Central serous chorioretinopathy (CSC) is a multifactorial disease of the retina and the choroid in the human eye. The disease is characterized by a serous detachment of the neurosensory retina in... Show moreCentral serous chorioretinopathy (CSC) is a multifactorial disease of the retina and the choroid in the human eye. The disease is characterized by a serous detachment of the neurosensory retina in the central macula, which causes visual complaints including blurred vision, a central relative scotoma, metamorphopsia, and alterations in color and contrast vision. Multimodal imaging techniques have revealed that abnormally thickened, leaking choroidal blood vessels cause an excessive fluid outflow into the interstitial space, which presumably causes the characteristic thickened choroid. This thesis addresses the clinical spectrum of CSC including the acute CSC, the chronic CSC and the severe chronic CSC. Here we suggest a strict but practical classification of CSC phenotypes based on findings on multimodal imaging techniques. We also report on the outcome of treatment, especially photodynamic therapy (PDT), in all phenotypes of CSC and provide recommendation regarding disease management and therapy. Furthermore, in this thesis we assess the roll of genetic variations among different phenotypes of CSC for a better understanding of the pathogenesis of the disease. Despite the genetic associations found in CSC phenotypes, we conclude that the so far known genetic variations do not explain the different clinical disease presentation of CSC phenotypes. Show less
The treatment of community-acquired pneumonia (CAP) is based on early diagnosis and swift initiation of appropriate antibiotic treatment. Despite effective treatment, CAP is still one of the... Show moreThe treatment of community-acquired pneumonia (CAP) is based on early diagnosis and swift initiation of appropriate antibiotic treatment. Despite effective treatment, CAP is still one of the leading causes of morbidity and mortality due to infectious diseases worldwide. This thesis aimed to identify strategies to optimise the treatment of hospitalised CAP patients outside an intensive care unit (ICU) setting with a focus on corticosteroid treatment. First, this thesis focused on the question whether oral adjunctive corticosteroid treatment improves outcomes in hospitalised CAP patients and tries to identify a subgroup of CAP patients, based on inflammatory status at admission, in whom the beneficial effects of adjunctive corticosteroid treatment outweigh the disadvantages associated with corticosteroid use. Next, this thesis investigated whether obesity and overweight are associated with worse clinical outcomes in a population of hospitalised COVID-19 patients who were all treated with the recommended 6 mg dexamethasone dose. Last, this thesis focused on optimising antibiotic treatment by exploring whether extensive microbiological testing facilitates early antibiotic alterations in CAP patients. Show less
Have, L. ten; Visser, E.; Meulmeester, F.L.; Bendien, S.A.; Braunstahl, G.J.; Broeders, M.E.A.C.; ... ; Brinke, A. ten 2023
Background: Many patients with severe asthma are overweight or obese, often attributed to unintentional weight gain as a side effect of oral corticosteroids (OCSs). Anti-IL-5/5Ra biologics... Show moreBackground: Many patients with severe asthma are overweight or obese, often attributed to unintentional weight gain as a side effect of oral corticosteroids (OCSs). Anti-IL-5/5Ra biologics significantly reduce OCS use, but their long-term effects on weight are unknown.Objectives: To examine (1) weight change up to 2 years after anti-IL-5/5Ra initiation in subgroups on the basis of maintenance OCS use at start of treatment and (2) whether cumulative OCS exposure before or changes in OCS exposure during treatment are related to weight change.Methods: Real-world data on weight and cumulative OCS dose from adults included in the Dutch Registry of Adult Patients with Severe asthma for Optimal DIsease management before and at least 2 years after starting anti-IL-5/5Ra were analyzed using linear mixed models and linear regression analyses.Results: For the included 389 patients (55% female; mean body mass index, 28 +/- 5 kg/m(2); 58% maintenance OCS), mean weight decreased -0.27 kg/y (95% CI, -0.51 to -0.03; P = .03), with more weight loss in patients with maintenance OCS use than in those without maintenance OCS use (-0.87 kg/y [95% CI, -1.21 to -0.52; P < .001] vs +0.54 kg/y [0.26 to 0.82; P < .001]). Greater weight loss at 2 years was associated with higher cumulative OCS dose in the 2 years before anti-IL-5/5Ra initiation (beta = -0.24 kg/g; 95% CI, -0.38 to -0.10; P < .001) and, independently, greater reduction in cumulative OCS dose during follow-up (beta = 0.27 kg/g; 95% CI, 0.11 to 0.43; P < .001).Conclusions: Anti-IL-5/5Ra therapy is associated with long-term weight reduction, especially in patients with higher OCS exposure before treatment and those able to reduce OCS use during treatment. However, the effect is small and does not apply to all patients, and so additional interventions seem necessary if weight change is desired. Show less
