Immunomodulation in community-acquired pneumonia

Community-acquired pneumonia (CAP) is a common disease with considerable morbidity and mortality, despite effective antibiotic treatment. In this thesis, we showed that the major causative microorganisms in CAP trigger distinct inflammatory response profiles in the host. While an inflammatory response as such is required to combat invading pathogens, an excessive inflammatory response may contribute to adverse clinical outcome. Modulation of the immune response could therefore offer promising new treatment options in CAP. In this thesis, we focused on the immunomodulatory properties of corticosteroids, macrolide antibiotics and vitamin D, and their potential role in prevention and treatment of CAP. A randomised placebo-controlled trial in hospitalised, non-immunocompromised patients with CAP showed that administration of dexamethasone adjuvant to antibiotics reduced length of hospital stay by one day. In addition, our data indicate that certain subgroups of patients might benefit in particular from dexamethasone treatment. Differences in dexamethasone effect were found for different microbial aetiologies. Next, in patients with a high pro-inflammatory cytokine response, but a discrepantly low cortisol, adjuvant dexamethasone was associated with a significant decrease in mortality/intensive care unit admission (combined endpoint). In a literature review, we provided an overview of the existing evidence from in vitro and in vivo studies on the immunomodulatory effects of macrolides in CAP. Macrolides have been shown to change the nature of the immune response during acute inflammation in three ways: by suppression of the cytokine response, by changing the behaviour of inflammatory cells to a more anti-inflammatory nature and by affecting structural cells of the respiratory tract. However, experimental and clinical studies on the immunomodulatory effects of macrolides when given adjuvant to β-lactam antibiotics, are lacking. In order to further elucidate the mechanisms of immunomodulation by macrolides during acute inflammation, in particular when given in combination with β-lactam antibiotics, we designed an in vitro model of acute infection with Streptococcus pneumoniae. We found that macrolides, alone or adjuvant to β-lactam antibiotics, attenuated the pro-inflammatory cytokine response in whole blood stimulated with heat-killed S. pneumoniae. This suggests an immunomodulatory effect. However, this effect was not observed in subsequent series of experiments with viable S. pneumoniae (either macrolide-susceptible or -resistant). Vitamin D has pleiotropic immunomodulatory properties, apart from its function in calcium and bone homeostasis. Vitamin D deficiency is common worldwide. In our cohort of patients with CAP, 53% of the patients was vitamin D deficient. We showed that vitamin D deficiency is associated with adverse clinical outcome in CAP. Vitamin D status at the time of hospital admission appeared to be an independent predictor for 30-day mortality, adding prognostic value to other biomarkers and prognostic scores, in particular the Pneumonia Severity Index (PSI) score. In former studies, vitamin D deficiency has been associated with an increased susceptibility to respiratory tract infections. Whether this association is based on a causal relationship is unknown.Three parallel large independent case-control studies showed no preventive association between vitamin D supplementation and pneumonia in adults. This suggests that there is no causal relation between vitamin D deficiency and the risk of pneumoni

Compassionate Use of Avacopan in Difficult-to-Treat Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Nephrolog

ExploriNg DUrable Remission with Rituximab in ANCA-associatEd vasculitis (ENDURRANCE trial): protocol for a randomised controlled trial

Introduction Both rituximab (RTX) and cyclophosphamide (CYC) are effectively used in combination with steroids as remission induction therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Several studies have shown that the effect on achieving (clinical) remission, frequency and severity of relapses is equivalent for both therapies, but there is accumulating data that the long-term safety profile of RTX might outperform CYC. Combination of RTX with low-dose CYC (LD-CYC) has been investigated in only a few uncontrolled cohort studies, in which clinical remission and a favourable immunological state with low relapse rates was quickly achieved. In this randomised controlled trial, we aim to investigate whether the combination treatment (RTX+LD CYC) is superior in comparison to standard care with RTX only.Methods and analysis This study is an open-label, multicentre, 1:1 randomised, prospective study for patients with AAV with generalised disease, defined as involvement of major organs, that is, kidneys, lungs, heart and nervous system. In total, 100 patients will be randomised 1:1 to receive either remission induction therapy with standard of care (RTX) or combination treatment (RTX+LD CYC) in addition to steroids and both arms are followed by maintenance with RTX retreatments (tailored to B-cell and ANCA status). Our primary outcome is the number of retreatments needed to maintain clinical remission over 2 years. Secondary outcomes are relevant clinical endpoints, safety, quality of life and immunological responses.Ethics and dissemination This study has received approval of the Medical Ethics Committee of the Leiden University Medical Center (P18.216, NL67515.058.18, date: 7 March 2019). The results of this trial (positive and negative) will be submitted for publication in relevant peer-reviewed publications and the key findings presented at national and international conferences.Nephrolog

Clinical Practice Audit on the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in the Netherlands

