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  • 1.
    Abate, E.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. University of Gondar, Ethiopia.
    Elias, D.
    University of Southern Denmark, Denmark.
    Getachew, A.
    University of Gondar, Ethiopia.
    Alemu, S.
    University of Gondar, Ethiopia.
    Diro, E.
    University of Gondar, Ethiopia.
    Britton, S.
    Karolinska Hospital, Sweden.
    Aseffa, A.
    Armauer Hansen Research Institute, Ethiopia.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Kalmar County Hospital, Sweden.
    Effects of albendazole on the clinical outcome and immunological responses in helminth co-infected tuberculosis patients: a double blind randomised clinical trial2015In: International Journal of Parasitology, ISSN 0020-7519, E-ISSN 1879-0135, Vol. 45, no 2-3, p. 133-140Article in journal (Refereed)
    Abstract [en]

    Despite several review papers and experimental studies concerning the impact of chronic helminth infection on tuberculosis in recent years, there is a scarcity of data from clinical field studies in highly endemic areas for these diseases. We believe this is the first randomised clinical trial investigating the impact of albendazole treatment on the clinical and immunological outcomes of helminth co-infected tuberculosis patients. A randomised, double-blind, placebo-controlled trial of albendazole (400 mg per day for 3 days) in helminth-positive tuberculosis patients was conducted in Gondar, Ethiopia. The primary outcome was clinical improvement (Delta TB score) after 2 months. Among secondary outcomes were changes in the levels of eosinophils, CD4+ T cells, regulatory T cells, IFN-gamma, IL-5 and IL-10 after 3 months. A total of 140 helminth co-infected tuberculosis patients were included with an HIV co-infection rate of 22.8%. There was no significant effect on the primary outcome (Delta TB score: 5.6 +/- 2.9 for albendazole versus 5.9 +/- 2.5 for placebo, P = 0.59). The albendazole-treated group showed a decline in eosinophil cells (P = 0.001) and IL-10 (P = 0.017) after 3 months. In an exploratory analysis after 12 weeks, the albendazole treated group showed a trend towards weight gain compared with the placebo group (11.2 +/- 8.5 kg versus 8.2 +/- 8.7 kg, P = 0.08)). The reductions in eosinophil counts and IL-10 show that asymptomatic helminth infection significantly affects host immunity during tuberculosis and can be effectively reversed by albendazole treatment. The clinical effects of helminth infection on chronic infectious diseases such as tuberculosis merit further characterisation. (C) 2014 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

  • 2.
    Abate, Ebba
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Belayneh, Meseret
    University of Addis Ababa, Ethiopia .
    Gelaw, Aschalew
    University of Gondar, Ethiopia .
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Getachew, Assefa
    University of Gondar, Ethiopia .
    Alemu, Shitaye
    University of Gondar, Ethiopia .
    Diro, Ermias
    University of Gondar, Ethiopia .
    Fikre, Nigussu
    University of Addis Ababa, Ethiopia .
    Britton, Sven
    Karolinska Hospital, Sweden .
    Elias, Daniel
    University of So Denmark, Denmark .
    Aseffa, Abraham
    Armauer Hansen Research Institute, Ethiopia .
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    The Impact of Asymptomatic Helminth Co-Infection in Patients with Newly Diagnosed Tuberculosis in North-West Ethiopia2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 8Article in journal (Refereed)
    Abstract [en]

    Background: Areas endemic of helminth infection, tuberculosis (TB) and HIV are to a large extent overlapping. The aim of this study was to assess the impact of asymptomatic helminth infection on the immunological response among TB patients with and without HIV, their house hold contacts and community controls. less thanbrgreater than less thanbrgreater thanMethodology: Consecutive smear positive TB patients (n = 112), their household contacts (n = 71) and community controls (n = 112) were recruited in Gondar town, Ethiopia. Stool microscopy, HIV serology, serum IgE level, eosinophil and CD4 counts were performed and tuberculosis patients were followed up for 3 months after initiation of anti-TB treatment. less thanbrgreater than less thanbrgreater thanResults: Helminth co-infection rate was 29% in TB patients and 21% in both community control and household contacts (p = 0.3) where Ascaris lumbricoides was the most prevalent parasite. In TB patients the seroprevalence of HIV was 47% (53/112). Eosinophilia and elevated IgE level were significantly associated with asymptomatic helminth infection. During TB treatment, the worm infection rate of HIV+/TB patients declined from 31% (10/32) at week 0 to 9% (3/32) at week 2 of TB treatment, whereas HIV2/TB patients showed no change from baseline to week 2, 29% (13/45) vs. 22.2% (10/45). This trend was stable at week 8 and 12 as well. less thanbrgreater than less thanbrgreater thanConclusion: One third of smear positive TB patients were infected with helminths. Eosinophilia and elevated IgE level correlated with asymptomatic worm infection, indicating an effect on host immunity. The rate of worm infection declined during TB treatment in HIV+/TB co-infected patients whereas no decline was seen in HIV2/TB group.

  • 3.
    Abate, Ebba
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. University of Gondar, Ethiopia.
    Belayneh, Meseret
    University of Addis Ababa, Ethiopia.
    Idh, Jonna
    Vastervik Hospital, Sweden.
    Diro, Ermias
    University of Gondar, Ethiopia.
    Elias, Daniel
    University of Southern Denmark, Denmark.
    Britton, Sven
    Karolinska Hospital, Sweden.
    Aseffa, Abraham
    Armauer Hansen Research Institute, Ethiopia.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Asymptomatic Helminth Infection in Active Tuberculosis Is Associated with Increased Regulatory and Th-2 Responses and a Lower Sputum Smear Positivity2015In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 9, no 8, article id e0003994Article in journal (Refereed)
    Abstract [en]

    Background The impact of intestinal helminth infection on the clinical presentation and immune response during active tuberculosis (TB) infection is not well characterized. Our aim was to investigate whether asymptomatic intestinal helminth infection alters the clinical signs and symptoms as well as the cell mediated immune responses in patients with active TB.

    Methodology Consecutive, newly diagnosed TB patients and healthy community controls (CCs) were recruited in North-west Ethiopia. TB-score, body mass index and stool samples were analyzed. Cells from HIV-negative TB patients (HIV-/TB) and from CCs were analyzed for regulatory T-cells (Tregs) and cytokine responses using flow cytometry and ELISPOT, respectively.

    Results A significantly higher ratio of helminth co-infection was observed in TB patients without HIV (Helm+/HIV-/TB) compared to HIV negative CCs, (40% (121/306) versus 28% (85/306), p = 0.003). Helm+/HIV-/TB patients showed significantly increased IL-5 secreting cells compared to Helm-/HIV-/TB (37 SFU (IQR:13-103) versus 2 SFU (1-50); p = 0.02, n = 30). Likewise, levels of absolute Tregs (9.4 (3.2-16.7) cells/mu l versus 2.4 (1.1-4.0) cells/mu l; p = 0.041) and IL-10 secreting cells (65 SFU (7-196) versus 1 SFU (0-31); p = 0.014) were significantly higher in Helm+/HIV-/TB patients compared to Helm-/HIV-/TB patients. In a multivariate analysis, a lower rate of sputum smear positivity for acid fast bacilli, lower body temperature, and eosinophilia were independently associated with helminth infection in TB patients.

    Conclusions Asymptomatic helminth infection is associated with increased regulatory T-cell and Th2-type responses and a lower rate of sputum smear positivity. Further studies are warranted to investigate the clinical and immunological impact of helminth infection in TB patients.

  • 4.
    Abate, Ebba
    et al.
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia; Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Elias, Daniel
    University of Southern Denmark, Institute of Molecular Medicine, Department of cancer and inflammation, Odense, Denmark.
    Getachew, Assefa
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia.
    Alemu, Shitaye
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia.
    Diro, Ermias
    Department of Radiology, University of Gondar, Gondar, Ethiopia.
    Britton, Sven
    Department of Infectious Diseases, Karolinska Hospital, Stockholm, Sweden.
    Aseffa, Abraham
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Effects of albendazole treatment on the clinical outcome and immunological responses in patients with helminth infection and pulmonary tuberculosis: a randomized clinical trial2013Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: The impact of helminth infection on the host immune response to tuberculosis (TB) has been characterized in experimental models but less so in the clinical setting. The objective of this study was to investigate the impact of deworming on the clinical outcome and cell mediated immune response in active TB.

    Methods: Newly diagnosed pulmonary TB patients in Gondar, Ethiopia were examined for helminth infection. Helminth-positive TB patients (W+/TB) were randomized to albendazole (400mg X III per os) or placebo. The primary outcome was change in TB-score after 2 months, and secondary outcomes were sputum smear conversion at the 2nd month, and changes in chest x-ray pattern, CD4+ T-cell count, eosinophil count, IgE-levels and immunological responses after 3 months. In a subset of W+/TB, W-/TB patients and healthy controls, flow cytometry and ELISPOT assays were used to characterize the regulatory T-cell population (Tregs) and the frequency of PPD- stimulated IFN-γ, IL-5 and IL-10 producing peripheral blood mononuclear cells (PBMCs).

    Results: A total of 140 helminth co-infected TB patients were included with an HIV coinfection rate of 22.8 %. Following albendazole treatment of the W+/TB patients, there was a significant decrease in helminth infection compared to placebo (8% (4/49) vs. 48 % (22/46), p<0.001). No significant effect was observed for albendazole compared to placebo on the primary outcome as evaluated by the TB-score (5.6 ±2.87 vs. 5.87 ±2.54, p=0.59). Eosinophil counts decreased significantly in the albendazole group. In a subgroup analysis of helminthnegative patients following albendazole treatment versus placebo, the albendazole group showed a trend for lower levels of IL-10 producing cells at month three (p=0.08). At baseline, W+/TB patients had a significantly higher mean level of Tregs (% Tregs/CD4+) compared to W-/TB patients and helminth-positive community controls. Additionally, the frequency of IFN-γ, IL-5 and spontaneous IL-10 levels was increased in helminth-positive compared to helminth-negative TB patients.

    Conclusions: No significant effects on the clinical outcome as measured with the TB-score was detected after albendazole treatment of helminth-positive TB patients compared to placebo. However, significant changes were observed in specific immunological responses such as reduced eosinophil counts and a trend towards lower levels of IL-10 producing cells. At baseline, helminth co-infected TB patients exhibited an increased Treg response as well as an increased IL-5 and spontaneous IL-10 production.

  • 5.
    Abate, Ebba
    et al.
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia; Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Belayneh, Meseret
    School of Medical Laboratory Sciences, Medical Faculty, Addis Ababa University, Addis Ababa.
    Getachew, Assefa
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia.
    Alemu, Shitaye
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia.
    Diro, Ermias
    Department of Radiology, University of Gondar, Gondar, Ethiopia.
    Britton, Sven
    Department of Infectious Diseases, Karolinska Hospital, Stockholm, Sweden.
    Elias, Daniel
    University of Southern Denmark, Institute of Molecular Medicine, Department of cancer and inflammation, Odense, Denmark.
    Aseffa, Abraham
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Impact of helminth infection on the clinical presentation 1 of pulmonary tuberculosis2013Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: The effects of helminth infection on chronic infectious diseases such as HIV and tuberculosis (TB) merit further characterization. Thus, we assessed the baseline clinical characteristics of helminth infection in patients with active TB in a high endemic area.

    Methodology: Consecutive, newly diagnosed TB patients were recruited from three health institutions in the north Gondar administrative zone, Ethiopia. Structured questionnaires were used to collect socio-demographic and clinical characteristics. Additionally, the TB score, mid upper arm circumference, body mass index (BMI), BCG vaccination status, stool and sputum microscopy as well as HIV serology and CD4+T cells counts were evaluated.

    Results: A total of 377 pulmonary TB patients were included in the study. The helminth co infection rate was 33% (123/377) and the most prevalent parasite was Ascaris lumbricoides (53%, 65/123). The HIV co-infection rate was 29% (110/377). Seventy percent (77/110) of the HIV co-infected patients were on anti- retroviral therapy at the time of TB diagnosis. Helminth infection was more prevalent in HIV-negative TB patients compared to HIV-positive TB patients (p=0.025). Smoking and walking bare foot were independently associated to helminth infection in TB patients after adjusting for the influence of HIV. Other than increased eosinophilia, no other significant differences were observed between helminth positive and helminth negative TB patients in the clinical presentation including the TB score, CD4+T-cells, BMI or bacterial load.

    Conclusion: The clinical presentation of active pulmonary tuberculosis was not affected by helminth infection. Helminth infection was less frequent among HIV-positive TB patients and this finding merits further investigation.

