Declining Hepatitis C Virus (HCV) Incidence in Dutch Human Immunodeficiency Virus-Positive Men Who Have Sex With Men After Unrestricted Access to HCV Therapy.

Background: Direct-acting antivirals (DAAa) cure hepatitis C virus (HCV) infections in 95% of infected patients. Modeling studies predict that universal HCV treatment will lead to a decrease in the incidence of new infections but real-life data are lacking. The incidence of HCV among Dutch human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) has been high for >10 years. In 2015 DAAs became available to all Dutch HCV patients and resulted in a rapid treatment uptake in HIV-positive MSM. We assessed whether this uptake was followed by a decrease in the incidence of HCV infections. Methods: Two prospective studies of treatment for acute HCV infection enrolled patients in 17 Dutch HIV centers, having 76% of the total HIV-positive MSM population in care in the Netherlands. Patients were recruited in 2014 and 2016, the years before and after unrestricted DAA availability. We compared the HCV incidence in both years. Results: The incidence of acute HCV infection decreased from 93 infections during 8290 person-years of follow-up (PYFU) in 2014 (11.2/1000 PYFU; 95% confidence interval [CI], 9.1-13.7) to 49 during 8961 PYFU in 2016 (5.5/1000 PYFU; 4.1-7.2). The incidence rate ratio of 2016 compared with 2014 was 0.49 (95% CI, .35-.69). Simultaneously, a significant increase in the percentage positive syphilis (+2.2%) and gonorrhea (+2.8%) tests in HIV-positive MSM was observed at sexual health clinics across the Netherlands and contradicts a decrease in risk behavior as an alternative explanation. Conclusions: Unrestricted DAA availability in the Netherlands was followed by a 51% decrease in acute HCV infections among HIV-positive MSM.

Risk of Pneumocystis jiroveci pneumonia in patients long after renal transplantation.

BACKGROUND: Pneumocystis jiroveci pneumonia (PCP) is an important cause of morbidity and mortality in renal transplant recipients (RTRs). Chemoprophylaxis with trimethoprim/sulphamethoxazole is recommended during the early post-transplantation period, but the optimal duration has not been determined and a main drawback of chemoprophylaxis is the development of resistance of the commensal faecal flora. A cluster outbreak of PCP occurred in our outpatient Renal Transplant Unit. We aimed to investigate risk factors for PCP in RTRs to determine who should receive long-term chemoprophylaxis. METHODS: In a case-control study, we investigated common demographic variables and immunological parameters. Nine PCP cases diagnosed between August 2006 and April 2007 were matched with 18 control patients, who did not develop PCP, received their transplant in the same time-period and had a similar follow-up period with a comparable immunosuppressive drug regimen. RESULTS: The median time from transplantation to PCP was 19 months. We observed no significant differences in gender, age, donor type or number of rejections. In PCP cases, the median lymphocyte count just before PCP diagnosis was 0.49 (0.26-0.68), which was significantly reduced compared to the control patients after a similar follow-up period (median 1.36, 0.59-3.04, P = 0.002). This lymphocytopaenia was chronic and existed in most patients already for many months. CD4(+) T-cell counts were also significantly reduced in the PCP cases. We found no difference in the Th1, Th2 and Th17 subsets between PCP cases and control patients. CONCLUSION: Long-term prophylactic therapy for PCP may be indicated for RTR with persistent severe lymphocytopaenia.

A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease.

Although Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens, the influence of polymorphisms in this gene family on human susceptibility to infection is poorly understood. We demonstrated recently that TLR5 recognizes flagellin, a potent inflammatory stimulus present in the flagellar structure of many bacteria. Here, we show that a common stop codon polymorphism in the ligand-binding domain of TLR5 (TLR5392STOP) is unable to mediate flagellin signaling, acts in a dominant fashion, and is associated with susceptibility to pneumonia caused by Legionella pneumophila, a flagellated bacterium. We also show that flagellin is a principal stimulant of proinflammatory cytokine production in lung epithelial cells. Together, these observations suggest that TLR5392STOP increases human susceptibility to infection through an unusual dominant mechanism that compromises TLR5's essential role as a regulator of the lung epithelial innate immune response.

The appropriateness of antimicrobial use in the outpatient clinics of three hospitals in the Netherlands.