Introduction: Managing complex and rare systemic autoimmune diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) can be challenging and is often accompanied by undesirable variations in clinical practice. Adequate understanding of clinical practice can help identify essential issues to improve the care for AAV patients. Therefore, we studied the real-life management and outcomes of AAV patients in the Netherlands.Methods: In this cohort study, we investigated clinical practice in university and nonuniversity teaching hospitals with respect to patients with a clinical diagnosis of AAV. We retrospectively collected clinical data encompassing clinical variables, medication details, and outcome parameters.Results: Data of 230 AAV patients were collected in 9 Dutch hospitals. Of these, 167 patients (73%) were diagnosed with granulomatosis with polyangiitis, 54 (24%) with microscopic polyangiitis and 9 (4%) with eosinophilic granulomatosis with polyangiitis. One hundred sixty-six patients (72%) had generalized disease. The median year of diagnosis was 2013 (range 1987-2018). Besides steroids, oral cyclophosphamide was the most used drug (50%) for induction therapy and azathioprine (68%) for maintenance therapy. Adverse outcomes were major infections in 35%, major relapses in 23%, malignancy in 10%, major cardiovascular events in 8%, and end-stage renal disease in 7%.Conclusion: Oral cyclophosphamide was the most frequently used induction therapy, azathioprine for maintenance therapy; over time, the use of rituximab is increasingly employed. Major infection and relapses are the most prevalent adverse outcomes. This audit resulted in important indicators for treatment of AAV patients that can be implemented for future, national audits to improve the outcomes of AAV patients.Nephrolog

Identifying relevant determinants of in-hospital time to diagnosis for ANCA-associated vasculitis patients

Objectives Diagnosing patients with ANCA-associated vasculitis (AAV) can be challenging owing to its rarity and complexity. Diagnostic delay can have severe consequences, such as chronic organ damage or even death. Given that few studies have addressed diagnostic pathways to identify opportunities to improve, we performed a clinical audit to evaluate the diagnostic phase. Methods This retrospective, observational study of electronic medical records data in hospitals focused on diagnostic procedures during the first assessment until diagnosis. Results We included 230 AAV patients from nine hospitals. First assessments were mainly performed by a specialist in internal medicine (52%), pulmonology (14%), ENT (13%) or rheumatology (10%). The overall median time to diagnosis was 13 [interquartile range: 2-49] days, and in patients primarily examined by a specialist in internal medicine it was 6 [1-25] days, rheumatology 14 [4-45] days, pulmonology 15 [5-70] days and ENT 57 [16-176] days (P = 0.004). Twenty-two of 31 (71%) patients primarily assessed by a specialist in ENT had non-generalized disease, of whom 14 (64%) had ENT-limited activity. Two hundred and nineteen biopsies were performed in 187 patients (81%). Histopathological support for AAV was observed in 86% of kidney biopsies, 64% of lung biopsies and 34% of ENT biopsies. Conclusion In The Netherlands, AAV is diagnosed and managed predominantly by internal medicine specialists. Diagnostic delay was associated with non-generalized disease and ENT involvement at presentation. Additionally, ENT biopsies had a low diagnostic yield, in contrast to kidney and lung biopsies. Awareness of this should lead to more frequent consideration of AAV and early referral for a multidisciplinary approach when AAV is suspected

Identifying relevant determinants of in-hospital time to diagnosis for ANCA-associated vasculitis patients

Objectives Diagnosing patients with ANCA-associated vasculitis (AAV) can be challenging owing to its rarity and complexity. Diagnostic delay can have severe consequences, such as chronic organ damage or even death. Given that few studies have addressed diagnostic pathways to identify opportunities to improve, we performed a clinical audit to evaluate the diagnostic phase. Methods This retrospective, observational study of electronic medical records data in hospitals focused on diagnostic procedures during the first assessment until diagnosis. Results We included 230 AAV patients from nine hospitals. First assessments were mainly performed by a specialist in internal medicine (52%), pulmonology (14%), ENT (13%) or rheumatology (10%). The overall median time to diagnosis was 13 [interquartile range: 2-49] days, and in patients primarily examined by a specialist in internal medicine it was 6 [1-25] days, rheumatology 14 [4-45] days, pulmonology 15 [5-70] days and ENT 57 [16-176] days (P = 0.004). Twenty-two of 31 (71%) patients primarily assessed by a specialist in ENT had non-generalized disease, of whom 14 (64%) had ENT-limited activity. Two hundred and nineteen biopsies were performed in 187 patients (81%). Histopathological support for AAV was observed in 86% of kidney biopsies, 64% of lung biopsies and 34% of ENT biopsies. Conclusion In The Netherlands, AAV is diagnosed and managed predominantly by internal medicine specialists. Diagnostic delay was associated with non-generalized disease and ENT involvement at presentation. Additionally, ENT biopsies had a low diagnostic yield, in contrast to kidney and lung biopsies. Awareness of this should lead to more frequent consideration of AAV and early referral for a multidisciplinary approach when AAV is suspected.Nephrolog

A Dutch consensus statement on the diagnosis and treatment of ANC A-associated vasculitis

Introduction: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidisciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands.Methods: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement.Results: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 5o statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV.Conclusion: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.Nephrolog