Kronisk transplantat-mot-vertsykdom

Kronisk transplantat-mot-vert-sykdom er en senkomplikasjon etter allogen stamcelletransplantasjon, og medfører kronisk inflammasjon og fibrose i forskjellige organer på grunn av feil regulering av donors immunceller. Sykdommen kan forekomme i alle organer, men sees hyppigst i hud, øyne, munnhule, gastrointestinaltraktus, genitalia, lunger, muskler, fascier og ledd. Kronisk transplantat-mot-vert-sykdom er assosiert med betydelig sykelighet og dødelighet, og behandling krever tett samarbeid mellom forskjellige deler av spesialisthelsetjenesten. Vi gir i denne artikkelen en klinisk oversikt over kronisk transplantat-mot-vert-sykdom basert på ikke-systematiske litteratursøk og egne kliniske erfaringer.publishedVersio

A Nationwide Study of GATA2 Deficiency in Norway-the Majority of Patients Have Undergone Allo-HSCT

PurposeGATA2 deficiency is a rare primary immunodeficiency that has become increasingly recognized due to improved molecular diagnostics and clinical awareness. The only cure for GATA2 deficiency is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The inconsistency of genotype-phenotype correlations makes the decision regarding "who and when" to transplant challenging. Despite considerable morbidity and mortality, the reported proportion of patients with GATA2 deficiency that has undergone allo-HSCT is low (~ 35%). The purpose of this study was to explore if detailed clinical, genetic, and bone marrow characteristics could predict end-point outcome, i.e., death and allo-HSCT.MethodsAll medical genetics departments in Norway were contacted to identify GATA2 deficient individuals. Clinical information, genetic variants, treatment, and outcome were subsequently retrieved from the patients' medical records.ResultsBetween 2013 and 2020, we identified 10 index cases or probands, four additional symptomatic patients, and no asymptomatic patients with germline GATA2 variants. These patients had a diverse clinical phenotype dominated by cytopenia (13/14), myeloid neoplasia (10/14), warts (8/14), and hearing loss (7/14). No valid genotype-phenotype correlations were found in our data set, and the phenotypes varied also within families. We found that 11/14 patients (79%), with known GATA2 deficiency, had already undergone allo-HSCT. In addition, one patient is awaiting allo-HSCT. The indications to perform allo-HSCT were myeloid neoplasia, disseminated viral infection, severe obliterating bronchiolitis, and/or HPV-associated in situ carcinoma. Two patients died, 8 months and 7 years after allo-HSCT, respectively.ConclusionOur main conclusion is that the majority of patients with symptomatic GATA2 deficiency will need allo-HSCT, and a close surveillance of these patients is important to find the "optimal window" for allo-HSCT. We advocate a more offensive approach to allo-HSCT than previously described

Gram-positive endotoxemia and modulation of the innate immune response

Sepsis is a systemic inflammatory response caused by an infection. Although it is the leading cause of death in surgical intensive care units, limited progress has been made in recent decades to improve outcome and mortality. Gram-positive bacteria, such as Staphylococcus aureus, account for up to 50 % of all cases, but how this type of bacteria cause systemic inflammation has been scarcely studied. This thesis aimed to explore the structural requirements of peptidoglycan, the major wall component of Gram-positive bacteria, to induce inflammation and organ injury, and the capacity of peptidoglycan to induce the release of inflammatory mediators considered to be important in the pathogenesis of sepsis. Further aims were to explore the potential of amelogenin, a protein known to promote periodontal wound healing, and liver X receptor, a nuclear nutrient receptor and transcription factor involved in multiple cellular functions, to modulate inflammation induced by bacterial endotoxins, such as peptidoglycan. We discovered that peptidoglycan relies on its glycan backbone to induce organ injury and inflammation in rats, and that peptidoglycan is a potent inducer of several inflammatory mediators (specifically interleukin-8 and matrix metalloproteinase-9) from whole human blood and primary human monocytes and neutrophils. Amelogenin attenuated the release of pro-inflammatory cytokines caused by endotoxins in human blood, and this effect was probably mediated through induction of the second messenger cAMP. Finally, activation of the liver X receptor by synthetic ligands inhibited the release of a multitude of different cytokines from human monocytes. The precise mechanism, however, remains to be elucidated. In summary, this thesis elucidates some mechanisms by which Gram-positive bacteria cause sepsis, as well as proposing new targets in modulating the exaggerated inflammation associated with sepsis, which might have therapeutic potentials

Clinical outcomes of antimicrobial resistance in cancer patients: a systematic review of multivariable models

