The research group on Infectious diseases is led by Britt-Marie Eriksson and consists of four independent project groups covering the following reserch areas:
1 SEPSIS and Septic schock; Mia Furebring, Elisabeth Löwdin and Jan Sjölin.
2 Antibiotic resistance; Tomas Tängdén
The prevalence of resistant bacteria is accelerating and the development of new antibiotics is slow. Infections caused by bacteria that cannot be treated with standard therapy is therefore increasing and results in higher patient morbidity and higher costs for health care and the society. The activity of existing drugs can be improved by combining two or three drugs, that have insufficient activities alone, and by finding new dosage regimens that will enhance the effects and minimize emergence of resistance. Rapid diagnostics can shorten the time to adequate therapy and thus contribute to reduced overuse of antibiotics and delayed resistance development.
In a European joint research project, we are exploring the effects of combinations including antibiotics as well as non-antibiotics against multidrug-resistant gram-negative bacteria in vitro. Further, we are evaluating the accuracy of a rapid diagnostic assay for antibiotic susceptibility testing in collaboration with Gradientech AB. In clinical studies, we evaluate the efficacy of different antibiotics against resistant ESBL-producing bacteria causing urinary tract infections and the impact of different drugs on the intestinal microbiota.
3 Infections in solid organ transplantation and infections in the brain; Britt-Marie Eriksson
The number of solid organ transplant recipients increases continously demanding more knowledge about opportunistic infections. Main focus has been research on cytomegalovirus infections in renal transplant recipients but also in other groups of patients. Another trail of research is infections in the central nervous system; encephalitis and external drainage related meningitis. Read more about our projects.
4 Infections in and vaccination of immunocompromised patients; Karlis Pauksens
Data on safety, immunogenicity, and efficacy of vaccines for immunocompromised populations are limited. We have studied response to vaccination in different immunocompromised individuals such as elderly patients, patients with rheumatoid arthritis, and patients with cancer. Furthermore, we study opportunistic infections with special focus on Epstein-Barr virus (EBV) and post-transplant lymphoproliferative disorder (PTLD) after allogeneic stem cell transplantation and solid organ transplantation.
Sepsis and Septic schock
Interplay between antibacterial and antifungal treatment and innate and specific immunological responses in severe infections
Mia Furebring (projektledare), Jan Sjölin, Elisabeth Löwdin, Markus Castegren, Jesper Sperber, Eva Tano, Helena Janols, Anna Hedberg, Paul Skorup, Anna-Karin Smekal, Siri Kurland, Axel Nyberg, Frida Wilske, Katja Hanslin
The overall aim is to study the interplay between treatment and innate and specific immunological responses in severe sepsis and septic shock as well as in bacterial infections in the central nervous system. Translational projects involving clinical studies, in vitro experiments and intensive care animal models as clinically relevant as possible with the use of sedation, mechanical ventilation, vasopressors all known to influence the inflammatory response. Animal experiments focus mainly on clinical issues that cannot be solved by randomized clinical trials.
In previous sepsis models we have demonstrated that the inflammatory response and bacterial killing in the blood may be reduced in secondary sepsis, in which inflammatory and anti-inflammatory activities have been activated by preceding infection or trauma. This was also seen in a clinical pilot study published in 2015. In a new study bacterial killing of the phagocytic cells in the liver and the spleen was investigated after a 24-h infusion of endotoxin in our intensive care large animal (porcine) model and compared to that in healthy animals. Surprisingly, an increased bacterial killing was noticed and thus the concern that bacterial killing is negatively affected if bacteria enter the bloodstream once the inflammatory systems have been activated seems not valid. In another study on ventilator associated pneumonia there was, in contrast, a reduced bacterial killing in the lung using the same model indicating different systemic and local capacities to kill bacteria. During 2016 we have continued our efforts to develop a tertiary sepsis model, in which the inflammatory response is blunted by an endotoxin-induced anti-inflammatory response in combination with high-dose steroid treatment. This model will primarily be used to test in vivo killing of bacteria and Candida. We have almost solved the problems with this model and, if so, it will be the first large animal model of candidemia. With these varying models established, the antibacterial activity of different treatments with antibiotics and immunomodulatory drugs will be the primary focus. The present models will increase our knowledge and ability to conduct future clinical trials.