  • 6.
    Abate Waktola, Ebba Abate
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. EPHI, Ethiopia.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Belayneh, Meseret
    Univ Addis Abeba, Ethiopia.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Kalmar, Sweden.
    Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 3126Article in journal (Refereed)
    Abstract [en]

    Innate immunity is a first line defense against Mycobacterium tuberculosis infection where inflammasome activation and secretion of the pro-inflammatory cytokine IL-1beta, plays a major role. Thus, genetic polymorphisms in innate immunity-related genes such as CARD8 and NLRP3 may contribute to the understanding of why most exposed individuals do not develop infection. Our aim was to investigate the association between polymorphisms in CARD8 and NLRP3 and active tuberculosis (TB) as well as their relationship to treatment outcome in a high-endemic setting for TB. Polymorphisms in CARD8 (C10X) and NLRP3 (Q705K) were analysed in 1190 TB patients and 1990 healthy donors (HD). There was a significant association between homozygotes in the CARD8 polymorphism and extrapulmonary TB (EPTB), which was not the case for pulmonary TB or HDs. Among TB-patients, there was an association between poor treatment outcome and the NLRP3 (Q705K) polymorphism. Our study shows that inflammasome polymorphisms are associated with EPTB and poor clinical outcome in active TB in Ethiopia. The practical implications and determining causal relationships on a mechanistic level needs further study.

  • 7.
    Abdalla, Hana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Effects of CNI-1493 on human granulocyte functions2006In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 211, no 3, p. 191-197Article in journal (Refereed)
    Abstract [en]

    During acute bacterial infections such as sepsis and meningitis, activation of inflammatory mediators such as nitric oxide (NO) plays a crucial role in both pathogenesis and host defense. We have previously reported that CNI-1493, a macrophage deactivator, reduced mortality in infant rats infected with Haemophilus influenzae type b (Hib) with associated decrease in the number of granulocytes in the infected tissue. The aim of the present study was to investigate how CNI-1493 affects granulocytes and macrophages in vitro. Murine macrophages (RAW 264.7) pre-incubated with CNI-1493 prior to activation with lipopolysaccharide (LPS)/interferon gamma (IFNγ) had decreased NO production measured as NO2/NO3 levels and reduction in inducible NO-synthase (iNOS) expression. Reactive oxygen species (ROS) production was increased in formylmethionyl-leucyl-phenylalanine (FMLP)-stimulated granulocytes following CNI-1493 treatment, whereas F-actin content, motility and chemotaxis were decreased under the same conditions. The effects of CNI-1493 on both NO production in LPS/IFNγ-activated macrophages and ROS production, F-actin content, motility and chemotaxis in granulocytes, may contribute to the reduced inflammatory response and increased survival in Hib-infected animals treated with CNI-1493.

  • 8.
    Ajileye, Adebisi
    et al.
    Birmingham Heartlands Hospital, England.
    Alvarez, Nataly
    Corp Invest Biol, Colombia; University of Pontificia Bolivariana, Colombia.
    Merker, Matthias
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Walker, Timothy M.
    University of Oxford, England.
    Akter, Suriya
    Institute Trop Med, Belgium.
    Brown, Kerstin
    Birmingham Heartlands Hospital, England.
    Moradigaravand, Danesh
    Wellcome Trust Sanger Institute, England.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Andres, Soenke
    Research Centre Borstel, Germany.
    Schleusener, Viola
    Research Centre Borstel, Germany.
    Omar, Shaheed V.
    Centre TB, South Africa.
    Coll, Francesc
    London School Hyg and Trop Med, England.
    Huang, Hairong
    Capital Medical University, Peoples R China.
    Diel, Roland
    University Hospital, Germany.
    Ismail, Nazir
    Centre TB, South Africa.
    Parkhill, Julian
    Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    de Jong, Bouke C.
    Institute Trop Med, Belgium.
    Peto, Tim E. A.
    University of Oxford, England.
    Crook, Derrick W.
    University of Oxford, England; Public Health England Microbiol Serv, England.
    Niemann, Stefan
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Robledo, Jaime
    Corp Invest Biol, Colombia; University of Pontificia Bolivariana, Colombia.
    Grace Smith, E.
    Birmingham Heartlands Hospital, England.
    Peacock, Sharon J.
    Wellcome Trust Sanger Institute, England; London School Hyg and Trop Med, England; University of Cambridge, England.
    Koeser, Claudio U.
    University of Cambridge, England.
    Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 4, article id e02169-16Article in journal (Refereed)
    Abstract [en]

    In this study, using the Hain GenoType MTBDRsl assays (versions 1 and 2), we found that some nonsynonymous and synonymous mutations in gyrA in Mycobacterium tuberculosis result in systematic false-resistance results to fluoroquinolones by preventing the binding of wild-type probes. Moreover, such mutations can prevent the binding of mutant probes designed for the identification of specific resistance mutations. Although these mutations are likely rare globally, they occur in approximately 7% of multidrug-resistant tuberculosis strains in some settings.

  • 9.
    Balcha, Taye T.
    et al.
    Lund University, Sweden Minist Heatlh, Ethiopia .
    Sturegard, Erik
    Clin Microbiol Regional and University of Labs, Sweden .
    Winqvist, Niclas
    Lund University, Sweden Regional Department Infect Disease Control and Prevent, Sweden .
    Skogmar, Sten
    Lund University, Sweden .
    Reepalu, Anton
    Lund University, Sweden .
    Habtamu Jemal, Zelalem
    Oromia Health Bur, Ethiopia .
    Tibesso, Gudeta
    Columbia University, Ethiopia .
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Department of Clinical Microbiology and Infectious diseases, Kalmar County Hospital, Sweden.
    Bjorkman, Per
    Lund University, Sweden .
    Intensified Tuberculosis Case-Finding in HIV-Positive Adults Managed at Ethiopian Health Centers: Diagnostic Yield of Xpert MTB/RIF Compared with Smear Microscopy and Liquid Culture2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. 85478-Article in journal (Refereed)
    Abstract [en]

    Background: Detection of active tuberculosis (TB) before antiretroviral therapy (ART) initiation is important, but optimal diagnostic methods for use in resource-limited settings are lacking. We assessed the prevalence of TB, evaluated the diagnostic yield of Xpert MTB/RIF in comparison with smear microscopy and culture, and the impact of Xpert results on clinical management in HIV-positive adults eligible for ART at health centers in a region of Ethiopia. Methods: Participants were prospectively recruited and followed up at 5 health centers. Trained nurses collected data on socio-demographic characteristics, medical history and symptoms, and performed physical examination. Two paired morning sputum samples were obtained, and lymph node aspirates in case of lymphadenopathy. Diagnostic yield of Xpert MTB/RIF in sputum was compared with smear microscopy and liquid culture. Results: TB was diagnosed in 145/812 participants (17.9%), with bacteriological confirmation in 137 (16.9%). Among bacteriologically confirmed cases, 31 were smear-positive (22.6%), 96 were Xpert-positive (70.1%), and 123 were culture-positive (89.8%). Xpert MTB/RIF increased the TB detection rate by 64 cases (47.4%) compared with smear microscopy. The overall sensitivity of Xpert MTB/RIF was 66.4%, and was not significantly lower when testing one compared with two samples. While Xpert MTB/RIF was 46.7% sensitive among patients with CD4 cell counts greater than200 cells/mm(3), this increased to 82.9% in those with CD4 cell counts less than= 100 cells/mm(3). Compared with Xpert-positive TB patients, Xpert-negative cases had less advanced HIV and TB disease characteristics. Conclusions: Previously undiagnosed TB is common among HIV-positive individuals managed in Ethiopian health centers. Xpert MTB/RIF increased TB case detection, especially in patients with advanced immunosuppression. An algorithm based on the use of a single morning sputum sample for individuals with negative sputum smear microscopy could be considered for intensified case finding in patients eligible for ART. However, technical and cost-effectiveness issues relevant for low-income countries warrant further study.

  • 10.
    Balcha, Taye T.
    et al.
    Lund University, Sweden Minist Heatlh, Ethiopia .
    Winqvist, Niclas
    Lund University, Sweden Regional Department Infect Disease Control and Prevent, Sweden .
    Sturegard, Erik
    Clin Microbiol Regional and University of Labs, Sweden .
    Skogmar, Sten
    Lund University, Sweden .
    Reepalu, Anton
    Lund University, Sweden .
    Jemal, Zelalem H.
    Oromia Regional Health Bur, Ethiopia .
    Tibesso, Gudeta
    Columbia University, Ethiopia .
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden.
    Bjorkman, Per
    Lund University, Sweden .
    Detection of lipoarabinomannan in urine for identification of active tuberculosis among HIV-positive adults in Ethiopian health centres2014In: Tropical medicine & international health, ISSN 1360-2276, E-ISSN 1365-3156, Vol. 19, no 6, p. 734-742Article in journal (Refereed)
    Abstract [en]

    ObjectiveTo assess the diagnostic performance of urine lipoarabinomannan (LAM) detection for TB screening in HIV-positive adults in Ethiopia. MethodsTesting for LAM was performed using the Determine TB-LAM lateral flow assay on urine samples from participants in a prospective cohort with baseline bacteriological categorisation for active TB in sputum. Characteristics of TB patients with regard to LAM status were determined. Participants were followed for 6months to evaluate survival, retention in care and incident TB. ResultsPositive LAM results were found in 78/757 participants. Among 128 subjects with definite (confirmed by culture and/or Xpert MTB/RIF) TB, 33 were LAM-positive (25.8%); the respective figure for clinically diagnosed cases was 2/20 (10%). Five of the remaining 43 LAM-positive individuals had died during the 6-month follow-up period, whereas 38 remained in care without clinical signs of TB. The overall sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 25.8%, 92.9%, 42.3% and 86.0%, respectively. Among TB patients, LAM positivity was associated with higher WHO clinical stage, lower body mass index (BMI), CD4 cell and haemoglobin levels, and with increased mortality. A combination algorithm of urine LAM testing and sputum smear microscopy detected 49 (38.2%) of definite TB cases; among those with CD4 count 100cells/mm(3), this proportion was 66.7%. ConclusionsThe performance of urine LAM testing for TB detection was poor in this population. However, this was improved among subjects with CD4 count 100cells/mm(3). In combination with sputum microscopy urine, LAM could be considered for targeted TB screening in this subgroup.

  • 11.
    Chesov, Dumitru
    et al.
    State University of Medical and Pharm Nicolae Testemitanu, Moldova.
    Ciobanu, Nelly
    Phthisiopneumol Institute Chiril Draganiuc, Moldova.
    Lange, Christoph
    German Centre Infect Research DZIF, Germany; University of Lubeck, Germany; Karolinska Institute, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Heyckendorf, Jan
    German Centre Infect Research DZIF, Germany.
    Crudu, Valeriu
    Phthisiopneumol Institute Chiril Draganiuc, Moldova.
    Lack of evidence of isoniazid efficacy for the treatment of MDR/XDR-TB in the presence of the katG 315T mutation2017In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 50, no 4, article id 1701752Article in journal (Other academic)
    Abstract [en]

    n/a

  • 12.
    Davies Forsman, L.
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital Solna, Sweden.
    Giske, C. G.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Bruchfeld, J.
    Karolinska Institute, Sweden; Karolinska University Hospital Solna, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Jureen, P.
    Public Health Agency Sweden, Sweden.
    Angeby, K.
    Karolinska University Hospital, Sweden; University of W Indies, Jamaica.
    Meropenem-Clavulanic Acid Has High In Vitro Activity against Multidrug-Resistant Mycobacterium tuberculosis2015In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 6, p. 3630-3632Article in journal (Refereed)
    Abstract [en]

    We investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68 Mycobacterium tuberculosis isolates. We included predominantly multi- and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB.

  • 13.
    Davies Forsman, L.
    et al.
    Karolinska Institute, Sweden; Karolinska University, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences. Linnaeus University, Sweden.
    Simonsson, U. S. H.
    Uppsala University, Sweden.
    Bruchfeld, J.
    Karolinska Institute, Sweden; Karolinska University, Sweden.
    Larsson, Marie C
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Jureen, P.
    Public Health Agency Sweden, Sweden.
    Sturegard, E.
    Regional and University of Labs, Sweden.
    Giske, C. G.
    Karolinska University Hospital, Sweden.
    Angeby, K.
    Karolinska University Hospital, Sweden; University of W Indies, Jamaica.
    Intra- and Extracellular Activities of Trimethoprim-Sulfamethoxazole against Susceptible and Multidrug-Resistant Mycobacterium tuberculosis2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 12, p. 7557-7559Article in journal (Refereed)
    Abstract [en]

    We investigated the activity of trimethoprim-sulfamethoxazole (SXT) against Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90 of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC(0-24)/MIC) using greater than= 25 as a potential target, the cumulative fraction response was greater than= 90% at doses of greater than= 2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.

  • 14.
    Davies Forsman, Lina
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Niward, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Hu, Yi
    Fudan Univ, Peoples R China; Fudan Univ, Peoples R China.
    Zheng, Rongrong
    Xiamen City Ctr Dis Control, Peoples R China.
    Zheng, Xubin
    Fudan Univ, Peoples R China.
    Ke, Ran
    Xiamen City Ctr Dis Control, Peoples R China.
    Cai, Weiping
    Xiamen City Ctr Dis Control, Peoples R China.
    Hong, Chao
    Xiamen City Ctr Dis Control, Peoples R China.
    Li, Yang
    Fudan Univ, Peoples R China.
    Gao, Yazhou
    Fudan Univ, Peoples R China.
    Werngren, Jim
    Publ Hlth Agcy Sweden, Sweden.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Kuhlin, Johanna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Simonsson, Ulrika S. H.
    Uppsala Univ, Sweden.
    Eliasson, Erik
    Karolinska Univ Hosp, Sweden.
    Alffenaar, Jan-Willem
    Univ Groningen, Netherlands.
    Mansjo, Mikael
    Publ Hlth Agcy Sweden, Sweden.
    Hoffner, Sven
    Karolinska Inst, Sweden.
    Xu, Biao
    Fudan Univ, Peoples R China.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Bruchfeld, Judith
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study2018In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 8, no 9, article id e023899Article in journal (Refereed)
    Abstract [en]

    Introduction Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for Mycobacterium tuberculosis isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB. Methods and analysis Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960. Ethics and dissemination This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal. Trial registration number NCT02816931; Pre-results.