OBJECTIVES: Antimicrobial Stewardship Programs commonly have an in-hospital focus. Little is known about the quality of antimicrobial use in hospital outpatient clinics. We investigated the extent and appropriateness of antimicrobial prescriptions in the outpatient clinics of three hospitals. METHODS: From June 2018 to January 2019, we performed ten point prevalence surveys in outpatient clinics of one university hospital and two large teaching hospitals. All prophylactic and therapeutic prescriptions were retrieved from the electronic medical records. Appropriateness was defined as being in accordance with guidelines. Furthermore, we investigated the extent to which the dose was adjusted to renal function and documentation of an antibiotic plan in the case notes. RESULTS: We retrieved 720 prescriptions for antimicrobial drugs, of which 173 prescriptions (24%) were prophylactic. A guideline was present for 95% of prescriptions, of which the guideline non-adherence rate was 25.6% (n = 42/164) for prophylaxis and 43.1% (n = 224/520) for therapy. Of all inappropriate prescriptions (n = 266), inappropriate prescriptions for skin and soft tissue infections (n = 60/226) and amoxicillin-clavulanic acid (n = 67/266) made up the largest proportion. In only 13 of 138 patients with impaired or unknown renal function the dosage regimen was adjusted. Amoxicillin-clavulanic acid was the drug for which most often renal function was not taken into account. In 94.6% of prescriptions the antibiotic plan was documented. CONCLUSIONS: In hospital outpatient clinics, a substantial part of therapeutics were inappropriately prescribed. Amoxicillin-clavulanic acid was the most inappropriately prescribed drug, due to non-adherence to the guidelines and because dose adjustment to renal function was often not considered.

Behavioral Approach to Appropriate Antimicrobial Prescribing in Hospitals: The Dutch Unique Method for Antimicrobial Stewardship (DUMAS) Participatory Intervention Study.

Importance: Inappropriate antimicrobial prescribing leads to antimicrobial resistance and suboptimal clinical outcomes. Changing antimicrobial prescribing is a complex behavioral process that is not often taken into account in antimicrobial stewardship programs. Objective: To examine whether an antimicrobial stewardship approach grounded in behavioral theory and focusing on preserving prescriber autonomy and participation is effective in improving appropriateness of antimicrobial prescribing in hospitals. Design, Setting, and Participants: The Dutch Unique Method for Antimicrobial Stewardship (DUMAS) study was a prospective, stepped-wedge, participatory intervention study performed from October 1, 2011, through December 31, 2015. Outcomes were measured during a baseline period of 16 months and an intervention period of 12 months. The study was performed at 7 clinical departments (2 medical, 3 surgical, and 2 pediatric) in a tertiary care medical center and a general teaching hospital in the Netherlands. Physicians prescribing systemic antimicrobial drugs for any indication for patients admitted to the participating departments during the study period were included in the study. Interventions: We offered prescribers a free choice of how to improve their antimicrobial prescribing. Prescribers were stimulated to choose interventions with higher potential for success based on a root cause analysis of inappropriate prescribing. Main Outcomes and Measures: Appropriateness of antimicrobial prescriptions was determined using a validated approach based on guideline adherence and motivated guideline deviation and measured with repeated point prevalence surveys (6 per year). Appropriateness judgment was masked for the study period. Antimicrobial consumption was extracted from pharmacy records and measured as days of therapy per admission. We used linear and logistic mixed-model regression analysis to model outcomes over time. Results: A total of 1121 patient cases with 700 antimicrobial prescriptions were assessed during the baseline period and 882 patient cases with 531 antimicrobial prescriptions during the intervention period. The mean antimicrobial appropriateness increased from 64.1% at intervention start to 77.4% at 12-month follow-up (+13.3%; relative risk, 1.17; 95% CI, 1.04-1.27), without a change in slope. No decrease in antimicrobial consumption was found. Conclusions and Relevance: Use of a behavioral approach preserving prescriber autonomy resulted in an increase in antimicrobial appropriateness sustained for at least 12 months. The approach is inexpensive and could be easily transferable to various health care environments.

Sensitivity of three serum antibody tests in a large outbreak of Legionnaires' disease in the Netherlands.

In 1999, an outbreak involving 188 patients with Legionnaires' disease (LD) occurred at a flower show in the Netherlands. This large outbreak provided the opportunity to evaluate serum antibody tests to assay anti-Legionella pneumophila, since limited data are available on the sensitivity of these tests. The sensitivities of an indirect serotype 1-6 immunofluorescence antibody test (IFAT), a rapid micro-agglutination test (RMAT) IgM serotype 1 antibody assay, and an ELISA to detect IgM and IgG serotype 1-7 antibodies, were evaluated using serum samples from LD patients related to the 1999 outbreak. Sensitivity was calculated using positive culture and/or a positive urinary antigen test as the gold standard in outbreak-related patients with radiographically confirmed pneumonia who fulfilled the epidemiological criteria. The IFAT, RMAT and ELISA showed sensitivities of 61, 44 and 64%, respectively. The sensitivity of the three tests combined was 67%. In epidemic situations, however, high standing titres may be included in the laboratory evidence of LD cases. In the study population, high standing titres were found in 16% of cases. If the presence of high standing antibody titres was added to the criteria of a positive test, the sensitivities of IFAT, RMAT and ELISA were 86, 48 and 75%, respectively. The sensitivity was 91% for all tests combined. The higher sensitivity for the combined use of tests is offset by a reduction in specificity to 97.6%. The results of this study indicate that using a combination of serologic tests in pneumonia patients suspected to have LD does not substantially improve sensitivity. The results suggest that in the microbiological diagnosis of LD, both IFAT and ELISA are reasonably sensitive assays. In an epidemic situation, both tests are highly sensitive, the IFAT more so than the ELISA.