The effect of neurosurgical trauma and the innate immune response on the specific immunity by vaccination of patients with a T-cell dependent vaccine was published in 2015. A reduced response was seen if vaccinated during the 10 first days after trauma. We have now extended that analysis to the response to a T-cell independent pneumococcal vaccine that is not affected and thus preferably should be used for an early protection against pneumococcal meningitis. In 2016 the effect of immunomodulation by corticosteroids given before antibiotic treatment has been assessed in a registry comprising 1500 patients with meningitis. This is up to now the largest study on corticosteroids and meningitis.
Clinical studies evaluating the effect of the systemic inflammatory response on pharmacokinetics of antibiotics and antifungals have continued during the year. Furthermore, the work with an ex vivo antifungal model has been initiated determining the antifungal activity of patient blood.
- Carlsson M, Lipcsey M, Larsson A, Rubertsson S, Eriksson M, Sjölin J. Inflammatory and circulatory effects of the reduction in endotoxin in established porcine endotoxic shock – a model of endotoxin elimination. Critical Care Medicine 2009;37:1031-7.
- Lipcsey M, Carlsson M, Larsson A, Algotsson L, Eriksson M, Sjölin J. Effect of a single dose of tobramycin on systemic inflammatory-induced kidney injury in a 6-hour porcine model. Critical Care Medicine 2009;37:2782-90.
- Lipcsey M, Olovsson M, Larsson E, Sjölin J, Larsson A, The brain is a major source of S100B increase in procine endotoxic shock. Anesth Analg. 2010;110:174-80
- Tängdén T, Enblad P, Ullberg M, Sjölin J. Neurosurgical Gram-negative bacillary meningitis; a retrospective study evaluating the efficacy of intraventricular gentamicin therapy in 31 consecutive cases. Clin Infect Dis. 2011;52:1310-6.
- Edberg M, Furebring M, Sjölin J, Enblad P. Neurointensive care of patients with severe community-acquired meningitis. Acta Anaesthesiol Scand. 2011;55:732-9.
- Castegren M, Lipcsey M, Söderberg E, Skorup P, Eriksson M, Larsson A, Sjölin J. Differences in organ dysfunction in endotoxin-tolerant pigs under intensive care exposed to a second hit of endotoxin. Shock. 2012;37:501-10.
- Söderberg E, Lipcsey M, Sjölin J, Larsson A, Eriksson M. Counteraction of early circulatory derangement by administration of low dose steroid treatment at the onset of established endotoxemic shock is not directly mediated by TNF-a and IL-6. Steroids. 2012;77:1101-6.
- Castegren M, Skorup P, Lipcsey M, Larsson A, Sjölin J. Endotoxin Tolerance Variation over 24 h during Porcine Endotoxemia: Association with Changes in Circulation and Organ Dysfunction. PLoS One. 2013;8:e53221.
- Ericsson J, Chryssanthou E, Klingspor L, Johansson AG, Ljungman P, Svensson E, Sjölin J. Candidaemia in Sweden: a nationwide prospective observational survey. Clin Microbiol Infect. 2013;19:E218-21.
- Skorup P, Maudsdotter L, Lipcsey M, Castegren M, Larsson A, Jonsson AB, Sjölin J. Beneficial antimicrobial effect of the addition of an aminoglycoside to a β-lactam antibiotic in an E. coli porcine intensive care severe sepsis model. PLoS One. 2014 F;9:e90441
- Sperber J, Lipcsey M, Larsson A, Larsson A, Sjölin J, Castegren M. Lung protective ventilation induces immunotolerance and nitric oxide metabolites in porcine experimental postoperative sepsis. PLoS One. 2013;8:e83182Linnér A, Darenberg J, Sjölin J, Henriques-Normark B, Norrby-Teglund A. Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study. Clin Infect Dis. 2014;59:851-7.