  • 15.
    Deshpande, Devyani
    et al.
    Baylor Univ, TX USA.
    Alffenaar, Jan-Willem C.
    Univ Groningen, Netherlands.
    Koser, Claudio U.
    Univ Cambridge, England.
    Dheda, Keertan
    Univ Cape Town, South Africa.
    Chapagain, Moti L.
    Baylor Univ, TX USA.
    Simbar, Noviana
    Univ Groningen, Netherlands.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sturkenboom, Marieke G. G.
    Univ Groningen, Netherlands.
    McIlleron, Helen
    Univ Cape Town, South Africa.
    Lee, Pooi S.
    Baylor Univ, TX USA.
    Koeuth, Thearith
    Baylor Univ, TX USA.
    Mpagama, Stellah G.
    Kibongoto Infect Dis Hosp, Tanzania.
    Banu, Sayera
    Int Ctr Diarrhoeal Dis Res, Bangladesh.
    Foongladda, Suporn
    Mahidol Univ, Thailand.
    Ogarkov, Oleg
    Sci Ctr Family Hlth and Human Reprod Problem, Russia.
    Pholwat, Suporn
    Univ Virginia, VA USA.
    Houpt, Eric R.
    Univ Virginia, VA USA.
    Heysell, Scott K.
    Univ Virginia, VA USA.
    Gumbo, Tawanda
    Baylor Univ, TX USA.
    D-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal2018In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 67, p. S308-S316Article in journal (Refereed)
    Abstract [en]

    Background. D-cycloserine is used to treat multidrug-resistant tuberculosis. Its efficacy, contribution in combination therapy, and best clinical dose are unclear, also data on the D-cycloserine minimum inhibitory concentration (MIC) distributions is scant. Methods. We performed a systematic search to identify pharmacokinetic and pharmacodynamic studies performed with D-cycloserine. We then performed a combined exposure-effect and dose fractionation study of D-cycloserine in the hollow fiber system model of tuberculosis (HFS-TB). In parallel, we identified D-cycloserine MICs in 415 clinical Mycobacterium tuberculosis (Mtb) isolates from patients. We utilized these results, including intracavitary concentrations, to identify the clinical dose that would be able to achieve or exceed target exposures in 10 000 patients using Monte Carlo experiments (MCEs). Results. There were no published D-cycloserine pharmacokinetics/pharmacodynamics studies identified. Therefore, we performed new HFS-TB experiments. Cyloserine killed 6.3 log(10) colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (% T-MIC), with 1.0 log(10) CFU/mL kill achieved by % T-MIC = 30% (target exposure). The tentative epidemiological cutoff value with the Sensititre MYCOTB assay was 64 mg/L. In MCEs, 750 mg twice daily achieved target exposure in lung cavities of 92% of patients whereas 500 mg twice daily achieved target exposure in 85% of patients with meningitis. The proposed MCE-derived clinical susceptibility breakpoint at the proposed doses was 64 mg/L. Conclusions. Cycloserine is cidal against Mtb. The susceptibility breakpoint is 64 mg/L. However, the doses likely to achieve the cidality in patients are high, and could be neurotoxic.

  • 16.
    Eklund, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Persson, Hans Lennart
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Larsson, Marie C.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Welin, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Fransson, Sven-Göran
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Vitamin D enhances IL-1β secretion and restricts growth of Mycobacterium tuberculosis in macrophages from TB patients2013In: International Journal of Mycobacteriology, ISSN 2212-5531, Vol. 2, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB), the bacterium responsible for tuberculosis (TB), has rekindled the interest in the role of nutritional supplementation of micronutrients, such as vitamin D, as adjuvant treatment. Here, the growth of virulent MTB in macrophages obtained from the peripheral blood of patients with and without TB was studied. The H37Rv strain genetically modified to express Vibrio harveyi luciferase was used to determine the growth of MTB by luminometry in the human monocyte-derived macrophages (hMDMs) from study subjects. Determination of cytokine levels in culture supernatants was performed using a flow cytometry-based bead array technique. No differences in intracellular growth of MTB were observed between the different study groups. However, stimulation with 100 nM 1,25-dihydroxyvitamin D significantly enhanced the capacity of hMDMs isolated from TB patients to control the infection. This effect was not observed in hMDMs from the other groups. The interleukin (IL)-1β and IL-10 release by hMDMs was clearly increased upon stimulation with 1,25-dihydroxyvitamin D. Furthermore, the 1,25-dihydroxyvitamin D stimulation also led to elevated levels of TNF-α (tumor necrosis factor-alpha) and IL-12p40. It was concluded that vitamin D triggers an inflammatory response in human macrophages with enhanced secretion of cytokines, as well as enhancing the capacity of hMDMs from patients with active TB to restrict mycobacterial growth.

  • 17.
    Elias, D.
    et al.
    Microbiol. and Tumor Biology Center, Karolinska Institute, Box 280, 17177 Stockholm, Sweden, Swed. Inst. for Infect. Dis. Contr., Stockholm, Sweden, Armauer Hansen Research Institute, Box 1005, Addis Ababa, Ethiopia.
    Akuffo, H.
    Microbiol. and Tumor Biology Center, Karolinska Institute, Box 280, 17177 Stockholm, Sweden.
    Pawlowski, A.
    Swed. Inst. for Infect. Dis. Contr., Stockholm, Sweden.
    Haile, M.
    Swed. Inst. for Infect. Dis. Contr., Stockholm, Sweden.
    Schön, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Britton, S.
    Department of Medicine, Unit of Infectious Diseases, Karolinska Institute, 17176 Stockholm, Sweden.
    Schistosoma mansoni infection reduces the protective efficacy of BCG vaccination against virulent Mycobacterium tuberculosis2005In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 23, no 11, p. 1326-1334Article in journal (Refereed)
    Abstract [en]

    We hypothesized that the ability of BCG vaccination to protect against Mycobacterium tuberculosis is less in hosts exposed to chronic helminthes infection compared to unexposed individuals. To test this hypothesis we evaluated the efficacy of BCG vaccination in protecting against M. tuberculosis challenge in Schistosoma mansoni pre-infected mice by analyzing their ability to limit the replication of TB bacilli in the lung and liver and the histology of lung sections. The results show that BCG vaccinated mice with prior S. mansoni infection show significantly higher number of colony forming units of TB bacilli as well as significant reduction in air exchange area in the lung compared to controls. In addition, spleen cells from S. mansoni infected mice were found to produce significantly less IFN-? and nitric oxide when stimulated in vitro with PPD and several fold higher soluble egg antigen (SEA) and Concanavalin A induced IL-4 and IL-5 secretion. Taken together, our data show that S. mansoni infection reduces the protective efficacy of BCG vaccination against M. tuberculosis possibly by attenuation of protective immune responses to mycobacterial antigens and/or by polarizing the general immune responses to the Th2 profile. © 2004 Published by Elsevier Ltd.

  • 18.
    Fridlund, Jimmy
    et al.
    Kalmar County Hospital, Sweden.
    Woksepp, Hanna
    Kalmar County Hospital, Sweden; Linnaeus University, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden; Linnaeus University, Sweden.
    A microbiological method for determining serum levels of broad spectrum beta-lactam antibiotics in critically ill patients2016In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 129, p. 23-27Article in journal (Refereed)
    Abstract [en]

    Background: Recent studies show that suboptimal blood levels of beta-lactam antibiotics are present in intensive care unit (ICU) patients. A common reference method for assessing drug concentrations is liquid chromatography coupled with mass-spectrometry (LC-MS) which is highly accurate but rarely available outside reference centres. Thus, our aim was to develop a microbiological method for monitoring beta-lactam antibiotic serum levels which could be used at any hospital with a microbiological laboratory. Methods: The method was developed as a 96-well broth microdilution format to assess the concentrations of cefotaxime (CTX), meropenem (MER), and piperacillin (PIP). Patient serum containing antibiotics were diluted in suspensions of bacteria with known minimal inhibitory concentrations (MICs). Serum antibiotic concentrations were calculated by dividing the MIC with the dilution factor at which the serum inhibited growth of the bacterial suspension. Serum (n = 88) from ICU patients at four hospitals in south-east Sweden were analysed and compared to LC-MS analysis. Results: The overall accuracy and precision for spiked samples and patient samples was within the pre-set target of +/- 20.0% for all drugs. There was a significant correlation between the microbiological assay and LC-MS for the patient samples (CTX: r = 0.86, n = 31; MER: r = 0.96, n = 11; PIP: r = 0.88, n = 39) and the agreement around the clinical cut-off for CTX (4.0 mg/l), MER (2.0 mg/l) and PIP (16.0 mg/l) was 90%, 100% and 87%, respectively. Conclusion: The microbiological method has a performance for determination of serum levels of meropenem, piperacillin and cefotaxime suitable for clinical use. It is an inexpensive method applicable in any microbiology laboratory. (C) 2016 Elsevier B.V. All rights reserved.

  • 19.
    Hernández-Pando, R.
    et al.
    Experimental Pathology Laboratory. Department of Pathology, Instituto Nacional De Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico city, Mexico.
    Schön, Thomas
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Orozco, E. H.
    Experimental Pathology Laboratory. Department of Pathology, Instituto Nacional De Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico city, Mexico.
    Serafin, J.
    Department of Immunology, Escuela Nacional de Ciencias Biológicas. Instituto Politecnico Nacional, México city, Mexico.
    Estradea-Garcia, I.
    Department of Immunology, Escuela Nacional de Ciencias Biológicas. Instituto Politecnico Nacional, México city, Mexico.
    Expression of inducible nitric oxide synthase and nitrotyrosineduring the evolution of experimental pulmonary tuberculosis2001In: Experimental and Toxicological Pathology, ISSN 0940-2993, E-ISSN 1618-1433, Vol. 53, no 4, p. 257-265Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) is a relevant antimycobacterial factor in mouse macrophages. NO is a product of inducible nitric oxide synthase (iNOS). NO toxicity is greatly enhanced by reacting with superoxide to form peroxynitrite that reacts with many biological molecules. Tyrosine is one of the molecules with which NO reacts and the product is nitrotyrosine (NT). The production of peroxynitrite and the nitrosylation of proteins might play a role in bacterial killing and also in mediating host injury. In this study, we used a well-characterized mouse model of pulmonary tuberculosis to examine the local kinetics of expression and cellular distribution of iNOS and NT at the cellular and subcellular level. The histopathological study showed two phases of the disease: early and late. The early phase was characterized by mononuclear inflammation and granuloma formation. During this phase, high percentages of activated macrophages were observed that were immunostained for iNOS and NT. Immuno-electronmicroscopy showed NT immunoreactivity in lysosomes and mycobacterial wall and cytoplasm. The concentration of iNOS mRNA and NO metabolites were also elevated. The late phase was characterized by progressive pneumonia with focal necrosis and a decrease of iNOS mRNA and NO metabolites. The strongest NT immunostained areas were the necrotic tissue. Macrophages became foamy cells with scarce iNOS immunostaining but strong NT immunoreactivity. At the ultrastructural level, these cells showed NT immunolabeling in cytoskeleton, mitochondria, lysosomes and cell membrane. NT was also located in bronchial epithelial cell mitochondria, in cell membranes and cytoplasm of endothelial cells and in actin bundles within smooth muscle cells. These results suggest an important role of NO in mycobacterial killing, particularly during the early phase of the infection. They also suggest an important participation by NO in tissue damage during the late phase of the disease.

