC), two-thirds applied rapid technologies. Of laboratories that provided data, 42.2% (78/185) were able to start incubating BC in automated BC incubators around-the-clock, and only 13% (25/192) had established a 24-h service to start immediate processing of positive BC. Only 4.7% (9/190) of laboratories validated and transmitted the results of identification and antimicrobial susceptibility testing (AST) of BC pathogens to clinicians 24 h/day. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry from briefly incubated sub-cultures on solid media was the most commonly used approach to rapid pathogen identification from positive BC, and direct disc diffusion was the most common rapid AST method from positive BC. CONCLUSIONS: Laboratories have started to implement novel technologies for rapid identification and AST for positive BC. However, progress is severely compromised by limited operating hours such that current practice of BC diagnostics in Europe complies only partly with the requirements for optimal BSI management.

Towards precision medicine in sepsis: a position paper from the European Society of Clinical Microbiology and Infectious Diseases.

BACKGROUND: Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored. AIMS: To summarize the current evidence on precision medicine in sepsis, with an emphasis on translation from theory to clinical practice. A secondary objective is to develop a framework enclosing recommendations on management and priorities for further research. SOURCES: A global search strategy was performed in the MEDLINE database through the PubMed search engine (last search December 2017). No restrictions of study design, time, or language were imposed. CONTENT: The focus of this Position Paper is on the interplay between therapies, pathogens, and the host. Regarding the pathogen, microbiologic diagnostic approaches (such as blood cultures (BCs) and rapid diagnostic tests (RDTs)) are discussed, as well as targeted antibiotic treatment. Other topics include the disruption of host immune system and the use of biomarkers in sepsis management, patient stratification, and future clinical trial design. Lastly, personalized antibiotic treatment and stewardship are addressed (Fig. 1). IMPLICATIONS: A road map provides recommendations and future perspectives. RDTs and identifying drug-response phenotypes are clear challenges. The next step will be the implementation of precision medicine to sepsis management, based on theranostic methodology. This highly individualized approach will be essential for the design of novel clinical trials and improvement of care pathways.

Management of community-acquired pneumonia in adults: 2016 guideline update from the Dutch Working Party on Antibiotic Policy (SWAB) and Dutch Association of Chest Physicians (NVALT).

The Dutch Working Party on Antibiotic Policy in collaboration with the Dutch Association of Chest Physicians, the Dutch Society for Intensive Care and the Dutch College of General Practitioners have updated their evidence-based guidelines on the diagnosis and treatment of community-acquired pneumonia (CAP) in adults who present to the hospital. This 2016 update focuses on new data on the aetiological and radiological diagnosis of CAP, severity classification methods, initial antibiotic treatment in patients with severe CAP and the role of adjunctive corticosteroids. Other parts overlap with the 2011 guideline. Apart from the Q fever outbreak in the Netherlands (2007-2010) no other shifts in the most common causative agents of CAP or in their resistance patterns were observed in the last five years. Low-dose CT scanning may ultimately replace the conventional chest X-ray; however, at present, there is insufficient evidence to advocate the use of CT scanning as the new standard in patients evaluated for CAP. A pneumococcal urine antigen test is now recommended for all patients presenting with severe CAP; a positive test result can help streamline therapy once clinical stability has been reached and no other pathogens have been detected. Coverage for atypical microorganisms is no longer recommended in empirical treatment of severe CAP in the non-intensive care setting. For these patients (with CURB-65 score >2 or Pneumonia Severity Index score of 5) empirical therapy with a 2nd/3rd generation cephalosporin is recommended, because of the relatively high incidence of Gram-negative bacteria, and to a lesser extent S. aureus. Corticosteroids are not recommended as adjunctive therapy for CAP.

[A day in the life of a medical resident on the ward]. / Een dag uit het leven van de zaalarts interne geneeskunde.

OBJECTIVE: To investigate how internal medicine residents allocate their time during a hospital dayshift on the wards. DESIGN: Prospective observational cohort study (time and motion study). METHODS: Data were collected from 36 internal medicine residents working at the Internal Medicine Department of the Academic Medical Centre in Amsterdam, the Netherlands. Trained observers monitored 22 residents using a newly developed smartphone-application, registering their dayshift activities (meetings and education, direct patient contact, administrative tasks, lunch/break, other) and location (workstation, conference room, ward and patient rooms, other). Data of 14 residents on work-related activities during after-hours in the hospital and at home were collected through a questionnaire. RESULTS: Residents were observed for a total of 210 hours. The average workday encompassed 9.5 hours. During this dayshift, residents spent an average of 38% of their time on administrative tasks, and 37% on interprofessional consultation and educational activities. Direct patient/family contact accounted for 13% of the workday. After the evening handover at 5 pm, on average another 80 minutes of work was performed in the hospital, of which 73 minutes (91%) entailed administration. At home, they spent on average another 52 minutes on patient care related work, of which 51 minutes (98%) consisted of administration. CONCLUSION: The internal medicine residents on the ward spend most of their dayshift on indirect patient care. This comprises mostly computer-based administrative tasks. After the dayshift, many residents continue to work in their own time to finish remaining paperwork. Study limitations are the limited total number of monitored residents, the total observation time and possible self-report bias.