- Hedberg AL, Pauksens K, Ronne-Engström E, Lundberg M, Johansson B, Käyhty H, Sjölin J. Lower response to early T-cell-dependent vaccination after neurotrauma or neurosurgery in adults. J Infect. 2015;70:1162-9.
- Glimåker M, Johansson B, Grindborg Ö, Bottai M, Lindquist L, Sjölin J. Adult Bacterial Meningitis: Earlier Treatment and Improved Outcome Following Guideline Revision Promoting Prompt Lumbar Puncture. Clin Infect Dis. 2015;60:1162-9.
- von Seth M, Sjölin J, Larsson A, Eriksson M, Hillered L, Lipcsey M. Effects of Tigecycline and Doxycycline on Inflammation and Hemodynamics in Porcine Endotoxemia; a Prospective, Randomized and Placebo Controlled Trial. Shock. 2015;43:604-11.
- Grindborg Ö, Naucler P, Sjölin J, Glimåker M. Adult bacterial meningitis - A quality registry study: Earlier treatment and favourable outcome if initial management by infectious diseases physicians. Clin Microbiol Infect. 2015:21:560-6.
- Sperber J, Lipcsey M, Larsson A, Larsson A, Sjölin J, Castegren M. Evaluating the effects of protective ventilation on organ-specific cytokine production in porcine experimental postoperative sepsis. BMC Pulm Med. 2015;15:60 doi: 10.1186/s12890-015-0052-9.
- Castegren M, Jonasson M, Castegren S, Lipcsey M, Sjölin J. Initial levels of organ failure, microbial findings and mortality in intensive care-treated primary, secondary and tertiary sepsis. Crit Care Resusc. 2015;17:174-81.
- Glimåker M, Brink M, Naucler P, Sjölin J. Betamethasone and dexamethasone in adult community-acquired bacterial meningitis: a quality registry study from 1995 to 2014. Clin Microbiol Infect. 2016;22:814.e1-814.
- von Seth M, Lipcsey M, Engström P, Larsson A, Hillered L, Maripuu E, Widström C, Sjölin J. Rapid Bolus Administration Does Not Increase the Extravasation Rate of Albumin: A Randomized Controlled Trial in the Endotoxemic Pig. Shock. 2016 Oct 5. [Epub ahead of print]
- Hedberg AL, Pauksens K, Enblad P, Söderberg J, Johansson B, Käyhty H, Sjölin J. Pneumococcal polysaccharide vaccination administered early after neurotrauma or neurosurgery. Vaccine. 2017;35:909-915.
Improved antibiotic therapy for multidrug-resistant bacteria and studies on the impact of antibiotics on the intestinal microbiota
Thomas Tängdén, Otto Cars, Pernilla Lagerbäck, Hanna Montelin, Kari-Pekka Skarp, Ayda Shams, Pikkei Yuen, Christer Malmberg
Ongoing in vitro studies include experiments aiming to find antibiotic combinations effective against multidrug-resistant bacteria and the evaluation of rapid antibiotic susceptibility tests. During 2016, we have completed an evaluation on automated methods for potential use in high-throughput screening for combinations against multidrug-resistant strains. The oCelloScope, which is based on automated microscopy and image analysis, has been considered feasible and is being used for this purpose in a 3-year project (CO-ACTION) funded by the Swedish research council within the framework of JPIAMR. A microfluidic assay using a linear antibiotic gradient to determine antibiotic susceptibility with high accuracy, CellDirector 3D, has been evaluated in collaboration with Gradientech AB within a 2-year project funded by VINNOVA, with promising results and will be further improved for use with positive blood cultures.