  • 20.
    Heyckendorf, Jan
    et al.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Andres, Soenke
    Res Ctr Borstel, Germany.
    Koser, Claudio U.
    Univ Cambridge, England.
    Olaru, Ioana D.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Sturegard, Erik
    Lund Univ, Sweden.
    Beckert, Patrick
    German Ctr Infect Res DZIF, Germany; Karolinska Inst, Sweden.
    Schleusener, Viola
    Karolinska Inst, Sweden.
    Kohl, Thomas A.
    German Ctr Infect Res DZIF, Germany; Karolinska Inst, Sweden.
    Hillemann, Doris
    Res Ctr Borstel, Germany.
    Moradigaravand, Danesh
    Wellcome Trust Sanger Inst, England.
    Parkhill, Julian
    Wellcome Trust Sanger Inst, England.
    Peacock, Sharon J.
    Wellcome Trust Sanger Inst, England; London Sch Hyg and Trop Med, England.
    Niemann, Stefan
    German Ctr Infect Res DZIF, Germany; Univ Cambridge, England; Res Ctr Borstel, Germany.
    Lange, Christoph
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany; Karolinska Inst, Sweden; Univ Namibia, Namibia.
    Merker, Matthias
    German Ctr Infect Res DZIF, Germany; Res Ctr Borstel, Germany.
    What Is Resistance? Impact of Phenotypic versus Molecular Drug Resistance Testing on Therapy for Multi-and Extensively Drug-Resistant Tuberculosis2018In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 2, article id e01550-17Article in journal (Refereed)
    Abstract [en]

    Rapid and accurate drug susceptibility testing (DST) is essential for the treatment of multi-and extensively drug-resistant tuberculosis (M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using Bactec 960 MGIT or Lowenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TB drugs. Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs; Hain GenoType MTBDRplus 2.0 and MTBDRsl 2.0) and whole-genome sequencing (WGS) were translated into individual algorithmderived treatment regimens for each patient. We further analyzed if discrepancies between the various methods were due to flaws in the genotypic or phenotypic test using MIC results. Compared with pDST, the average agreement in the number of drugs prescribed in genotypic regimens ranged from just 49% (95% confidence interval [ CI], 39 to 59%) for Xpert and 63% (95% CI, 56 to 70%) for LPAs to 93% (95% CI, 88 to 98%) for WGS. Only the WGS regimens did not contain any drugs to which pDST showed resistance. Importantly, MIC testing revealed that pDST likely underestimated the true rate of resistance for key drugs (rifampin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high. WGS can be used to rule in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be reexamined to avoid systematic false-susceptible results in low-level resistant isolates.

  • 21.
    Idh, Jonna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Abate, Ebba
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia; Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Westman, Anna
    Department of Infectious Diseases, Karolinska Hospital, Stockholm, Sweden.
    Elias, Daniel
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Janols, Helena
    Department of Infectious Diseases, Malmö University Hospital, Malmö, Sweden.
    Gelaw, Aschalew
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia.
    Getachew, Assefa
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia.
    Alemu, Shitaye
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia.
    Aseffa, Abraham
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Britton, Sven
    Department of Infectious Diseases, Karolinska Hospital, Stockholm, Sweden.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Kinetics of the QuantiFERON((R))-TB Gold In-Tube test during treatment of patients with sputum smear-positive tuberculosis in relation to initial TST result and severity of disease2010In: Scandinavian journal of infectious diseases, ISSN 1651-1980, Vol. 42, no 9, p. 650-657Article in journal (Refereed)
    Abstract [en]

    Abstract The QuantiFERON((R))-TB Gold In-Tube test (QFN) measures interferon-gamma production in response to Mycobacterium tuberculosis antigens. Our aim was to assess the kinetics of the QFN and initial tuberculin skin test (TST) result in relation to severity of disease in a tuberculosis (TB) endemic area. Smear-positive TB patients (n = 71) were recruited at Gondar University Hospital, Ethiopia. The TST, QFN, CD4+ cell count and clinical symptoms (TB score) were assessed and followed up during treatment. From baseline to 7 months after treatment, there was a significant decrease in QFN reactivity (93.8% to 62.5% in HIV-negative/TB; 70.3% to 33.3% in HIV-positive/TB patients) down to a level comparable to a control group of blood donors (51.2%). The agreement between TST and QFN was poor in TB patients compared to healthy controls. A negative TST correlated to more advanced TB in contrast to a negative QFN test. We conclude that the QFN reactivity is significantly reduced at the end of treatment against active TB to the background level of healthy blood donors, and that the agreement between TST and QFN is poor including correlation to the severity of disease.

  • 22.
    Idh, Jonna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Blanka
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Raffetseder, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Woksepp, Hanna
    Linneaus University, Sweden; Kalmar County Hospital, Sweden.
    Werngren, Jim
    Public Health Agency Sweden, Sweden.
    Mansjo, Mikael
    Public Health Agency Sweden, Sweden.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linneaus University, Sweden; Kalmar County Hospital, Sweden.
    Reduced susceptibility of clinical strains of Mycobacterium tuberculosis to reactive nitrogen species promotes survival in activated macrophages2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 7, article id e0181221Article in journal (Refereed)
    Abstract [en]

    Background Drugs such as isoniazid (INH) and pretomanid (PRT), used against Mycobacterium tuberculosis are active partly through generation of reactive nitrogen species (RNS). The aim of this study was to explore variability in intracellular susceptibility to nitric oxide (NO) in clinical strains of M. tuberculosis. Method Luciferase-expressing clinical M. tuberculosis strains with or without INH resistance were exposed to RNS donors (DETA/NO and SIN-1) in broth cultures and bacterial survival was analysed by luminometry. NO-dependent intracellular killing in a selection of strains was assessed in interferon gamma/lipopolysaccharide-activated murine macrophages using the NO inhibitor L-NMMA. Results When M. tuberculosis H37Rv was compared to six clinical isolates and CDC1551, three isolates with inhA mediated INH resistance showed significantly reduced NO-susceptibility in broth culture. All strains showed a variable but dose-dependent susceptibility to RNS donors. Two clinical isolates with increased susceptibility to NO exposure in broth compared to H37Rv were significantly inhibited by activated macrophages whereas there was no effect on growth inhibition when activated macrophages were infected by clinical strains with higher survival to NO exposure in broth. Furthermore, the most NO-tolerant clinical isolate showed increased resistance to PRT both in broth culture and the macrophage model compared to H37Rv in the absence of mutational resistance in genes associated to reduced susceptibility against PRT or NO. Conclusion In a limited number of clinical M. tuberculosis isolates we found a significant difference in susceptibility to NO between clinical isolates, both in broth cultures and in macrophages. Our results indicate that mycobacterial susceptibility to cellular host defence mechanisms such as NO need to be taken into consideration when designing new therapeutic strategies.

  • 23.
    Janols, Helena
    et al.
    Department of Clinical Sciences, Section for Infectious Diseases, Skåne University Hospital, Lund University, Malmö, Sweden.
    Abate, Ebba
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Idh, Jonna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Senbeto, Meseret
    Department of Medical Laboratory Sciences, University of Gondar, Ethiopia.
    Britton, Sven
    Department of Infectious Diseases, Karolinska Hospital, Stockholm, Sweden.
    Alemu, Shitaye
    Department of Internal Medicine, University of Gondar, Gondar, Ethiopia.
    Aseffa, Abraham
    Armauer Hansen Research Institute (AHRI), Addis Ababa, Ethiopia.
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Schön, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Early treatment response evaluated by a clinical scoring system correlates with the prognosis of pulmonary tuberculosis patients in Ethiopia: A prospective follow-up study.2012In: Scandinavian journal of infectious diseases, ISSN 1651-1980, Vol. 44, no 11, p. 828-834Article in journal (Refereed)
    Abstract [en]

    Background: In resource-limited settings the monitoring of tuberculosis (TB) patients is challenging, and early identification of TB patients with a high mortality risk is important. The aim of this study was to investigate prospectively whether early changes in a clinical scoring system (TB score) can predict treatment outcome in Ethiopian patients with pulmonary tuberculosis. Method: TB patients (n = 250) and blood donors (n = 82) were recruited prospectively at Gondar University Hospital, Ethiopia. Clinical scoring was performed using an interview-based questionnaire and clinical examination. Results: Among TB patients (53.6% of whom were HIV co-infected) the median TB score declined from week 0 to week 2 (8 (interquartile range (IQR) 6-9) vs 4 (IQR 2-6)) and dropped to a low level at week 8, which was still significantly higher than that found in blood donors (2 (IQR 1-4) vs 0 (IQR 0-1), p < 0.0001). Patients who died had a significantly higher TB score at week 0, week 2, and week 8 than survivors. Mortality was associated with a failure to achieve a decrease greater than 25% in the TB score at 2 weeks. Baseline CD4 + cell counts (< 200 cells/mm(3)) were associated with mortality but not with initial TB score results. Conclusions: The TB score was increased during the first 2 months of treatment among patients who died. Failure to achieve a greater than 25% decrease in TB score after 2 weeks of treatment was associated with increased mortality. Repeated clinical scoring during the intensive phase of TB treatment could be useful to identify high-risk patients.

  • 24.
    Jonsson, Jerker
    et al.
    Public Health Agency Sweden, Sweden; Karolinska Institute, Sweden.
    Westman, Anna
    Danderyd Hospital, Sweden; Karolinska University Hospital Lab, Sweden.
    Bruchfeld, Judith
    Karolinska Institute, Sweden; Karolinska University Hospital Solna, Sweden.
    Sturegard, Erik
    Lund University, Sweden.
    Gaines, Hans
    Public Health Agency Sweden, Sweden; Karolinska Institute, Sweden; Karolinska University Hospital Solna, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    A borderline range for Quantiferon Gold In-Tube results2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187313Article in journal (Refereed)
    Abstract [en]

    Objective Interferon gamma release assays like Quantiferon Gold In-Tube (QFT) are used to identify individuals infected with Mycobacterium tuberculosis. A dichotomous cut-off (0.35 IU/ml) defines a positive QFT without considering test variability. Our objective was to evaluate the introduction of a borderline range under routine conditions. Methods Results of routine QFT samples from Sweden (2009-2014) were collected. A borderline range (0.20-0.99 IU/ml) was introduced in 2010 recommending a follow-up sample. The association between borderline results and incident active TB within 3 to 24 months was investigated through linkage with the national TB-register. Results Using the recommended QFT cut-off, 75.1 % tests were negative, 21.4% positive and 3.5% indeterminate. In total, 9% (3656/40773) were within the borderline range. In follow-up samples, individuals with initial results between 0.20-0.34 IU/ml and 0.35-0.99 IU/ml displayed negative results below the borderline range (amp;lt;0.20 IU/ml) in 66.1% (230/348) and 42.5% (285/671) respectively, and none developed incident TB. Among 6712 individuals with a positive initial test amp;gt;0.99 IU/ml, 65 (0.97%) developed incident TB within 3-24 months. Conclusions We recommend retesting of subjects with QFT results in the range 0.20-0.99 IU/ml to enhance reliability and validity of the test. Half of the subjects in the borderline range will be negative at a levelamp;lt;0.20 IU/ml when retested and have a very low risk of developing incident active TB.

  • 25.
    Koeser, Claudio U.
    et al.
    Univ Cambridge, England; Res Ctr Borstel, Germany.
    Heyckendorf, Jan
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Andres, Sonke
    Res Ctr Borstel, Germany.
    Olaru, Ioana D.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Sturegard, Erik
    Lund Univ, Sweden.
    Beckert, Patrick
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Schleusener, Viola
    Res Ctr Borstel, Germany.
    Kohl, Thomas A.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Hillemann, Doris
    Res Ctr Borstel, Germany.
    Moradigaravand, Danesh
    Wellcome Trust Sanger Inst, England.
    Parkhill, Julian
    Wellcome Trust Sanger Inst, England.
    Peacock, Sharon J.
    Univ Cambridge, England; Wellcome Trust Sanger Inst, England; London Sch Hyg and Trop Med, England.
    Niemann, Stefan
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Lange, Christoph
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany; Karolinska Inst, Sweden.
    Merker, Matthias
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Reply to Dookie et al., "Whole-Genome Sequencing To Guide the Selection of Treatment for Drug-Resistant Tuberculosis"2018In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 8, article id e00616-18Article in journal (Other academic)
    Abstract [en]

    n/a

  • 26.
    Lange, C.
    et al.
    Res Ctr Borstel, Germany; Univ Lubeck, Germany; German Ctr Infect Res DZIF, Germany; Karolinska Inst, Sweden.
    Aarnoutse, R. E.
    Radboud Univ Nijmegen, Netherlands.
    Alffenaar, J. W. C.
    Univ Groningen, Netherlands.
    Bothamley, G.
    Homerton Univ Hosp, England; QMUL, England; London Sch Hyg and Trop Med, England.
    Brinkmann, F.
    Ruhr Univ Bochum, Germany.
    Costa, J.
    Ctr Hosp Leiria, Portugal; Ctr Innovat Technol and Hlth Care, Portugal.
    Chesov, D.
    Nicoale Testemitanu State Univ Med and Pharm, Moldova; Res Ctr Borstel, Germany.
    van Crevel, R.
    Radboud Univ Nijmegen, Netherlands; Univ Oxford, England.
    Dedicoat, M.
    Univ Hosp Birmingham, England.
    Dominguez, J.
    Univ Autonoma Barcelona, Spain.
    Duarte, R.
    Portuguese Natl TB Program, Portugal; Ctr Hosp Vila Nova de Gaia, Portugal; Univ Porto, Portugal; Univ Porto, Portugal.
    Grobbel, H. P.
    Res Ctr Borstel, Germany; Univ Lubeck, Germany; German Ctr Infect Res DZIF, Germany.
    Guenther, G.
    Res Ctr Borstel, Germany; Univ Namibia, Namibia.
    Guglielmetti, L.
    Hop Univ Pitie Salpetriere Charles Foix, France; Univ Pierre and Marie Curie 06, France.
    Heyckendorf, J.
    Res Ctr Borstel, Germany; Univ Lubeck, Germany; German Ctr Infect Res DZIF, Germany.
    Kay, A. W.
    Texas Childrens Hosp, TX 77030 USA; Baylor Coll Med, TX 77030 USA; Baylor Coll Med Childrens Fdn, Swaziland.
    Kirakosyan, O.
    MSF France OCP, Armenia.
    Kirk, O.
    Univ Copenhagen, Denmark; Univ Southern Denmark, Denmark.
    Koczulla, R. A.
    Philipps Univ Marburg, Germany; German Ctr Lung Res DZL, Germany.
    Kudriashov, G. G.
    St Petersburg State Res Inst Phthisiopulmonol, Russia.
    Kuksa, L.
    Riga East Univ Hosp, Latvia; Riga Stradins Univ, Latvia.
    van Leth, F.
    Univ Amsterdam, Netherlands.
    Magis-Escurra, C.
    Radboud Univ Nijmegen, Netherlands.
    Mandalakas, A. M.
    Texas Childrens Hosp, TX 77030 USA; Baylor Coll Med, TX 77030 USA.
    Molina-Moya, B.
    Univ Autonoma Barcelona, Spain.
    Peloquin, C. A.
    Univ Florida, FL USA.
    Reimann, M.
    Res Ctr Borstel, Germany; Univ Lubeck, Germany; German Ctr Infect Res DZIF, Germany.
    Rumetshofer, R.
    Otto Wagner Hosp Vienna, Austria.
    Schaaf, H. S.
    Stellenbosch Univ, South Africa.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Tiberi, S.
    Barts Hlth NHS Trust, England; Queen Mary Univ, England.
    Valda, J.
    Otto Wagner Hosp Vienna, Austria.
    Yablonskii, P. K.
    St Petersburg State Res Inst Phthisiopulmonol, Russia; St Petersburg State Univ, Russia.
    Dheda, K.
    Univ Cape Town, South Africa.
    Management of patients with multidrug-resistant tuberculosis2019In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 23, no 6, p. 645-662Article in journal (Refereed)
    Abstract [en]