Health-related quality of life and posttraumatic stress disorder among survivors of an outbreak of Legionnaires disease.

A follow-up study of 122 survivors of an outbreak of legionnaires disease (LD) in The Netherlands was conducted to determine persistence of symptoms, health-related quality of life (HRQL), and presence of posttraumatic stress disorder (PTSD). Seventeen months after diagnosis of LD, survivors completed a questionnaire assessing symptoms and HRQL and a questionnaire assessing PTSD. The most prevalent new symptoms were fatigue (in 75% of patients), neurologic symptoms (in 66%), and neuromuscular symptoms (in 63%). HRQL was impaired in 7 of the 8 dimensions assessed by the HRQL questionnaire, and 15% of patients experienced PTSD. Symptoms and impaired HRQL persisted for >1.5 years. As a result of the design of this study, it could not be inferred whether Legionella pneumophila infection, severe pneumonia in general, or the outbreak situation was responsible for impaired well-being. However, awareness of this problem by health care providers may improve the aftercare of patients.

[Health risks and advice for Hajj pilgrims]. / Gezondheidsrisico's en adviezen voor hadjpelgrims.

The Hajj, the pilgrimage to Mecca, is the largest mass migration in the world. Each year, 2.5 million Muslims from over 160 countries travel to the same place, 5000-6000 of these being from the Netherlands. During the Hajj, the pilgrims undergo great physical and emotional strain. Good medical preparation including vaccinations is very important for pilgrims who undertake the Hajj, in particular for those who are older and have chronic disease. The chance of transmission of infective disease is also high and rapid contagion of Hajj pilgrims could cause a pandemic. It is therefore important that the responsible doctor is aware of the health risks to the Hajj pilgrim and his environment.

[Castleman's disease, a fatal cause of lymph node enlargement and fever]. / De ziekte van Castleman: een fatale oorzaak van lymfkliervergroting en koorts.

A 71-year old Turkish man with fever, night sweats and generalized lymphadenopathy was diagnosed as having multicentric Castleman's disease. This is a rare and often fatal cause of lymph node enlargement and fever. Histological investigation confirms the diagnosis, but the morphological features closely resemble reactive lymphadenopathy or lymphoma. Infection with human herpes virus 8 is associated with Castleman's disease, in both hiv-positive and hiv-negative patients. An interleukin-6 mediated immune response against HHV-8 seems to play an important role in the pathogenesis of the multicentric form of Castleman's disease. The disease is usually rapidly progressive, but can have a milder course. There is no standard treatment: usually systemic chemotherapy in combination with steroids is applied..Recently, promising results have been obtained using rituximab and anti-IL-6-receptor antibodies.

[Dengue infection with fatal ending]. / Dengue-infectie met fatale afloop.

A 54-year-old man was admitted with fever following a trip to St. Maarten in the Dutch Antilles, from where he had returned 6 days earlier. One year prior to this he had been treated on an Intensive Care Unit for a severe influenza A infection. Physical examination revealed remarkably cold extremities, furthermore there was metabolic acidosis, extreme haemoconcentration, prolongation of prothrombin time and activated partial thromboplastin time. His clinical condition deteriorated rapidly and he died the day after admission. Neither IgG nor IgM antibodies against dengue were found, but PCR on dengue virus RNA was positive. Over past decades there has been a strong increase in the number of dengue virus infections in travellers returning from Southeast Asia, Central and South America, the Caribbean and Africa. Whilst in general a primary dengue virus infection does not result in severe disease, this case illustrates the potentially fatal consequences of dengue in travellers.

Deficient mannose-binding lectin-mediated complement activation despite mannose-binding lectin-sufficient genotypes in an outbreak of Legionella pneumophila pneumonia.