Clinical studies include a multicenter study on optimal antibiotic therapy for urinary tract infections caused by ESBL-producing bacteria and a study addressing the impact of antibiotics on the intestinal microbiota in hematological patients. The inclusion of patients in these studies will be completed in Q1 2017. A study on patients treated at the intensive care unit for burn injuries is ongoing and will address not only the impact of antibiotic therapy on the intestinal microbiota but also the feasibility to restore the microbial diversity with fecal transplantation.
Infections in organ transplantation and infections of the brain
Britt-Marie Eriksson, Camilla Lorant, Gabriel Westman, Jakob Sparby, Fredrik Sund
We have previously studied cytomegalovirus infections in organ transplantation, congenital infection, inflammatory bowel disease and in patients with Alzheimer´s disease. In
collaboration with Department of Clinical Immunology, different aspects of T-cell immunity has been studied. Ongoing is a project of BK-virus infection after renal transplantation, an infection with potential to destroy graft function.
Another part of research is concerning infections of the brain. During a ten-year period we have been part of an international multi-centre study of additional valaciclovir therapy to patients with herpes simplex encephalitis (HSE). In a follow-up study of the Swedish patients we have been able to show that 25 %, about four months after disease onset, develop synaptic antibodies which seems to affect the recovery of neuro-cognitive function. These are new data that probably will change treatment policies of a sub-group of patients with HSE. In another study we have mapped the incidence and the handling of ventricle-drainage related infections after neurosurgery. The findings of that study show the need for better diagnostics and we are now planning new studies for the valuation of molecular biology methods. The purpose is to substantially reduce the need of empirical anibiotic treatment.
- Westman G, Blomberg J, Yun Z, Lannfelt L, Ingelsson M, Eriksson BM. Decreased HHV-6 IgG in Alzheimer´s disease. Front Neurol. In press.
- Widén J, Eriksson BM, Ronne-Engström E, Enblad P, Westman G. Ventriculostomy-related infection in subarachnoidal haemorrhage patients- aretrospective study of incidence, etiology, and antimicrobial therapy. Acta Neurochir (Wien) (2):317-23; 2017
- Westman G, Studahl M, Persson B, Eriksson BM, Rönnelid J, Schliamser S, Aurelius E. N-Methyl-D-Aspartate Receptor Autoimmunity Affects Cognitive Performance in Herpes Simplex Encephalitis. Clin Microbiol Infect (22): 934-40; 2016
- Thörn M, Rorsman F, Rönnblom A, Sangfeldt P, Wanders A, Eriksson BM, Bondeson K Active cytomegalovirus infection diagnosed by real-time PCR in patients with inflammatory bowel disease; a prospective, controlled observational study. Scand J Gastroenterol (9): 1075-80; 2016
- Gnann, JW, Sköldenberg B, John Hart J, Aurelius E, Schliamser S, Studahl M, Eriksson BM, Hanley D, Aoki F, Jackson AC, Griffiths P, Miedzinskil L, Hanfelt-Goadel D, Hinthorn D, Ahlm C, Aksamit A, Cruz-Flores S, Dale I, Cloud G, Jester P, Whitley RJ, and the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG). Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-Term Valacyclovir Therapy. Clin Inf Dis (5):683-91; 2015
- Westman G, Berglund D, Widén J, Ingelsson M, Korsgren O, Lannfelt L, Sehlin D, Lidehall AK, Eriksson BM. Increased inflammatory response in cytomegalovirus seropositive patients with Alzheimer´s disease. PloS One 7;9(5):e96779. doi: 10.1371/2014
