Molecular surveillance of carbapenemase-producing Enterobacterales in Finland

Carbapenemase-producing (CP) Enterobacterales (CPE) are a growing menace to healthcare systems worldwide. CPE infections are difficult to treat because few antimicrobials remain effective. One of the new drug combinations, ceftazidimeavibactam (CAZ-AVI), was launched in Europe in 2016, however, a few years later concerns rose about CAZ-AVI resistance. Currently, whole genome sequencing (WGS) is an essential tool for public health surveillance and for studying the molecular epidemiology of CPE. Molecular surveillance data of WGS-characterized CPE in Finland during 2012-2018 were analyzed. In addition, isolates belonging to clusters caused by CP Citrobacter freundii were studied up to April 2020. The largest CPE clusters and discovered resistance to CAZ-AVI were investigated in detail in collaboration with regional infection control teams. The annual number of CPE isolates increased from 9 in 2012 to 70 in 2018 and different sequence types from 7 to 33. Of the isolates, 59% were found by screening and of the cases 61% had preceding travelling or hospitalization abroad. The most common CPE species were Klebsiella pneumoniae (45%), Escherichia coli (40%) and C. freundii (6%), and the most prevalent carbapenemase genes were blaNDM-like, blaOXA-48-like and blaKPC-like. We detected 10 CPE clusters; three of them were linked to abroad. Seven clusters were caused by K. pneumoniae (2-23 cases per cluster) and three by C. freundii (2-16 cases per cluster). All K. pneumoniae sequence types belonged to international high-risk clones. The largest clusters spread via patient transfers to several healthcare facilities with environmental contamination most likely playing a role in the persistence of the clusters. We describe a patient case developing CAZ-AVI resistance during CAZ-AVI treatment and showed that the resistance was probably due to a mutation in K. pneumoniae carbapenemase gene. During 2012-2018 a remarkable increase in CPE isolates was observed and most were detected by screening. The hospital environment can be a CPE reservoir prolonging the outbreaks, hence the national guidelines of CPE control were updated for terminal cleaning and screening. Real-time nationwide surveillance using WGS and team collaboration were crucial when identifying clusters, tracing back transmission chains and controlling the spread.Karbapenemaasia tuottavien Enterobacterales bakteerien molekulaarinen seuranta Suomessa Karbapenemaaseja tuottavat (CP) Enterobacterales -bakteerit (CPE) ovat kasvava uhka terveydenhuoltojärjestelmälle maailmanlaajuisesti. CPE:n aiheuttamien infektioiden hoito on hankalaa, sillä tehokkaita mikrobilääkkeitä on vähän. Yksi uusista lääkeyhdistelmistä on 2016 Euroopassa markkinoille tullut keftatsidiimiavibaktaami (CAZ-AVI). Huoli resistenssin kehittymisestä CAZ-AVI kohtaan alkoi jo muutama vuosi käyttöönoton jälkeen. Nykyisin kokogenomisekvensointi (WGS) on keskeinen työväline CPE:n molekyyliepidemiologisessa seurannassa. Väitöskirjassa tutkittiin WGS:lla tuotettua CPE:n molekulaarista seurantatietoa Suomesta vuosilta 2012–2018. Lisäksi CP Citrobacter freundii bakteerin aiheuttamien rypäiden kantoja tutkittiin huhtikuuhun 2020 asti. Suurimmat CPErypäät ja havaittu CAZ-AVI resistenssi tutkittiin tarkemmin yhteistyössä alueellisten infektioiden torjuntatiimien kanssa. CPE-tapausten määrä kasvoi vuoden 2012 9:stä vuoden 2018 70:een ja erilaiset sekvenssityypit 7:stä 33:een. Tapauksista 61 %:lla oli taustalla edeltänyt matkustus tai sairaalahoito ulkomailla ja 59 %:ia löytyi seulonnalla. Yleisimmät bakteerilajit olivat Klebsiella pneumoniae (45 %), Escherichia coli (40 %) ja C. freundii (6 %). Vallitsevat karbapenemaasigeenit olivat blaNDM-like, blaOXA-48-like and blaKPC-like. Tutkimuksen aikana havaittiin 10 CPE-ryvästä, joista kolmella oli linkki ulkomaille. K. pneumoniae aiheutti rypäistä seitsemän (2–23 tapausta/ryväs) ja C. freundii kolme (2–16 tapausta/ryväs). Kaikki rypäitä aiheuttaneet K. pneumoniae sekvenssityypit kuuluivat kansainvälisiin korkeanriskin klooneihin. Suurin ryväs levisi potilassiirtojen välityksellä useisiin terveydenhuollon yksiköihin ja ympäristön kontaminaatiolla todennäköisesti oli merkitystä ongelman pitkittymiseen. Kuvasimme potilastapauksen, jossa CAZ-AVI-resistenssi kehittyi hoidon aikana ja osoitimme, että resistenssin aiheutti mahdollisesti mutaatio K. pneumoniae karbapenemaasigeenissä. Vuosina 2012–2018 CPE-kannoissa nähtiin merkittävä lisääntyminen ja valtaosa löytyi seulonnalla. Sairaalaympäristö voi toimia CPE-kantojen lähteenä pitkittäen epidemioita, minkä vuoksi kansallista torjuntaohjetta päivitettiin loppusiivousta ja seulontaa koskien. Reaaliaikainen, kansallinen WGS-seuranta ja eri tahojen yhteistyö oli ratkaisevaa rypäiden havaitsemisessa sekä jäljitys- ja torjuntatyössä