Polymorphisms leading to deficiency of mannose-binding lectin (MBL) are associated with predisposition to infection. However, MBL deficiency can be protective against intracellular pathogens that use MBL to enter host cells. The role of MBL genotype and activity in infection with the intracellular pathogen Legionella pneumophila was studied in a large outbreak of legionellosis at a Dutch flower show. A total of 141 patients, 65 exposed asymptomatic exhibition staff members and 670 unexposed blood bank donors were included for the study of MBL2 genotypes and MBL-mediated complement activation. Genotypic MBL deficiency was equally prevalent in patients and controls. Deficient MBL-mediated complement activation was more prevalent in patients. Even in patients with genotypes that confer MBL sufficiency, 20.6% lacked MBL-mediated complement activation. In most patients with MBL-sufficient genotypes who lacked MBL-mediated activation at the acute phase of disease, lectin pathway functionality was restored at convalescence. In conclusion, genotypic MBL deficiency was not a risk factor for legionellosis. However, patients with legionellosis displayed deficient MBL-mediated complement activation even with MBL-sufficient genotypes. Together, these genotypical and functional data suggest that the observed deficiency of lectin pathway activation is an effect of legionellosis rather than a risk factor for acquiring it.

Toll-like receptor 4 is not involved in host defense against pulmonary Legionella pneumophila infection in a mouse model.

Legionella pneumophila is a gram-negative microorganism that causes a severe pneumonia known as "legionnaires disease." Toll-like receptor 4 (TLR4) transduces the lipopolysaccharide signal and is therefore considered to play a role in host defense against gram-negative bacterial infection. To determine the role of TLR4 in L. pneumophila pneumonia, C3H/HeJ mice, which display a nonfunctional gene encoding TLR4 (TLR4), and wild-type (wt) C3H/HeN mice were intranasally inoculated with L. pneumophila serogroup 1. Infection proceeded in an identical way in TLR4 mutant and wt mice, as reflected by similar bacterial outgrowth in the lungs. In addition, the inflammatory responses to L. pneumophila infection-as assessed by histopathologic analysis, cell influx in bronchoalveolar lavage fluid, myeloperoxidase activity in lungs, and lung cytokine concentrations-were indistinguishable in TLR4 mutant and wt mice. These data suggest that, in this mouse model, TLR4 does not play a role in resistance to L. pneumophila.

Sensitivity of three urinary antigen tests associated with clinical severity in a large outbreak of Legionnaires' disease in The Netherlands.

In 1999 an outbreak involving 188 patients with Legionnaires' disease (LD) occurred among visitors to a flower show in the Netherlands. Two enzyme immunoassays (Binax and Biotest) and one immunochromatographic assay (Binax NOW) were tested, using urine samples from LD patients from the 1999 outbreak. Sensitivity was calculated using positive culture and/or seroconversion as the "gold standard" in outbreak-related patients with radiographically confirmed pneumonia who fulfilled the epidemiological critera. The Binax EIA, Biotest EIA, and Binax NOW assay showed overall sensitivities of 69, 71, and 72%, respectively. When the tests were performed with concentrated urine samples, the overall sensitivities increased to 79, 74, and 81%, respectively. Using multiple logistic regression analysis with backward elimination, a statistically significant association was found between clinical severity and test sensitivity for all tests. For patients with mild LD, the test sensitivities ranged from 40 to 53%, whereas for patients with severe LD who needed immediate special medical care, the sensitivities reached 88 to 100%. These findings have major implications for the diagnostic process in patients with mild pneumonia and suggest that patients with mild pneumonia may go underdiagnosed if urine antigen tests alone are used.

Legionnaires' disease at a Dutch flower show: prognostic factors and impact of therapy.

After a large outbreak of Legionnaires' disease in the Netherlands, we determined risk factors for intensive care unit (ICU) admission and death and the impact of adequate therapy on ICU-free survival among 141 hospitalized patients. Overall mortality rate was 13%, and ICU mortality rate was 36%. Smoking, temperature >38.5 degrees C, and bilateral infiltrates shown on chest x-ray were independent risk factors for ICU admission or death (all p<0.05). Starting adequate therapy within 24 hours after admission resulted in a higher ICU-free survival rate compared to therapy initiation after 24 hours: 78% versus 54%, respectively (p=0.005). However, delay in providing therapy to patients with urinary antigen tests with negative results did not influence outcome. These data suggest that by using the urinary antigen test on admission a more tailored approach to patients with community-acquired pneumonia may be applied.

A large outbreak of Legionnaires' disease at a flower show, the Netherlands, 1999.

In 1999, an outbreak of Legionnaires' disease affected many visitors to a flower show in the Netherlands. To identify the source of the outbreak, we performed an environmental investigation, as well as a case-control study among visitors and a serologic cohort study among exhibitors to measure exposure to possible sources. Of 77,061 visitors, 188 became ill (133 confirmed and 55 probable cases), for an attack rate of 0.23% for visitors and 0.61% for exhibitors. Two whirlpool spas in halls 3 and 4 of the exhibition and a sprinkler in hall 8 were culture positive for Legionella pneumophila. One of three genotypes found in both whirlpool spas was identical to the isolates from 28 of 29 culture-positive patients. Persons who paused at the whirlpool spa in hall 3 were at increased risk for becoming ill. This study illustrates that whirlpool spas may be an important health hazard if disinfection fails.