Objectives: Corticosteroids are used to prevent or treat lung disease of prematurity. While neurological side effects have been reported, detailed effects on cerebellar growth are unknown. This... Show moreObjectives: Corticosteroids are used to prevent or treat lung disease of prematurity. While neurological side effects have been reported, detailed effects on cerebellar growth are unknown. This study aimed to compare cerebellar growth in premature infants who received dexamethasone or hydrocortisone to premature infants who did not receive postnatal corticosteroids. Study Design: Retrospective case-control study in infants born at a gestational age of <29 weeks and admitted to two level 3 neonatal intensive care units. Exclusion criteria were severe congenital anomalies and cerebellar or severe supratentorial lesions. Infants were treated with dexamethasone (unit 1) or hydrocortisone (unit 2) for chronic lung disease. Controls (unit 1) did not receive postnatal corticosteroids. Sequential head circumference (HC) and ultrasound measurements of transcerebellar diameter (TCD), biparietal diameter (BPD), and corpus callosum-fastigium length (CCFL) were performed until 40 weeks' postmenstrual age (PMA). Growth was assessed using linear mixed models correcting for PMA at measurement, sex, HC z-score at birth, and a propensity score indicating illness severity. Group differences before treatment were assessed using linear regression. Results: 346 infants were included (68 dexamethasone, 37 hydrocortisone, 241 controls). Before starting corticosteroids, TCD, BPD, and HC measurements did not differ between patients and controls at a comparable PMA. After starting treatment, both types of corticosteroid had a negative association with TCD growth. BPD, CCFL, and HC growth were not negatively affected. Conclusion: Administration of dexamethasone and hydrocortisone are both associated with impaired cerebellar growth in premature infants without evident negative associations with cerebral growth. Show less
We aimed to investigate BMI-z course in patients with Duchenne muscular dystrophy (DMD) during transition to loss of ambulation, and to explore the contribution of caloric intake and corticosteroid... Show moreWe aimed to investigate BMI-z course in patients with Duchenne muscular dystrophy (DMD) during transition to loss of ambulation, and to explore the contribution of caloric intake and corticosteroid use. A retrospective multicenter longitudinal study was conducted. First, analyses of characteristics at first visit were carried out. Second, discontinuous change models were fitted to explore associations between BMI-z, loss of ambulation, caloric intake and corticosteroid use. 790 visits of 159 patients were collected. Cross sectional first visit analyses showed the presence of overweight and obesity was 44% in the ambulant group and 51% in the non-ambulant group. In the non-ambulatory group, exceeding the recommended caloric intake was associated with higher BMI-z scores (r 0.36, p = 0.04). Patients who were using corticosteroids had significantly higher BMI-z scores compared with patients not using corticosteroids (1.06 and 0.51 respectively, p = 0.02). Longitudinal analyses on patients ambulant at first visit showed an increase in BMI-z score during transition to the non-ambulatory phase. Caloric intake and corticosteroid use were not associated with BMI-z. Transition to the non-ambulatory phase may be crucial in the development of excessive weight gain. Early measures - starting before this time frame - may contribute to reduce development of obesity. (c) 2022 The Author(s). Published by Elsevier B.V. Show less