Recurrent allograft C3 glomerulonephritis and unsuccessful eculizumab treatment

There is a great lack of efficient treatments for membranoproliferative glomerulonephritis (MPGN) and recently emerged complement therapies have been proposed to be useful. We report a patient with a complement mediated MPGN having recurrencies in kidney allografts and an unsuccessful treatment with complement inhibitor, eculizumab (anti-C5 monoclonal antibody). Nephritic factor (C3Nef), an autoantibody against C3bBb, in the patient serum activated C3 but not C5 showing that major damage was mediated by C3 activation with clearly less involvement of C5 explaining unresponsiveness to eculizumab. Analyzing C3Nef-mediated C3 and C5 activation separately could help in choosing the right patients for eculizumab therapy. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

Diagnostic and Prognostic Comparison of Immune-Complex-Mediated Membranoproliferative Glomerulonephritis and C3 Glomerulopathy

Membranoproliferative glomerulonephritis (MPGN) is subdivided into immune-complex-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G). Classically, MPGN has a membranoproliferative-type pattern, but other morphologies have also been described depending on the time course and phase of the disease. Our aim was to explore whether the two diseases are truly different, or merely represent the same disease process. All 60 eligible adult MPGN patients diagnosed between 2006 and 2017 in the Helsinki University Hospital district, Finland, were reviewed retrospectively and asked for a follow-up outpatient visit for extensive laboratory analyses. Thirty-seven (62%) had IC-MPGN and 23 (38%) C3G (including one patient with dense deposit disease, DDD). EGFR was below normal (≤60 mL/min/1.73 m2) in 67% of the entire study population, 58% had nephrotic range proteinuria, and a significant proportion had paraproteins in their serum or urine. A classical MPGN-type pattern was seen in only 34% of the whole study population and histological features were similarly distributed. Treatments at baseline or during follow-up did not differ between the groups, nor were there significant differences observed in complement activity or component levels at the follow-up visit. The risk of end-stage kidney disease and survival probability were similar in the groups. IC-MPGN and C3G have surprisingly similar characteristics, kidney and overall survival, which suggests that the current subdivision of MPGN does not add substantial clinical value to the assessment of renal prognosis. The high proportion of paraproteins in patient sera or in urine suggests their involvement in disease development