Cellulitis: current insights into pathophysiology and clinical management.

Cellulitis is a bacterial skin and soft tissue infection which occurs when the physical skin barrier, the immune system and/or the circulatory system are impaired. Diabetes, obesity and old age are associated with defects in all of these areas and as a result are major predisposing factors for cellulitis. In this review, we summarise current insights into the pathophysiology of cellulitis and place the Dutch guidelines on the clinical management of cellulitis of the lower extremities in perspective. Recent evidence on diagnostic strategies is discussed, the importance of which is underscored by findings that venous insufficiency, eczema, deep vein thrombosis and gout are frequently mistaken for cellulitis. Empiric antibiotic choices are designed against the background of a low prevalence of multi-resistant Staphylococcus aureus. Novel antimicrobial agents registered for cellulitis are also discussed. Relapses occur frequently due to a high prevalence of risk factors associated with cellulitis in combination with the ccurrence of persistent post-inflammatory lymphatic damage. Lastly, we identify knowledge gaps which, if addressed, will advance our understanding of the pathophysiology of cellulitis and improve its clinical management.

[Optimal duration of antibiotic therapy: there is no 'one size fits all']. / De optimale duur van antibiotische therapie.

The increasing use of antibiotics is the main driving force behind the rise of antibiotic resistance. Furthermore, there is a large variation in antibiotic use amongst prescribers. We describe the current duration of antibiotic therapy for common infections in the Netherlands and the new studies we can expect in this field in the years to come. We think that more research is needed to determine the duration of antibiotic therapy on the basis of different patient characteristics. It has, for example, recently been shown that the sex of the patient plays an important role in optimal duration of therapy for febrile urinary tract infections. Therefore, it is important to identify patients who fail on shorter courses of antibiotics in order to avoid overtreatment of all patients and to reduce the use of antibiotics in the future.

[Sepsis: new insights, new definition]. / Sepsis: nieuwe inzichten, nieuwe definitie.

- Incidence of sepsis is increasing, partly due to an ageing population, increased use of immunosuppressants, and antibiotic resistance. Sepsis survival has improved substantially, in part because of continuously improving intensive care and implementation of evidence-based guidelines.- Sepsis is defined as 'life-threatening organ dysfunction due to a dysregulated host response to infection'. The Sequential Organ Failure Assessment (SOFA) score can be used to estimate organ dysfunction severity.- In this article, we discuss the new sepsis definitions - including reactions to these definitions, an overview of current insights in sepsis pathogenesis, and the new treatment guidelines.- Prevention of sepsis, faster pathogen detection, new lung and kidney function-preserving treatment strategies, further individualisation of patient care and attention to long-term consequences of sepsis will determine the research agenda for the coming years.

Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy wasdeveloped at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroupsand among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.(AU)

[The microbiome: just a hype or really important?]. / Het microbioom: hype of écht belangrijk?

Many people question if the current microbiome research trend really does have medical implications for patients or if it is just hype to generate research funding. Cumulative funding for the microbiome likely runs into hundreds of millions and over the last five years there has been rapid and exponential growth of microbiome-related publications. Here we examine if the microbiome has any real relevance in current clinical practice.

The gut microbiota in internal medicine: implications for health and disease.

The human gut microbiota may be viewed as an organ, executing numerous functions in metabolism, development of the immune system and host defence against pathogens. It may therefore be involved in the development of a range of diseases such as gastrointestinal infections, inflammatory bowel disease, allergy and diabetes mellitus. Reversely, certain therapies that are often used, such as antibiotics and chemotherapy, may negatively affect the composition and function of the gut microbiota and thereby the wellbeing of patients. As the microbiota research field is currently moving from association studies to intervention studies and even clinical trials, implementation of this new knowledge into clinical practice is coming near. Several therapeutic interventions that target the gut microbiota are being evaluated, ranging from supplementation of food components to transplantation of faecal microbiota. In this review we provide an overview of current literature on the gut microbiota in both a healthy state and a range of diseases that are relevant for internal medicine. In anticipation of gut microbiota-targeted therapies, it is important to realise the key function of the gut microbiota in physiological processes and the collateral damage that may be caused when disrupting this ecosystem within us.