Abstract Background Infections are major causes of disease in cancer patients and pose a major obstacle to the success of cancer care. The global rise of antimicrobial resistance threatens to make these obstacles even greater and hinder continuing progress in cancer care. To prevent and handle such infections, better models of clinical outcomes building on current knowledge are needed. This internally funded systematic review (PROSPERO registration: CRD42021282769) aimed to review multivariable models of resistant infections/colonisations and corresponding mortality, what risk factors have been investigated, and with what methodological approaches. Methods We employed two broad searches of antimicrobial resistance in cancer patients, using terms associated with antimicrobial resistance, in MEDLINE and Embase through Ovid, in addition to Cinahl through EBSCOhost and Web of Science Core Collection. Primary, observational studies in English from January 2015 to November 2021 on human cancer patients that explicitly modelled infection/colonisation or mortality associated with antimicrobial resistance in a multivariable model were included. We extracted data on the study populations and their malignancies, risk factors, microbial aetiology, and methods for variable selection, and assessed the risk of bias using the NHLBI Study Quality Assessment Tools. Results Two searches yielded a total of 27,151 unique records, of which 144 studies were included after screening and reading. Of the outcomes studied, mortality was the most common (68/144, 47%). Forty-five per cent (65/144) of the studies focused on haemato-oncological patients, and 27% (39/144) studied several bacteria or fungi. Studies included a median of 200 patients and 46 events. One-hundred-and-three (72%) studies used a p-value-based variable selection. Studies included a median of seven variables in the final (and largest) model, which yielded a median of 7 events per variable. An in-depth example of vancomycin-resistant enterococci was reported. Conclusions We found the current research to be heterogeneous in the approaches to studying this topic. Methodological choices resulting in very diverse models made it difficult or even impossible to draw statistical inferences and summarise what risk factors were of clinical relevance. The development and adherence to more standardised protocols that build on existing literature are urgent

Allogeneic stem cell transplant recipients surviving at least 2 years without relapse: outcome and risk factors

Abstract Outcomes of 2‐year survivours undergoing allo‐haematopoietic stem cell transplantation at Oslo University Hospital were retrospectively assessed with the objectives of identification of risk factors for late death as possible means for precautionary measures and interventions to improve long‐term survival. 421 patients with haematological malignancy, transplanted between 2005 and 2019, alive and free of disease after 2 years were included with data reported from The OUS‐HSCT registry. Median follow‐up was 6.2 years (2.016.1), and 232 patients (55%) were observed for minimum 5 years. The probability of being alive 5 and 10 years after HSCT was 86% and 76%. Primary risk factors for late death included initial diagnosis of age ≥ 60 years, chronic lymphocytic leukaemia (CLL), previous blood stream‐ or invasive fungal infection (BSI, IFI), and chronic graft‐versus‐host disease (cGVHD). Transplant‐related mortality (TRM) and relapse at 5 years were 9.0% and 7.7%, respectively. Two factors were associated with the latter: cytomegalovirus (CMV) seronegative donor and CLL. Compared with the age‐ and gender‐matched Norwegian general population, life expectancy was lower for each disease, except for CML. The prospect for the long‐term survival is good for 2‐year survivors of the allogeneic hematopoietic stem cell transplantation. However, life expectancy remains inferior to the age‐ and gender‐matched general population. Optimising prophylaxis and treatment for chronic GVHD, BSI and IFI are needed along with the improved adherence to guidelines for early detection of secondary malignancies. Measures to improve immune reconstitution, possibly the microbiota, and the use of CMV seropositive donors regardless of recipient sero‐status may be warranted and should be addressed in further studies

A Nationwide Study of GATA2 Deficiency in Norway-the Majority of Patients Have Undergone Allo-HSCT

Purpose: GATA2 deficiency is a rare primary immunodeficiency that has become increasingly recognized due to improved molecular diagnostics and clinical awareness. The only cure for GATA2 deficiency is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The inconsistency of genotype-phenotype correlations makes the decision regarding "who and when" to transplant challenging. Despite considerable morbidity and mortality, the reported proportion of patients with GATA2 deficiency that has undergone allo-HSCT is low (~ 35%). The purpose of this study was to explore if detailed clinical, genetic, and bone marrow characteristics could predict end-point outcome, i.e., death and allo-HSCT. Methods: All medical genetics departments in Norway were contacted to identify GATA2 deficient individuals. Clinical information, genetic variants, treatment, and outcome were subsequently retrieved from the patients' medical records. Results: Between 2013 and 2020, we identified 10 index cases or probands, four additional symptomatic patients, and no asymptomatic patients with germline GATA2 variants. These patients had a diverse clinical phenotype dominated by cytopenia (13/14), myeloid neoplasia (10/14), warts (8/14), and hearing loss (7/14). No valid genotype-phenotype correlations were found in our data set, and the phenotypes varied also within families. We found that 11/14 patients (79%), with known GATA2 deficiency, had already undergone allo-HSCT. In addition, one patient is awaiting allo-HSCT. The indications to perform allo-HSCT were myeloid neoplasia, disseminated viral infection, severe obliterating bronchiolitis, and/or HPV-associated in situ carcinoma. Two patients died, 8 months and 7 years after allo-HSCT, respectively. Conclusion: Our main conclusion is that the majority of patients with symptomatic GATA2 deficiency will need allo-HSCT, and a close surveillance of these patients is important to find the "optimal window" for allo-HSCT. We advocate a more offensive approach to allo-HSCT than previously described