More than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation... Show moreMore than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation of the structurally comparable mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can lead to very different, or even opposite effects. It also remained unclear how the consequence of activation of a single receptor, GR, can differ from cell to cell and from situation to situation. In this thesis we have investigated two aspects of transcriptional regulation in response to glucocorticoids: the cause of MR/GR specificity, and the role of crosstalk with other transcription factors. Within the hippocampus, we found NeuroD factors to drive the specificity in corticosteroid receptor DNA binding and subsequent gene regulation, i.e. by stimulating MR signaling. We identified Jun dimerization protein 2 (Jdp2) as a stress-responsive MR-specific target gene. In a stress hormone relevant memory task, GR was suggested to act context-dependently and several novel GR target genes were detected. Further elucidation of distinct MR/GR downstream pathways will enable us to better understand the stress physiology and more specifically target aspects of glucocorticoid signaling for treatment of stress-related disorders. Show less
BackgroundIn the current SARS-CoV-2 pandemic, there has been worldwide debate on the use of corticosteroids in COVID-19. In the recent RECOVERY trial, evaluating the effect of dexamethasone, a... Show moreBackgroundIn the current SARS-CoV-2 pandemic, there has been worldwide debate on the use of corticosteroids in COVID-19. In the recent RECOVERY trial, evaluating the effect of dexamethasone, a reduced 28-day mortality in patients requiring oxygen therapy or mechanical ventilation was shown. Their results have led to considering amendments in guidelines or actually already recommending corticosteroids in COVID-19. However, the effectiveness and safety of corticosteroids still remain uncertain, and reliable data to further shed light on the benefit and harm are needed.ObjectivesThe aim of this systematic review and meta-analysis was to evaluate the effectiveness and safety of corticosteroids in COVID-19.MethodsA systematic literature search of RCTS and observational studies on adult patients was performed across Medline/PubMed, Embase and Web of Science from December 1, 2019, until October 1, 2020, according to the PRISMA guidelines. Primary outcomes were short-term mortality and viral clearance (based on RT-PCR in respiratory specimens). Secondary outcomes were: need for mechanical ventilation, need for other oxygen therapy, length of hospital stay and secondary infections.ResultsForty-four studies were included, covering 20.197 patients. In twenty-two studies, the effect of corticosteroid use on mortality was quantified. The overall pooled estimate (observational studies and RCTs) showed a significant reduced mortality in the corticosteroid group (OR 0.72 (95%CI 0.57-0.87). Furthermore, viral clearance time ranged from 10 to 29 days in the corticosteroid group and from 8 to 24 days in the standard of care group. Fourteen studies reported a positive effect of corticosteroids on need for and duration of mechanical ventilation. A trend toward more infections and antibiotic use was present.ConclusionsOur findings from both observational studies and RCTs confirm a beneficial effect of corticosteroids on short-term mortality and a reduction in need for mechanical ventilation. And although data in the studies were too sparse to draw any firm conclusions, there might be a signal of delayed viral clearance and an increase in secondary infections. Show less
Background The analysis of mobile health (mHealth) data has generated innovative insights into improving allergic rhinitis control, but additive information is needed. A cross-sectional real-world... Show moreBackground The analysis of mobile health (mHealth) data has generated innovative insights into improving allergic rhinitis control, but additive information is needed. A cross-sectional real-world observational study was undertaken in 17 European countries during and outside the estimated pollen season. The aim was to collect novel information including the phenotypic characteristics of the users. Methods The Allergy Diary-MASK-air-mobile phone app, freely available via Google Play and App, was used to collect the data of daily visual analogue scales (VASs) for overall allergic symptoms and medication use. Fluticasone Furoate (FF), Mometasone Furoate (MF), Azelastine Fluticasone Proprionate combination (MPAzeFlu) and eight oral H1-antihistamines were studied. Phenotypic characteristics were recorded at entry. The ARIA severity score was derived from entry data. This was an a priori planned analysis. Results 9037 users filled in 70,286 days of VAS in 2016, 2017 and 2018. The ARIA severity score was lower outside than during the pollen season. Severity was similar for all treatment groups during the pollen season, and lower in the MPAzeFlu group outside the pollen season. Days with MPAzeFlu had lower VAS levels and a higher frequency of monotherapy than the other treatments during the season. Outside the season, days with MPAzeFlu also had a higher frequency of monotherapy. The number of reported days was significantly higher with MPAzeFlu during and outside the season than with MF, FF or oral H1-antihistamines. Conclusions This study shows that the overall efficacy of treatments is similar during and outside the pollen season and indicates that medications are similarly effective during the year. Show less