- Sund F, Tufveson G, Döhler B, Opelz G, Eriksson BM. Clinical outcome with low-dose valacyclovir prophylaxis in high-risk renal transplant recipients: A 10-year experience. Nephrol Dial Transplant 28:758-65; 2013
- Westman G, Lidehall AK, Magnusson P, Ingelsson M, Kilander L, Lannfelt L, Korsgren O, Eriksson BM. Decreased proportion of cytomegalovirus specific CD8 T-cells but no signs of general immunosenescence in Alzheimer’s disease. PloS One 14: 8(10):e ,2013
- Lidehall AK, Engman ML, Sund F, Malm G, Lewensson- Fuchs I, Ewald U, Tötterman TH, Karltorp E, Korsgren O, Eriksson BM. Cytomegalovirus-specific CD4 and CD8 T cell responses in infants and children. Scand J Immunol 77:135-43; 2013
- Studahl M, Lindquist L, Eriksson BM, Günther G, Bengnér M, Franzen-Röhl E, Fohlman J, Bergström T, Aurelius E. Acute viral infections of the central nervous system in immunocompetent adults: diagnosis and management. Drugs 73:131-58; 2013
Infections in and vaccination in immune suppressed patients
Karlis Pauksens och Amelie Kinch
Please see page with text in Swedish for project description
- Hallböök H, Lidström AK, Pauksens K. Ciprofloxacin prophylaxis delays initiation of broad-spectrum antibiotic therapy and reduces the overall use of antimicrobial agents during induction therapy for acute leukaemia: A single-centre study. Infect Dis. 2016;48(6):443-8.
- Hertzell KB, Pauksens K, Rombo L, Knight A, Vene S, Askling HH. Tick-borne encephalitis (TBE) vaccine to medically immunosuppressed patients with rheumatoid arthritis: A prospective, open-label, multi-centre study. Vaccine. 2016 Jan 27;34(5):650-5.
- Chlibek R, Pauksens K, Rombo L, van Rijckevorsel G, Richardus JH, Plassmann G, Schwarz TF, Catteau G, Lal H, Heineman TC. Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults. Vaccine. 2016 Feb 3;34(6):863-8.
- Kinch A, Sundström C, Tufveson G, Glimelius I. Association between HLA-A1 and -A2 types and Epstein–Barr virus status of post-transplant lymphoproliferative disorder. Leukemia & Lymphoma. 2016 Oct;57(10):2351-8.
- Berglund D*, Kinch A*, Edman E, Backlin C, Enblad G, Larsson E, Molin D, Pauksens K, Sundström C, Baecklund E. Expression of intratumoral forkhead box protein 3 in posttransplant lymphoproliferative disorders: clinical features and survival outcomes. Transplantation. 2015 May;99(5):1036-42. *Delat förstaförfattarskap.
- Kinch A, Cavelier L, Bengtsson M, Baecklund E, Enblad G, Backlin C, Thunberg U, Sundström C, Pauksens K. Donor or recipient origin of posttransplant lymphoproliferative disorders following solid organ transplantation. Am J Transplant. 2014 Dec;14(12):2838-45.
- Berglund A, Willén L, Grödeberg L, Skattum L, Hagberg H, Pauksens K. The response to vaccination against influenza A(H1N1) 2009, seasonal influenza and Streptococcus pneumoniae in adult outpatients with ongoing treatment for cancer with and without rituximab. Acta Oncol. 2014 Sep;53(9):1212-20.
- Kinch A, Baecklund E, Backlin C, Ekman T, Molin D, Tufveson G, Fernberg P, Sundström C, Pauksens K, Enblad G. A population-based study of 135 lymphomas after solid organ transplantation: the role of Epstein-Barr virus, hepatitis C and diffuse large B-cell lymphoma subtype in clinical presentation and survival. Acta Oncol. 2014 May;53(5):669-79.
- Pauksens K, Nilsson AC, Caubet M, Pascal TG, Van Belle P, Poolman JT, Vandepapelière PG, Verlant V, Vink PE. Randomized controlled study of the safety and immunogenicity of pneumococcal vaccine formulations containing PhtD and detoxified pneumolysin with alum or adjuvant system AS02V in elderly adults. Clin Vaccine Immunol. 2014 May;21(5):651-60.