    The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

  • 27.
    Lange, C.
    et al.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany; Karolinska Inst, Sweden.
    Alghamdi, W. A.
    Univ Florida, FL USA.
    Al-Shaer, M. H.
    Univ Florida, FL USA.
    Brighenti, S.
    Karolinska Univ Hosp Huddinge, Sweden.
    Diacon, A. H.
    Task Appl Sci, South Africa; Stellenbosch Univ, South Africa.
    DiNardo, A. R.
    Baylor Coll Med, TX 77030 USA.
    Grobbel, H. P.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Groschel, M. I.
    Univ Groningen, Netherlands; Natl Reference Ctr Mycobacteria, Germany.
    von Groote-Bidlingmaier, F.
    Task Appl Sci, South Africa.
    Hauptmann, M.
    German Ctr Infect Res DZIF, Germany; Res Ctr Borstel, Germany.
    Heyckendorf, J.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Kohler, N.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Kohl, T. A.
    Natl Reference Ctr Mycobacteria, Germany.
    Merker, M.
    Natl Reference Ctr Mycobacteria, Germany.
    Niemann, S.
    German Ctr Infect Res DZIF, Germany; Natl Reference Ctr Mycobacteria, Germany.
    Peloquin, C. A.
    Univ Florida, FL USA.
    Reimann, M.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Schaible, U. E.
    German Ctr Infect Res DZIF, Germany; Res Ctr Borstel, Germany; Univ Lubeck, Germany; LRA INFECTIONS 21, Germany.
    Schaub, D.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Schleusener, V.
    Natl Reference Ctr Mycobacteria, Germany.
    Thye, T.
    Bernhard Nocht Inst Trop Med, Germany.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital.
    Perspectives for personalized therapy for patients with multidrug-resistant tuberculosis2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 284, no 2, p. 163-188Article, review/survey (Refereed)
    Abstract [en]

    According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug-resistance is complicating tuberculosis control in many high-burden countries. During the past 5years, the global number of patients identified with multidrug-resistant tuberculosis (MDR-TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR-TB. The management of MDR-TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug-resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor-made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR-TB. The challenge now is to bring these adances to those patients that need them most.

  • 28.
    Larsson, Marie C
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Microbiology.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ängeby, Kristian
    Karolinska University Hospital, Hospital, Stockholm, Sweden; University of the West Indies, Kingston, Jamaica.
    Nordvall, Michaela
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Microbiology.
    Jureen, Pontus
    Public Health Agency of Sweden, Stockholm, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences. Kalmar County Hospital, Sweden; Linnaeus University, Kalmar, Sweden.
    A luciferase-based assay for rapid assessment of drug activity against Mycobacterium tuberculosis including monitoring of macrophage viability2014In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 106, p. 146-150Article in journal (Refereed)
    Abstract [en]

    The intracellular (IC) effect of drugs against Mycobacterium tuberculosis (Mtb) is not well established but increasingly important to consider when combining current and future multidrug regimens into the best possible treatment strategies. For this purpose, we developed an IC model based on a genetically modified Mtb H37Rv strain, expressing the Vibrio harvei luciferase (H37Rv-lux) infecting the human macrophage like cell line THP-1. Cells were infected at a low multiplicity of infection (1:1) and subsequently exposed to isoniazid (INH), ethambutol (EMB), amikacin (AMI) or levofloxacin (LEV) for 5 days in a 96-well format. Cell viability was evaluated by Calcein AM and was maintained throughout the experiment. The number of viable H37Rv-lux was determined by luminescence and verified by a colony forming unit analysis. The results were compared to the effects of the same drugs in broth cultures. AMI, EMB and LEV were significantly less effective intracellularly (MIC90: greater than4 mg/L, 8 mg/L and 2 mg/L, respectively) compared to extracellularly (MIC90: 0.5 mg/L for AMI and EMB; 0.25 mg/L for LEV). The reverse was the case for INH (IC: 0.064 mg/L vs EC: 0.25 mg/L). In conclusion, this luciferase based method, in which monitoring of cell viability is included, has the potential to become a useful tool while evaluating the intracellular effects of anti-mycobacterial drugs.

  • 29.
    Nakatani, Yoshio
    et al.
    University of Otago, New Zealand; University of Auckland, New Zealand; University of Otago, New Zealand.
    Opel-Reading, Helen K.
    University of Otago, New Zealand.
    Merker, Matthias
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Machado, Diana
    University of Nova Lisboa, Portugal.
    Andres, Sonke
    National TB Reference Lab, Germany.
    Siva Kumar, S.
    National Institute Research TB, India.
    Moradigaravand, Danesh
    Wellcome Trust Sanger Institute, England.
    Coll, Francesc
    London School Hyg and Trop Med, England.
    Perdigao, Joao
    University of Lisbon, Portugal.
    Portugal, Isabel
    University of Lisbon, Portugal.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Nair, Dina
    National Institute Research TB, India.
    Uma Devi, K. R.
    National Institute Research TB, India.
    Kohl, Thomas A.
    Research Centre Borstel, Germany.
    Beckert, Patrick
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Clark, Taane G.
    London School Hyg and Trop Med, England.
    Maphalala, Gugu
    Minist Heatlh, Swaziland.
    Khumalo, Derrick
    Minist Heatlh, Swaziland.
    Diel, Roland
    University Hospital Schleswig Holstein, Germany.
    Klaos, Kadri
    Tartu University Hospital, Estonia.
    Lin Aung, Htin
    University of Otago, New Zealand; University of Auckland, New Zealand.
    Cook, Gregory M.
    University of Otago, New Zealand; University of Auckland, New Zealand.
    Parkhill, Julian
    Wellcome Trust Sanger Institute, England.
    Peacock, Sharon J.
    Wellcome Trust Sanger Institute, England; London School Hyg and Trop Med, England; University of Cambridge, England.
    Swaminathan, Soumya
    Indian Council Medical Research, India.
    Viveiros, Miguel
    University of Nova Lisboa, Portugal.
    Niemann, Stefan
    Research Centre Borstel, Germany; German Centre Infect Research, Germany.
    Krause, Kurt L.
    University of Auckland, New Zealand; University of Otago, New Zealand.
    Koser, Claudio U.
    University of Cambridge, England.
    Role of Alanine Racemase Mutations in Mycobacterium tuberculosis D-Cycloserine Resistance2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 12, article id e01575-17Article in journal (Refereed)
    Abstract [en]

    A screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to D-cycloserine.

  • 30.
    Niward, Katarina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Davies Forsman, Lina
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Bruchfeld, Judith
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Chryssanthou, Erja
    Karolinska Univ Hosp Solna, Sweden; Karolinska Inst, Sweden.
    Carlström, Oskar
    Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Alomari, Teba
    Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Pohanka, Anton
    Karolinska Univ Hosp Huddinge, Sweden.
    Mansjö, Mikael
    Publ Hlth Agcy Sweden, Sweden.
    Jonsson Nordvall, Michaela
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Johansson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Eliasson, Erik
    Karolinska Univ Hosp Huddinge, Sweden.
    Werngren, Jim
    Publ Hlth Agcy Sweden, Sweden.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Simonsson, Ulrika S. H.
    Uppsala Univ, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 10, p. 2838-2845Article in journal (Refereed)
    Abstract [en]

    Background: Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs. Objectives: To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs. Methods: Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (C-high) were determined, as well as estimates of C-high/MIC and area under the concentration-time curve (AUC(0-6))/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261). Results: After 2 weeks of treatment, the median C-high values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (amp;lt;8 mg/L), 19% for isoniazid (amp;lt;3 mg/L), 27% for pyrazinamide (amp;lt;35 mg/L) and 16% for ethambutol (amp;lt;2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC(0-6)/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid. Conclusions: We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.

  • 31.
    Niward, Katarina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Ek Blom, Linnea
    Karolinska Inst, Sweden.
    Davies Forsman, Lina
    Karolinska Inst, Sweden.
    Bruchfeld, Judith
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Eliasson, Erik
    Karolinska Univ Hosp Huddinge, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Chryssanthou, Erja
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay2018In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 5, article id e00218-18Article in journal (Refereed)
    Abstract [en]

    The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource-limited settings. In tuberculosis (TB) patients (n = 30), TDA and plasma levels of first-line drugs were analyzed 2 h post-dose, 2 weeks after treatment initiation. Patients with plasma levels of rifampin lower than 8 mg/liter had a significantly lower median TDA (1.40 versus 1.68, P = 0.0013). TDA may be used to identify TB patients with suboptimal rifampin levels during TB treatment.

  • 32.
    Niward, Katarina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Ängeby, Kristian
    Karolinska University Hospital, Stockholm, Sweden. The University of the West Indies, Kingston, Jamaica.
    Chryssanthou, Erja
    Karolinska University Hospital, Stockholm, Karolinska Institute, Stockholm, Sweden..
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Bruchfeld, Judith
    Karolinska University Hospital, Stockholm, Sweden Department of Medicine, Karolinska Institute, Solna, Sweden.
    Jureen, Pontus
    The Public Health Agency of Sweden, Stockholm, Sweden.
    Giske, Christian G
    Karolinska University Hospital, Stockholm, Karolinska Institute, Stockholm, Sweden.
    Kahlmeter, Gunnar
    Uppsala University, Uppsala, Sweden. Växjö Hospital, Växjö, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Kalmar.
    Susceptibility testing breakpoints for Mycobacterium tuberculosis categorize isolates with resistance mutations in gyrA as susceptible to fluoroquinolones: implications for MDR-TB treatment and the definition of XDR-TB.2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 2, p. 333-338Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Fluoroquinolones (FQs) are important in the treatment of MDR-TB and in the definition of XDR-TB. Our objective was to investigate how discrepancies in the phenotypic and genotypic methods for antimicrobial susceptibility testing could affect the interpretation of antimicrobial susceptibility test results.

    METHODS: We analysed MICs of ofloxacin and levofloxacin in Middlebrook 7H10 broth (7H10) as well as sequencing of the quinolone resistance-determining region of the gyrA gene and the MTBDRsl assay in 75 resistant isolates, including MDR and XDR strains of Mycobacterium tuberculosis.

    RESULTS: Among 75 resistant isolates, 27 had mutations associated with FQ resistance. Among isolates with resistance mutations in gyrA, 26% (seven of 27) were susceptible to levofloxacin and ofloxacin by phenotypic testing at 1 mg/L and 2 mg/L. The most common mutation was in codon 94 and these isolates had significantly increased MICs of levofloxacin (2-8 mg/L) compared with isolates with mutations in codon 90 (0.25-2 mg/L, P < 0.05). The sensitivity and specificity for the MTBDRsl assay compared with gyrA sequencing were 96% and 98%, respectively.

    CONCLUSION: Current critical concentrations may classify up to 26% of isolates with gyrA mutations as susceptible to FQs due to a close relationship between susceptible and resistant populations. These results should be considered while improving clinical breakpoints for M. tuberculosis and may have an impact on the definition of XDR-TB.

  • 33.
    Persson, Hans Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Welin, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Fransson, Sven-Göran
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Alveolar macrophages from patients with tuberculosis exhibit reduced capacity of restricting growth of Mycobacterium tuberculosis: a pilot study of vitamin D stimulation in vitro2013In: HOAJ Biology, ISSN 2050-0874Article in journal (Refereed)
    Abstract [en]

    Background: The role of vitamin D supplementation as adjuvant treatment of tuberculosis (TB) has lately attracted increasing interest. Our aim was to investigate the capacity of alveolar macrophages (AMs) from patients with or without exposure to TB to control intracellular growth of virulent Mycobacterium tuberculosis (Mtb).