Vascular Occlusion in Kidney Biopsy Is Characteristic of Clinically Manifesting Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) can sometimes manifest only histologically. Our aim was to retrospectively compare biopsy-proven adult TMA patients showing only histological (h-TMA) or both histological and clinical (c-TMA) TMA in 2006-2017. All native kidney biopsies with TMA were included. Biopsies were re-evaluated by light and electron microscopy, and immunofluorescence. Clinical characteristics, laboratory variables, and treatments were recorded from the electronic medical database. Patients were categorized into h-TMA and c-TMA and these groups were compared. In total, 30 biopsy-proven cases among 7943 kidney biopsies were identified and, of these, 15 had h-TMA and 15 c-TMA. Mean follow-up was 6.3 y, and 73.3% had secondary hemolytic uremic syndrome (HUS) and the rest were atypical HUS. Patient characteristics, treatments, and kidney, and patient survival in the groups were similar. Statistically significant differences were found in histological variables. Vascular myxoid swelling and vascular onion-skinning were almost exclusively detected in c-TMA and, thus, vascular occlusive changes indicate clinically apparent rather than merely histological TMA. In addition, regardless of clinical presentation, kidney and patient survival times were similar in the patient groups highlighting the importance of a kidney biopsy in the case of any kidney-related symptoms.Peer reviewe

Vascular Occlusion in Kidney Biopsy Is Characteristic of Clinically Manifesting Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) can sometimes manifest only histologically. Our aim was to retrospectively compare biopsy-proven adult TMA patients showing only histological (h-TMA) or both histological and clinical (c-TMA) TMA in 2006–2017. All native kidney biopsies with TMA were included. Biopsies were re-evaluated by light and electron microscopy, and immunofluorescence. Clinical characteristics, laboratory variables, and treatments were recorded from the electronic medical database. Patients were categorized into h-TMA and c-TMA and these groups were compared. In total, 30 biopsy-proven cases among 7943 kidney biopsies were identified and, of these, 15 had h-TMA and 15 c-TMA. Mean follow-up was 6.3 y, and 73.3% had secondary hemolytic uremic syndrome (HUS) and the rest were atypical HUS. Patient characteristics, treatments, and kidney, and patient survival in the groups were similar. Statistically significant differences were found in histological variables. Vascular myxoid swelling and vascular onion-skinning were almost exclusively detected in c-TMA and, thus, vascular occlusive changes indicate clinically apparent rather than merely histological TMA. In addition, regardless of clinical presentation, kidney and patient survival times were similar in the patient groups highlighting the importance of a kidney biopsy in the case of any kidney-related symptoms

Vascular Occlusion in Kidney Biopsy Is Characteristic of Clinically Manifesting Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) can sometimes manifest only histologically. Our aim was to retrospectively compare biopsy-proven adult TMA patients showing only histological (h-TMA) or both histological and clinical (c-TMA) TMA in 2006–2017. All native kidney biopsies with TMA were included. Biopsies were re-evaluated by light and electron microscopy, and immunofluorescence. Clinical characteristics, laboratory variables, and treatments were recorded from the electronic medical database. Patients were categorized into h-TMA and c-TMA and these groups were compared. In total, 30 biopsy-proven cases among 7943 kidney biopsies were identified and, of these, 15 had h-TMA and 15 c-TMA. Mean follow-up was 6.3 y, and 73.3% had secondary hemolytic uremic syndrome (HUS) and the rest were atypical HUS. Patient characteristics, treatments, and kidney, and patient survival in the groups were similar. Statistically significant differences were found in histological variables. Vascular myxoid swelling and vascular onion-skinning were almost exclusively detected in c-TMA and, thus, vascular occlusive changes indicate clinically apparent rather than merely histological TMA. In addition, regardless of clinical presentation, kidney and patient survival times were similar in the patient groups highlighting the importance of a kidney biopsy in the case of any kidney-related symptoms

Vaikea hemolyysi ja munuaisvaurio punasolusiirtojen jälkeen

VertaisarvioituPunasolusiirtojen tunnetuin haitta on välitön hemolyyttinen verensiirtoreaktio. Sen oireet alkavat usein jo verensiirron aikana. Viivästyneen reaktion oireet ovat yleensä lievempiä ja jäävät usein kokonaan toteamatta. Kuvaamme potilaan, jolla viivästynyt hemolyyttinen verensiirtoreaktio johti dialyysihoitoja vaatineeseen mu¬¬nuaisvaurioon. Koska oireiden yhteyttä äskettäiseen verensiirtoon ei heti osattu epäillä, diagnoosi viivästyi, aiheutui invasiivisia tutkimuksia ja munuaisten toipuminen vaarantui