Central serous chorioretinopathy (CSC) is a common form of vision loss, typically seen in working-age men. The pathophysiology behind CSC still eludes us, however significant advances have been... Show moreCentral serous chorioretinopathy (CSC) is a common form of vision loss, typically seen in working-age men. The pathophysiology behind CSC still eludes us, however significant advances have been made in understanding this disease over the last decade using information from genetic and cell-based studies and imaging modalities. This review aims to give an overview of the current pathophysiology hypotheses surrounding CSC in addition to future directions in cellular work from human induced pluripotent stem cell derived choroidal endothelial cells from CSC patients. Furthermore, this review will provide the reader with an update on the clinical aspects of CSC including risk factors, diagnostic challenges and findings from multimodal imaging. Show less
Ng, K.T.; Paassen, J. van; Langan, C.; Sarode, D.P.; Arbous, M.S.; Alston, R.P.; Dekkers, O. 2020
Corticosteroids are often administered prophylactically to attenuate the inflammatory response associated with cardiac surgery using cardiopulmonary bypass (CPB). However, the efficacy and safety... Show moreCorticosteroids are often administered prophylactically to attenuate the inflammatory response associated with cardiac surgery using cardiopulmonary bypass (CPB). However, the efficacy and safety profile of corticosteroids remain uncertain. The primary aim of this systematic review and meta-analysis was to investigate the effect of corticosteroids on mortality in adult cardiac surgery using CPB. Secondary aims were to examine the effect of corticosteroids on myocardial adverse events, pulmonary adverse events, atrial fibrillation, surgical site infection, gastrointestinal bleeding and duration of stay in the intensive care unit and hospital. Randomized controlled trials (RCTs) were systematically searched in electronic databases (MEDLINE, EMBASE, CINAHL, CENTRAL and Web of Science) from their inception until March 2019. Observational studies, case reports, case series and literature reviews were excluded. Sixty-two studies (n = 16 457 patients) were included in this meta-analysis. There was no significant difference in mortality between the corticosteroid and placebo groups [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.81-1.14; P = 0.65, participants = 14 693, studies = 24, evidence of certainty: moderate]. Compared to those receiving a placebo, patients who were given corticosteroids had a significantly higher incidence of myocardial adverse events (OR 1.17, 95% CI 1.03-1.33; P = 0.01, participants = 14 512, studies = 23) and a lower incidence of pulmonary adverse events (OR 0.86, 95% CI 0.75-0.98; P = 0.02, participants = 13 426, studies = 17). The incidences of atrial fibrillation (OR 0.87, 95% CI 0.81-0.94; P < 0.001, participants = 14 148, studies = 24) and surgical site infection (OR 0.81, 95% CI 0.73-0.90; P < 0.001, participants = 13 946; studies = 22) were all lower in patients who were given corticosteroids. In the present meta-analysis of 62 RCTs (16 457 patients), including the 2 major RCTs (SIRS and DECS trials: 12 001 patients), we found that prophylactic corticosteroids in cardiac surgery did not reduce mortality. The clinical significance of an increase in myocardial adverse events remains unclear as the definition of a relevant myocardial end point following cardiac surgery varied greatly between RCTs. Show less
Myasthenia gravis is an autoimmune disease characterized by dysfunction of the neuromuscular junction. Current treatment is based on lifestyle advice, symptomatic treatment, immunosuppressive drugs... Show moreMyasthenia gravis is an autoimmune disease characterized by dysfunction of the neuromuscular junction. Current treatment is based on lifestyle advice, symptomatic treatment, immunosuppressive drugs and thymectomy. Corticosteroids remain the cornerstone of treatment beside symptomatic medication due to their low cost, wide availability and fast mode of action. However, long term steroid use carries substantial risks of severe adverse side effects. Therefore, non-steroidal immunosuppressive drugs are commonly added to the treatment. Unfortunately, they have a delayed-onset effect and evidence of their efficacy appears to be difficult to obtain. Several trials using drugs that