    Methods: AMs were freshly harvested from the bronchoalveolar lavage fluid of 7 patients with a history of TB (4 patients with previous TB and 3 patients with current TB) and 4 non-TB subjects. The H37Rv strain, genetically modified to express Vibrio harveyi luciferase, was used to determine the growth of Mtb by luminometry in the AMs from study subjects. Cytokine levels in culture supernatants were determined using a flow cytometry-based bead array technique.

    Results: AMs from patients with a TB history were less efficient in restricting Mtb growth. Stimulation with 100 nM1, 25-dihydroxyvitamin D (1,25D3) did not significantly influence the capacity of AMs from any study subjects to control the infection. Out of the cytokines evaluated (TNF-α, IL-1β, IL-10 and IL-12p40) only TNF-α demonstrated detectable levels in culture supernatants, but did not respond to stimulation with 1,25D3.

    Conclusions: We conclude that AMs of TB-patients show reduced ability to control mycobacterial growth in vitro, and, that AMs in this pilot study do no respond to 1, 25D3-stimulation. The former observation supports the concept that innate immunity is crucial for the control of TB infection.

  • 34.
    Rudolf, Frauke
    et al.
    INDEPTH Network, Guinea Bissau .
    Lemvik, Grethe
    INDEPTH Network, Guinea Bissau .
    Abate, Ebba
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. University of Gondar, Ethiopia .
    Verkuilen, Jay
    CUNY, NY USA .
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Francisco Gomes, Victor
    INDEPTH Network, Guinea Bissau .
    Eugen-Olsen, Jesper
    INDEPTH Network, Guinea Bissau .
    Ostergaard, Lars
    Aarhus University Hospital, Denmark .
    Wejse, Christian
    INDEPTH Network, Guinea Bissau .
    TBscore II: Refining and validating a simple clinical score for treatment monitoring of patients with pulmonary tuberculosis2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 11, p. 825-836Article in journal (Refereed)
    Abstract [en]

    Background: The TBscore, based on simple signs and symptoms, was introduced to predict unsuccessful outcome in tuberculosis patients on treatment. A recent inter-observer variation study showed profound variation in some variables. Further, some variables depend on a physician assessing them, making the score less applicable. The aim of the present study was to simplify the TBscore. Methods: Inter-observer variation assessment and exploratory factor analysis were combined to develop a simplified score, the TBscore II. To validate TBscore II we assessed the association between start score and failure (i.e. death or treatment failure), responsiveness using Cohens effect size, and the relationship between severity class at treatment start and a decrease andlt; 25% in score from the start until the end of the second treatment month and subsequent mortality. Results: We analyzed data from 1070 Guinean (2003-2012) and 432 Ethiopian (2007-2012) pulmonary tuberculosis patients. For the refined score, items with less than substantial agreement (kappa andlt;= 0.6) and/or not associated with the underlying constructs were excluded. Items kept were: cough, dyspnea, chest pain, anemia, body mass index (BMI) andlt; 18 kg/m(2), BMI andlt; 16 kg/m(2), mid upper arm circumference (MUAC) andlt; 220 mm, and MUAC andlt; 200 mm. The effect sizes for the change between the start of treatment and the 2-month follow-up were 0.51 in Guinea-Bissau and 0.68 in Ethiopia, and for the change between the start of treatment and the end of treatment were 0.68 in Guinea-Bissau and 0.74 in Ethiopia. Severity class placement at treatment start predicted failure (p andlt; 0.001 Guinea-Bissau, p = 0.208 Ethiopia). Inability to decrease at least 25% in score was associated with a higher failure rate during the remaining 4 months of treatment (p = 0.063 Guinea-Bissau, p = 0.008 Ethiopia). Conclusion: The TBscore II could be a useful monitoring tool, aiding triage at the beginning of treatment and during treatment.

  • 35.
    Schon, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences. Kalmar County Hospital, Sweden .
    Jureen, P
    Swedish Institute Communicable Disease Control SMI, Sweden .
    Chryssanthou, E
    Karolinska University Hospital, Sweden .
    Giske, C G.
    Karolinska University Hospital, Sweden .
    Kahlmeter, G
    Vaxjo Hospital, Sweden .
    Hoffner, S
    Swedish Institute Communicable Disease Control SMI, Sweden .
    Angeby, K
    Karolinska University Hospital, Sweden .
    Rifampicin-resistant and rifabutin-susceptible Mycobacterium tuberculosis strains: a breakpoint artefact?2013In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 9, p. 2074-2077Article in journal (Refereed)
    Abstract [en]

    It has long been assumed that some rifampicin-resistant Mycobacterium tuberculosis strains are susceptible to, and thus treatable with, rifabutin. However, clinical breakpoints for susceptibility testing of rifabutin as well as the evidence for a clinical effect of rifabutin in rifampicin-resistant strains remains poorly defined. The objective of this study was to re-evaluate the breakpoint for rifabutin in relation to its MIC wild-type distribution and the presence of mutations in rpoB. less thanbrgreater than less thanbrgreater thanThe MIC in 7H10 Middlebrook medium was determined for clinical isolates of M. tuberculosis (n95), where a majority were multidrug resistant. Additionally, all strains were screened for rpoB mutations by sequencing and the GenoType MTBDRplus assay. less thanbrgreater than less thanbrgreater thanRifampicin resistance was confirmed by genotypical and/or phenotypical tests in 73 isolates (76.8). Nineteen isolates, defined as rifampicin resistant and rifabutin susceptible according to the present breakpoint, exhibited significantly higher MICs of rifabutin (0.0640.5 mg/L) than rifabutin-susceptible isolates without any detectable mutations in rpoB (P0.001). These 19 isolates were clearly resistant to rifampicin (MIC 2256 mg/L) and all but one had mutations in rpoB, with 9 (47.4) specifically in Asp516Val. less thanbrgreater than less thanbrgreater thanOur results indicate that rifampicin-resistant but rifabutin-susceptible isolates according to the present breakpoints harbour rpoB mutations and have a rifabutin MIC significantly higher than strains without any detectable mutations in rpoB. So far there are no clinical, pharmacological or microbiological data to confirm that such isolates can be treated with rifabutin and we suggest a revision of the current breakpoints.

  • 36.
    Schön, Thomas
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nitric oxide in tuberculosis and leprosy2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global disease that kills about two million people each year. Leprosy is caused by Mycobacterium leprae, and primarily affects the skin and peripheral nervous system. About 10-20% of leprosy patients suffer from reactions associated with acute inflammation that can lead to rapid and severe nerve damage. Most individuals infected with Mtb or M leprae do not develop clinical disease, which indicates that human hosts have effective defence mechanisms. In macrophages activated by cytokines such as IFN-γ, inducible nitric oxide synthase (iNOS) catalyses the production of nitric oxide (NO) from L-arginine. In an inflammatory environment, NO reacts with the superoxide radical (O2-) to yield peroxynitrite, an unstable metabolite that can rapidly nitrosylate tyrosine residues on proteins to form the stabile end product nitrotyrosine (NT). Many studies using experimental models have indicated that NO is important in host response to M leprae and Mtb, but this is controversial in human disease. Thus, our aim was to investigate the presence and the role of NO in the human mycobacterial infectious diseases TB and leprosy.

    Levels of the NO metabolites nitrite and nitrate were initially increased in urine from patients with reactional leprosy but were normalised by treatment with prednisolone, and this was associated with clinical improvement. Immunohistochemistry revealed local production of NO in skin biopsies from patients with borderline leprosy and reversal reactions, which was detected as reactivity to iNOS and NT in macrophage-rich granulomas. Ultrastructural studies showed NT-positive aggregations of neurofilaments in dermal nerves from leprosy patients. Patients with active tuberculosis had increased urinary levels of NO metabolites, which were normalised after anti-TB treatment. Household contacts of patients with tuberculosis had increased levels of NO metabolites in plasma and serum. Immunohistochemical examination of biopsies from patients with TB indicated local, iN OS-mediated generation ofNO in macrophage-rich granulomas. In an experimental model of TB, local production of NO in the lungs was substantial in the acute phase of infection, and immunoelectron microscopy detected NT in phagosomes containing Mtb and on the surface of the bacteria. In an in vitro model, NO and peroxynitrite killed Mtb H37Ra and induced upregulation of several bacterial proteins. Peroxynitrite also mediated tyrosine nitration of albumin associated with the surface of Mtb. In a randomised, double-blind trial in Ethiopia, arginine supplementation in patients receiving conventional chemotherapy increased sputum conversion and reduced the prevalence of cough in HIV -negative, smear-positive patients with active TB.

    In conclusion, these results demonstrate that iNOS-mediated production of NO occurs in human tuberculosis and leprosy; NO and peroxynitrite can kill Mtb and modify protein expression in the bacteria; and arginine leads to clinical improvement in TB patients.

    List of papers
    1. Increased levels of nitric oxide metabolites in urine from leprosy patients in reversal reaction
    Open this publication in new window or tab >>Increased levels of nitric oxide metabolites in urine from leprosy patients in reversal reaction
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    1999 (English)In: Leprosy Review, ISSN 0305-7518, E-ISSN 2162-8807, Vol. 70, no 1, p. 52-55Article in journal (Refereed) Published
    Abstract [en]

    We measured the metabolites of NO [nitrite (NŌ 2) and nitrate (NŌ 3)] in urine from Ethiopian patients suffering from leprosy. The urinary level of NŌ 2/NŌ 3 in a group of healthy Ethiopians was 1020 ± 471 μM (n = 22). Leprosy patients in reversal reaction had significantly higher levels of NŌ 2/NŌ 3 (1817 ± 492 μM, P < 0.001, n = 12) than both the control group and leprosy patients who were not in reversal reaction (1079 ± 446 μM, n = 12). We conclude that the reversal reaction in leprosy is associated with increased urinary levels of nitric oxide metabolites.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26097 (URN)10438255 (PubMedID)10556 (Local ID)10556 (Archive number)10556 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    2. Expression of inducible nitric oxide synthase and nitrotyrosine in borderline leprosy lesions
    Open this publication in new window or tab >>Expression of inducible nitric oxide synthase and nitrotyrosine in borderline leprosy lesions
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    2001 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 145, no 5, p. 809-815Article in journal (Refereed) Published
    Abstract [en]

    Background In the response to T-helper cell (Th1)-type cytokines and interactions with pathogens, high levels of nitric oxide (NO) are produced by activated macrophages expressing the inducible NO synthase (iNOS). The role and importance of reactive nitrogen intermediates (RNIs) such as NO and peroxynitrite in the host response to diseases caused by intracellular pathogens such as Mycobacterium leprae and M. tuberculosis is unclear.

    Objectives The aim of this study was to investigate the presence of local production of NO and peroxynitrite in borderline leprosy by using antibodies against iNOS and the product of peroxynitrite, nitrotyrosine (NT).

    Methods We detected the presence of iNOS and NT in skin biopsies from borderline leprosy patients, with and without reversal reaction (RR), by immunohistochemistry (n = 26).

    Results In general, the granulomas from borderline leprosy lesions with and without RR showed high and specific expression of iNOS and NT. Moreover, strong immunoreactivity to iNOS and NT was observed in granulomas surrounding and infiltrating dermal nerves. The expression of iNOS and NT was also strong in keratinocytes, fibroblasts and endothelial cells in close relation to the granulomatous reaction. In contrast, normal human skin showed no expression of iNOS and NT in these cells.

    Conclusions We conclude that iNOS and NT are expressed in granulomas from borderline leprosy patients with and without RR and propose that RNIs might be involved in the nerve damage following RR in leprosy.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26100 (URN)10.1046/j.1365-2133.2001.04491.x (DOI)10559 (Local ID)10559 (Archive number)10559 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    3. High dose prednisolone treatment of leprosy patients undergoing reactions is associated with a rapid decrease in urinary nitric oxide metabolites and clinical improvement
    Open this publication in new window or tab >>High dose prednisolone treatment of leprosy patients undergoing reactions is associated with a rapid decrease in urinary nitric oxide metabolites and clinical improvement
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    2000 (English)In: Leprosy Review, ISSN 0305-7518, E-ISSN 2162-8807, Vol. 71, no 3, p. 355-362Article in journal (Refereed) Published
    Abstract [en]

    Evidence is accumulating that nitric oxide (NO) produced by macrophages has a role in the pathogenesis of reactions in leprosy. We followed the urinary levels of the metabolites of NO [nitrite (NO 2 -) and nitrate (NO 3 -)] and the clinical response to prednisolone treatment in leprosy patients (n = 9) admitted to ALERT leprosy hospital Addis Ababa, Ethiopia, because of reversal reaction (RR) or erythema nodosum leprosum (ENL). In untreated reactional leprosy patients, the levels of urinary NO metabolites (1645 ± 454 μM, n = 9, ENL = 4, RR = 5) decreased significantly 2 weeks after high dose prednisolone treatment (1075 ± 414 μM, P < 0.05), and remained stable 4 (895 ± 385 μM, P < 0.02) and 6 weeks following treatment initiation (1048 ± 452 μM, P < 0.02). This decrease was also present when the reactional patients were subdivided according to the type of reaction (ENL, RR) and coincided with a clinical improvement. In patients showing a poor clinical response to steroids, no or minor effects on the urinary NO metabolite levels were observed. We conclude that there is a correlation between the decrease in urinary NO metabolites and a favourable clinical response after high dose prednisolone treatment of reactional leprosy patients.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26098 (URN)11105495 (PubMedID)10557 (Local ID)10557 (Archive number)10557 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    4. Nitrotyrosine localization to dermal nerves in borderline leprosy
    Open this publication in new window or tab >>Nitrotyrosine localization to dermal nerves in borderline leprosy
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    2004 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 150, no 3, p. 570-574Article in journal (Refereed) Published
    Abstract [en]

    Background  Nerve damage is a common and disabling feature of leprosy, with unclear aetiology. It has been reported that the peroxidizing agents of myelin lipids—nitric oxide (NO) and peroxynitrite—are produced in leprosy skin lesions.

    Objectives  To investigate the localization of nitrotyrosine (NT)—a local end-product of peroxynitrite—in leprosy lesions where dermal nerves are affected by a granulomatous reaction.

    Methods  We investigated by immunohistochemistry and immunoelectron microscopy the localization of the inducible NO synthase (iNOS) and NT in biopsies exhibiting dermal nerves from patients with untreated leprosy.

    Results  There were abundant NT-positive and iNOS-positive macrophages in the borderline leprosy granulomas infiltrating peripheral nerves identified by light microscopy, S-100 and neurofilament immunostaining. Immunoelectron microscopy showed NT reactivity in neurofilament aggregates and in the cell wall of Mycobacterium leprae.

    Conclusions  Our results suggest that NO and peroxynitrite could be involved in the nerve damage following borderline leprosy.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-22038 (URN)10.1046/j.1365-2133.2004.05764.x (DOI)1090 (Local ID)1090 (Archive number)1090 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    5. Effects of HIV co-infection and chemotherapy on the urinary levels of nitric oxide metabolites in patients with pulmonary tuberculosis
    Open this publication in new window or tab >>Effects of HIV co-infection and chemotherapy on the urinary levels of nitric oxide metabolites in patients with pulmonary tuberculosis
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    1999 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 31, no 2, p. 123-126Article in journal (Refereed) Published
    Abstract [en]

    The presence of nitric oxide (NO) and its role as a factor in host defence against intracellular pathogens in human macrophages is controversial. We measured the metabolites of NO (nitrite (NO 2 -) and nitrate (NO 3 -)) in urine from Ethiopian patients suffering from tuberculosis. The urinary level of NO 2 -/NO 3 - in a group of healthy Ethiopians was 1020 ± 471 μM (n = 22). Untreated HIV negative patients with active pulmonary tuberculosis (1574 ± 588 μM, p < 0.01, n = 12) and household contacts to tuberculosis patients (1949 ± 812 μM, p = 0.006; n = 7) had significantly higher levels of urinary NO 2 -/NO 3 -, than the control group. Untreated HIV positive patients with pulmonary tuberculosis did not have increased levels of urinary NO 2 -/NO 3 -, (1101 ± 614 μM, n = 6). Some of the HIV negative untreated patients with pulmonary tuberculosis (1710 ± 519 μM, n = 6) were followed up after treatment and showed a reduction in the levels of urinary NO 2 -/NO 3 - 1 week after treatment (945 ± 599 μM, p < 0.05). We conclude that HIV negative patients with active pulmonary tuberculosis have increased urinary levels of nitric oxide metabolites with a reduction following specific anti-tuberculous chemotherapy.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26096 (URN)10.1080/003655499750006137 (DOI)10555 (Local ID)10555 (Archive number)10555 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    6. Expression of inducible nitric oxide synthase and nitrotyrosine in granuloma-associated macrophages from patients with tuberculosis
    Open this publication in new window or tab >>Expression of inducible nitric oxide synthase and nitrotyrosine in granuloma-associated macrophages from patients with tuberculosis
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    NO produced by the inducible nitric oxide synthase (iNOS) is important in host defense against M tuberculosis. We investigated the expression of iNOS and nitrotyrosine (Ntyr) in untreated patients with tuberculosis. Many iNOS/Ntyr reactive macrophages were observed in pleuro-pulmonary granulomas comrrming the presence of high-output NO-production in human tuberculosis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81719 (URN)
    Available from: 2012-09-21 Created: 2012-09-21 Last updated: 2012-09-21Bibliographically approved
    7. Expression of inducible nitric oxide synthase and nitrotyrosineduring the evolution of experimental pulmonary tuberculosis
    Open this publication in new window or tab >>Expression of inducible nitric oxide synthase and nitrotyrosineduring the evolution of experimental pulmonary tuberculosis
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    2001 (English)In: Experimental and Toxicological Pathology, ISSN 0940-2993, E-ISSN 1618-1433, Vol. 53, no 4, p. 257-265Article in journal (Refereed) Published
    Abstract [en]

    Nitric oxide (NO) is a relevant antimycobacterial factor in mouse macrophages. NO is a product of inducible nitric oxide synthase (iNOS). NO toxicity is greatly enhanced by reacting with superoxide to form peroxynitrite that reacts with many biological molecules. Tyrosine is one of the molecules with which NO reacts and the product is nitrotyrosine (NT). The production of peroxynitrite and the nitrosylation of proteins might play a role in bacterial killing and also in mediating host injury. In this study, we used a well-characterized mouse model of pulmonary tuberculosis to examine the local kinetics of expression and cellular distribution of iNOS and NT at the cellular and subcellular level. The histopathological study showed two phases of the disease: early and late. The early phase was characterized by mononuclear inflammation and granuloma formation. During this phase, high percentages of activated macrophages were observed that were immunostained for iNOS and NT. Immuno-electronmicroscopy showed NT immunoreactivity in lysosomes and mycobacterial wall and cytoplasm. The concentration of iNOS mRNA and NO metabolites were also elevated. The late phase was characterized by progressive pneumonia with focal necrosis and a decrease of iNOS mRNA and NO metabolites. The strongest NT immunostained areas were the necrotic tissue. Macrophages became foamy cells with scarce iNOS immunostaining but strong NT immunoreactivity. At the ultrastructural level, these cells showed NT immunolabeling in cytoskeleton, mitochondria, lysosomes and cell membrane. NT was also located in bronchial epithelial cell mitochondria, in cell membranes and cytoplasm of endothelial cells and in actin bundles within smooth muscle cells. These results suggest an important role of NO in mycobacterial killing, particularly during the early phase of the infection. They also suggest an important participation by NO in tissue damage during the late phase of the disease.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26099 (URN)10.1078/0940-2993-00182 (DOI)10558 (Local ID)10558 (Archive number)10558 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    8. Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis
    Open this publication in new window or tab >>Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis
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    2003 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 21, no 3, p. 483-488Article in journal (Refereed) Published
    Abstract [en]

    Nitric oxide (NO) is involved in the host defence against tuberculosis (TB). Patients with TB exhibit increased catabolism and reduced energy intake. Thus the hypothesis for this study was that restoring a relative deficiency in the amino acid arginine, the substrate for mycobactericidal NO production, would improve the clinical outcome of TB by increasing NO production.

    In a randomised double-blind study, patients with smear-positive TB (n=120) were given arginine or placebo for 4 weeks in addition to conventional chemotherapy. Primary outcomes were sputum conversion, weight gain, and clinical symptoms after week 8. Secondary outcomes were sedimentation rate and levels of NO metabolites, arginine, citrulline, and tumour necrosis factor‐α.

    Compared with the human immunodeficiency virus (HIV)−/TB+ placebo group, the HIV−/TB+ patients in the arginine group showed significant improvement, defined as increased weight gain, higher sputum conversion rate and faster reduction of symptoms, such as cough. The arginine level increased after week 2 in the HIV−/TB+ arginine group (100.2 µM (range 90.5–109.9) versus 142.1 µM (range 114.1–170.1)) compared with the HIV−/TB+ placebo group (105.5 µM (range 93.7–117.3) versus 95.7 µM (range 82.4–108.9)). HIV seroprevalence was 52.5%. No clinical improvement or increase in serum arginine was detected in arginine supplemented HIV+/TB+ patients compared with placebo.

    Arginine is beneficial as an adjuvant treatment in human immunodeficiency virus-negative patients with active tuberculosis, most likely mediated by increased production of nitric oxide.

    Keywords
    arginine, human immunodeficiency virus, Mycobacterium tuberculosis, nitric oxide, tuberculosis, tumour necrosis factor-alpha
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-47812 (URN)10.1183/09031936.03.00090702 (DOI)
    Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
  • 37.
    Schön, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Chryssanthou, Erja
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Minimum inhibitory concentration distributions for Mycobacterium avium complex-towards evidence-based susceptibility breakpoints2017In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 55, p. 122-124Article in journal (Refereed)
    Abstract [en]

    Background: Patients with clinical infections caused by the Mycobacterium avium complex (MAC) are treated for at least 1 year following sputum conversion with a regimen that suffers from a suboptimal cure rate. The correlation between clinical outcome and drug susceptibility testing breakpoints other than for the macrolides is regarded to be poor. A systematic evaluation of clinical breakpoints for MAC has not been performed so far; thus, the aim of this study was to initiate the process by establishing minimum inhibitory concentration (MIC) distributions. Methods: The MICs of the major drugs used in the treatment of MAC infections were determined for 229 clinical MAC isolates in cation-adjusted Mueller-Hinton II broth. Results: The MIC50 and MIC ranges were established and compared to suggested susceptibility breakpoints for clarithromycin (2; 0.064-128 mg/l), rifabutin (0.25; amp;lt;= 0.25-16 mg/l), ethambutol (8; 0.5-32 mg/l), amikacin (16; 1-128 mg/l), moxifloxacin (2; 0.25-16 mg/l), linezolid (32; 1-128 mg/l), rifampicin (8; 0.125-16 mg/l), and trimethoprim-sulfamethoxazole (2/38; 0.125/2-16/304 mg/l). Conclusions: These results, together with those from available studies, indicate that MICs are high for drugs such as rifabutin, rifampicin, ethambutol, linezolid, and moxifloxacin used against MAC at levels unlikely to be associated with clinical efficacy at current dosing. This may partly explain the poor correlation between susceptibility testing and clinical outcomes for drugs other than clarithromycin. (C) 2017 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

  • 38.
    Schön, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Elias, D.
    Microbiology and Tumour Biology Centre, Karolinska Institute, Stockholm, Sweden and Armauer Hansen Research Institute (AHRI), Addis Ababa.
    Moges, F.
    Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
    Melese, E.
    Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
    Tessema, T.
    Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Britton, Sven
    Dept of Infectious Diseases, Karolinska Hospital, Stockholm.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis2003In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 21, no 3, p. 483-488Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) is involved in the host defence against tuberculosis (TB). Patients with TB exhibit increased catabolism and reduced energy intake. Thus the hypothesis for this study was that restoring a relative deficiency in the amino acid arginine, the substrate for mycobactericidal NO production, would improve the clinical outcome of TB by increasing NO production.

    In a randomised double-blind study, patients with smear-positive TB (n=120) were given arginine or placebo for 4 weeks in addition to conventional chemotherapy. Primary outcomes were sputum conversion, weight gain, and clinical symptoms after week 8. Secondary outcomes were sedimentation rate and levels of NO metabolites, arginine, citrulline, and tumour necrosis factor‐α.

    Compared with the human immunodeficiency virus (HIV)−/TB+ placebo group, the HIV−/TB+ patients in the arginine group showed significant improvement, defined as increased weight gain, higher sputum conversion rate and faster reduction of symptoms, such as cough. The arginine level increased after week 2 in the HIV−/TB+ arginine group (100.2 µM (range 90.5–109.9) versus 142.1 µM (range 114.1–170.1)) compared with the HIV−/TB+ placebo group (105.5 µM (range 93.7–117.3) versus 95.7 µM (range 82.4–108.9)). HIV seroprevalence was 52.5%. No clinical improvement or increase in serum arginine was detected in arginine supplemented HIV+/TB+ patients compared with placebo.

    Arginine is beneficial as an adjuvant treatment in human immunodeficiency virus-negative patients with active tuberculosis, most likely mediated by increased production of nitric oxide.

  • 39.
    Schön, Thomas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Elmberger, G
    KI.
    Negesse, Y
    Hernandez Pando, R
    Sundqvist, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Britton, S
    KI.
    Local production of nitric oxide in patients with tuberculosis2004In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 8, no 9, p. 1134-1137Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO), produced by the inducible nitric oxide synthase (iNOS), is important in host defence against Mycobacterium tuberculosis in rodents, but the presence of high-output NO production in human tuberculosis has been controversial. We investigated iNOS and nitrotyrosine (Ntyr) expression in pleural (n = 7), pulmonary (n = 5) and lymph node biopsies (n = 5) from untreated, newly diagnosed tuberculosis patients. Many iNOS and Ntyr reactive macrophages were observed in granulomas, including Langhans giant cells, indicating high-output NO production at the primary site of disease in tuberculosis.