have had clear positive results in other immunological disorders have failed in myasthenia. This failure may in part be related to difficulties in the design of clinical trial for myasthenia, which has a fluctuating disease course involving weakness that may be difficult to assess quantitively. This problem is exacerbated by the tendency of most clinical trials to select patients with a stable, but severe disease. Future trials should: select patients with weakness and fatigability that is completely explained by their myasthenia gravis, use a design that avoids the exclusion of patients with recent changes in medication, and explore the possibilities to completely avoid the use of corticosteroids. (C) 2019 The Author(s). Published by Elsevier B.V. Show less
Hypercortisolism causes numerous and potentially severe complications, which are often underestimated and not well recognized in clinical practice. There are two main causes for... Show moreHypercortisolism causes numerous and potentially severe complications, which are often underestimated and not well recognized in clinical practice. There are two main causes for hypercortisolism. Firstly, exogenous hypercortisolism through corticosteroid use, which is highly prevalent, since around 1% of the general population uses corticosteroids. Secondly, endogenous Cushing’s syndrome, which is rare, but the disease burden is considerable through increased morbidity and mortality risks. In this thesis, potential complications of exogenous hypercortisolism, and treatment and clinical outcomes of Cushing’s syndrome, are discussed. These studies on various aspects of hypercortisolism emphasize the importance of suppressing cortisol secretion to physiological ranges. Both hypercortisolism and adrenal insufficiency have enormous, and sometimes deleterious, impact on physical and psychological functioning. Treatment of hypercortisolism and adrenal insufficiency attempting to restore normal cortisol concentrations does not eliminate risk of adverse outcomes. Finally, increasing knowledge on the effects of endogenous Cushing’s syndrome and exogenous hypercortisolism is likely to improve patient care beyond the endocrinology department, as these conditions serve as a model for long-term exposure to stress, which is a highly prevalent condition. Insight into the potential consequences of long-term stress exposure, can aid all individuals exposed to long-term stress, including patients with chronic disease or long-term hospital admission. Show less
In chronic liver diseases, disturbances in liver function, for example in absorption of vitamin D, as well as factors related to the underlying primary liver disease, such as toxicity of alcohol or... Show moreIn chronic liver diseases, disturbances in liver function, for example in absorption of vitamin D, as well as factors related to the underlying primary liver disease, such as toxicity of alcohol or bile salts, may influence bone turnover. Low bone mass and vertebral fractures are already highly prevalent in patients with end-stage liver disease awaiting liver transplantation. There is rapid bone loss early after transplantation and new vertebral fractures occur in a third of transplanted patients within the first year after transplantation despite significant recovery of bone mass. Neither clinical parameters nor bone turnover markers or bone mineral density could reliably predict the risk of fractures. Furthermore, it is yet unclear how these patients should be treated in order to prevent fractures. Results from our and previous studies suggest that bisphosphonate treatment may decrease bone loss when initiated immediately after transplantation. In conclusion, fractures represent a significant cause of morbidity and mortality so that it is of high clinical relevance to correct all reversible aspects of liver failure to try and avoid the increased bone fragility associated with altered bone quality. Show less
Wevers-De Boer, K.V.C.; Heimans, L.; Huizinga, T.; Allaart, C. 2013
The scope of the work described in this thesis is to examine whether potential transfusion related and clinical risk factors modulate the risk of alloimmunization in a general, previously not... Show moreThe scope of the work described in this thesis is to examine whether potential transfusion related and clinical risk factors modulate the risk of alloimmunization in a general, previously not transfused, non alloimmunized population of transfusion recipients. In these studies we emphasize the methodological aspects of observational research in clinical transfusion medicine Show less
Pouwels, S.; Boer, A. de; Javaid, M.K.; Hilton-Jones, D.; Verschuuren, J.; Cooper, C.; ... ; Vries, F. de 2013