  • 40.
    Schön, Thomas
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Elmberger, Göran
    Dept of Pathology and Cytology, Karolinska Hospital, Stockholm, Sweden.
    Hernandez-Pando, Rogelio
    Experimental Pathology Laboratory, Dept of Pathology, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City.
    Yohannes, Negesse
    AHRI, Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Britton, Sven
    Dept of Infectious Diseases, Karolinska Hospital, Stockholm, Sweden.
    Expression of inducible nitric oxide synthase and nitrotyrosine in granuloma-associated macrophages from patients with tuberculosisManuscript (preprint) (Other academic)
    Abstract [en]

    NO produced by the inducible nitric oxide synthase (iNOS) is important in host defense against M tuberculosis. We investigated the expression of iNOS and nitrotyrosine (Ntyr) in untreated patients with tuberculosis. Many iNOS/Ntyr reactive macrophages were observed in pleuro-pulmonary granulomas comrrming the presence of high-output NO-production in human tuberculosis.

  • 41.
    Schön, Thomas
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gebre, Negussie
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Anderaye, Getachew
    Black Lion Hospital, Department of Internal Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Britton, Sven
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Effects of HIV co-infection and chemotherapy on the urinary levels of nitric oxide metabolites in patients with pulmonary tuberculosis1999In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 31, no 2, p. 123-126Article in journal (Refereed)
    Abstract [en]

    The presence of nitric oxide (NO) and its role as a factor in host defence against intracellular pathogens in human macrophages is controversial. We measured the metabolites of NO (nitrite (NO 2 -) and nitrate (NO 3 -)) in urine from Ethiopian patients suffering from tuberculosis. The urinary level of NO 2 -/NO 3 - in a group of healthy Ethiopians was 1020 ± 471 μM (n = 22). Untreated HIV negative patients with active pulmonary tuberculosis (1574 ± 588 μM, p < 0.01, n = 12) and household contacts to tuberculosis patients (1949 ± 812 μM, p = 0.006; n = 7) had significantly higher levels of urinary NO 2 -/NO 3 -, than the control group. Untreated HIV positive patients with pulmonary tuberculosis did not have increased levels of urinary NO 2 -/NO 3 -, (1101 ± 614 μM, n = 6). Some of the HIV negative untreated patients with pulmonary tuberculosis (1710 ± 519 μM, n = 6) were followed up after treatment and showed a reduction in the levels of urinary NO 2 -/NO 3 - 1 week after treatment (945 ± 599 μM, p < 0.05). We conclude that HIV negative patients with active pulmonary tuberculosis have increased urinary levels of nitric oxide metabolites with a reduction following specific anti-tuberculous chemotherapy.

  • 42.
    Schön, Thomas
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gebre, Negussie
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Selassie H/Mariam, Haile
    All Africa Leprosy Rehab. Train. C., Addis Ababa, Ethiopia.
    Engeda, Taye
    All Africa Leprosy Rehab. Train. C., Addis Ababa, Ethiopia.
    Britton, Sven
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia and .
    Increased levels of nitric oxide metabolites in urine from leprosy patients in reversal reaction1999In: Leprosy Review, ISSN 0305-7518, E-ISSN 2162-8807, Vol. 70, no 1, p. 52-55Article in journal (Refereed)
    Abstract [en]

    We measured the metabolites of NO [nitrite (NŌ 2) and nitrate (NŌ 3)] in urine from Ethiopian patients suffering from leprosy. The urinary level of NŌ 2/NŌ 3 in a group of healthy Ethiopians was 1020 ± 471 μM (n = 22). Leprosy patients in reversal reaction had significantly higher levels of NŌ 2/NŌ 3 (1817 ± 492 μM, P < 0.001, n = 12) than both the control group and leprosy patients who were not in reversal reaction (1079 ± 446 μM, n = 12). We conclude that the reversal reaction in leprosy is associated with increased urinary levels of nitric oxide metabolites.

  • 43.
    Schön, Thomas
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Hernández-Pando, R.
    Experimental Pathology Laboratory, Department of Pathology, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City, Mexico.
    Baquera-Heredia, J.
    Experimental Pathology Laboratory, Department of Pathology, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City, Mexico.
    Negesse, Y.
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Becerril-Villanueva, L. E.
    Experimental Pathology Laboratory, Department of Pathology, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City, Mexico.
    Leon-Contreras, J. C.
    Experimental Pathology Laboratory, Department of Pathology, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City, Mexico.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Britton, Sven
    Department of Infectious Diseases, Karolinska Institute, Stockholm, Sweden.
    Nitrotyrosine localization to dermal nerves in borderline leprosy2004In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 150, no 3, p. 570-574Article in journal (Refereed)
    Abstract [en]

    Background  Nerve damage is a common and disabling feature of leprosy, with unclear aetiology. It has been reported that the peroxidizing agents of myelin lipids—nitric oxide (NO) and peroxynitrite—are produced in leprosy skin lesions.

    Objectives  To investigate the localization of nitrotyrosine (NT)—a local end-product of peroxynitrite—in leprosy lesions where dermal nerves are affected by a granulomatous reaction.

    Methods  We investigated by immunohistochemistry and immunoelectron microscopy the localization of the inducible NO synthase (iNOS) and NT in biopsies exhibiting dermal nerves from patients with untreated leprosy.

    Results  There were abundant NT-positive and iNOS-positive macrophages in the borderline leprosy granulomas infiltrating peripheral nerves identified by light microscopy, S-100 and neurofilament immunostaining. Immunoelectron microscopy showed NT reactivity in neurofilament aggregates and in the cell wall of Mycobacterium leprae.

    Conclusions  Our results suggest that NO and peroxynitrite could be involved in the nerve damage following borderline leprosy.

  • 44.
    Schön, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Westman, A
    Karolinska Hospital.
    Elias, D
    Armauer Hansen Research Institute.
    Abate, E
    Armauer Hansen Res Instititute.
    Diro, E
    Gondar University.
    Moges, F
    Gondar University.
    Kassu, A
    Gondar University.
    Ayele, B
    Gondar University.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Getachew, A
    Gondar University.
    Britton, S
    Karolinska Hospital.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis - A randomised trial2011In: Tuberculosis, ISSN 1472-9792, E-ISSN 1873-281X, Vol. 91, no 5, p. 370-377Article in journal (Refereed)
    Abstract [en]

    In tuberculosis (TB), the production of nitric oxide (NO) is confirmed but its importance in host defense is debated. Our aim was to investigate whether a food supplement rich in arginine could enhance clinical improvement in TB patients by increased NO production. Smear positive TB patients from Gondar, Ethiopia (n = 180) were randomized to a food supplementation rich in arginine (peanuts, equivalent to 1 g of arginine/day) or with a low arginine content (wheat crackers, locally called daboqolo) during four weeks. The primary outcome was cure rate according to the WHO classification and secondary outcomes were sputum smear conversion, weight gain, sedimentation rate, reduction of cough and chest X-ray improvement as well as levels of NO in urine (uNO) or exhaled air (eNO) at two months. There was no effect of the intervention on the primary outcome (OR 1.44, 95% CI: 0.69-3.0, p = 0.39) or secondary outcomes. In the subgroup analysis according to HIV status, peanut supplemented HIV+/TB patients showed increased cure rate (83.8% (31/37) vs 53.1% (17/32), p andlt; 0.01). A low baseline eNO (andlt; 10 ppb) in HIV+/TB patients was associated with a decreased cure rate. We conclude that nutritional supplementation with a food supplement rich in arginine did not have any overall clinical effect. In the subgroup of HIV positive TB patients, it significantly increased the cure rate and as an additional finding in this subgroup, low initial levels of NO in exhaled air were associated with a poor clinical outcome but this needs to be confirmed in further studies.

  • 45.
    Schön, Thomas
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Leekassa, Ruth
    ALERT, All Africa Leprosy Relief and Training Hospital, Addis Ababa, Ethiopia.
    Gebre, Negussie
    AHRI, Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Bizuneh, Elisabeth
    ALERT, All Africa Leprosy Relief and Training Hospital, Addis Ababa, Ethiopia.
    Britton, Sven
    AHRI, Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    High dose prednisolone treatment of leprosy patients undergoing reactions is associated with a rapid decrease in urinary nitric oxide metabolites and clinical improvement2000In: Leprosy Review, ISSN 0305-7518, E-ISSN 2162-8807, Vol. 71, no 3, p. 355-362Article in journal (Refereed)
    Abstract [en]

    Evidence is accumulating that nitric oxide (NO) produced by macrophages has a role in the pathogenesis of reactions in leprosy. We followed the urinary levels of the metabolites of NO [nitrite (NO 2 -) and nitrate (NO 3 -)] and the clinical response to prednisolone treatment in leprosy patients (n = 9) admitted to ALERT leprosy hospital Addis Ababa, Ethiopia, because of reversal reaction (RR) or erythema nodosum leprosum (ENL). In untreated reactional leprosy patients, the levels of urinary NO metabolites (1645 ± 454 μM, n = 9, ENL = 4, RR = 5) decreased significantly 2 weeks after high dose prednisolone treatment (1075 ± 414 μM, P < 0.05), and remained stable 4 (895 ± 385 μM, P < 0.02) and 6 weeks following treatment initiation (1048 ± 452 μM, P < 0.02). This decrease was also present when the reactional patients were subdivided according to the type of reaction (ENL, RR) and coincided with a clinical improvement. In patients showing a poor clinical response to steroids, no or minor effects on the urinary NO metabolite levels were observed. We conclude that there is a correlation between the decrease in urinary NO metabolites and a favourable clinical response after high dose prednisolone treatment of reactional leprosy patients.

  • 46.
    Schön, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Matuschek, E.
    EUCAST Dev Lab, Sweden.
    Mohamed, S.
    Univ Virginia, VA USA.
    Utukuri, M.
    Univ Cambridge, England.
    Heysell, S.
    Univ Virginia, VA USA.
    Alffenaar, J. -W.
    Univ Sydney, Australia.
    Shin, S.
    Korean Inst TB, South Korea.
    Martinez, E.
    Univ Sydney, Australia; Inst Clin Pathol and Med Res Pathol West, Australia; Western Sydney Local Hlth Dist, Australia.
    Sintchenko, V.
    Univ Sydney, Australia; Inst Clin Pathol and Med Res Pathol West, Australia; Western Sydney Local Hlth Dist, Australia.
    Maurer, F. P.
    Res Ctr Borstel, Germany.
    Keller, P. M.
    Univ Bern, Switzerland.
    Kahlmeter, G.
    EUCAST Dev Lab, Sweden.
    Koser, C. U.
    Univ Cambridge, England.
    Standards for MIC testing that apply to the majority of bacterial pathogens should also be enforced for Mycobacterium tuberculosis complex2019In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 25, no 4, p. 403-405Article in journal (Other academic)
    Abstract [en]

    n/a

  • 47.
    Schön, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden, European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC), ESCMID, Basel, Switzerland.
    Miotto, P.
    Emerging Bacterial Pathogens Unit, Div. of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
    Koeser, C. U.
    University of Cambridge, England.
    Viveiros, M.
    European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC), ESCMID, Basel, Switzerland; Unidade de Microbiologia Médica, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, Lisboa, Portugal.
    Boettger, E.
    European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC), ESCMID, Basel, Switzerland; Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland.
    Cambau, E.
    European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC), ESCMID, Basel, Switzerland; National Reference Center for Mycobacteria and Antimycobacterial Resistance, Paris, France; APHP, Hôpital Lariboisière, Laboratory of Bacteriology, Paris, France; University Paris Diderot, INSERM IAME UMR1137, Sorbonne Paris Cité, Paris, France.
    Mycobacterium tuberculosis drug-resistance testing: challenges, recent developments and perspectives2017In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 23, no 3, p. 154-160Article, review/survey (Refereed)
    Abstract [en]

    Drug-resistance testing, or antimicrobial susceptibility testing (AST), is mandatory for Mycobacterium tuberculosis in cases of failure on standard therapy. We reviewed the different methods and techniques of phenotypic and genotypic approaches. Although multiresistant and extensively drug-resistant (MDR/ XDR) tuberculosis is present worldwide, AST for M. tuberculosis (AST-MTB) is still mainly performed according to the resources available rather than the drug-resistance rates. Phenotypic methods, i. e. culture-based AST, are commonly used in high-income countries to confirm susceptibility of new cases of tuberculosis. They are also used to detect resistance in tuberculosis cases with risk factors, in combination with genotypic tests. In low-income countries, genotypic methods screening hot-spot mutations known to confer resistance were found to be easier to perform because they avoid the culture and biosafety constraint. Given that genotypic tests can rapidly detect the prominent mechanisms of resistance, such as the rpoB mutation for rifampicin resistance, we are facing new challenges with the observation of false-resistance (mutations not conferring resistance) and false-susceptibility (mutations different from the common mechanism) results. Phenotypic and genotypic approaches are therefore complementary for obtaining a high sensitivity and specificity for detecting drug resistances and susceptibilities to accurately predict MDR/ XDR cure and to gather relevant data for resistance surveillance. Although AST-MTB was established in the 1960s, there is no consensus reference method for MIC determination against which the numerous AST-MTB techniques can be compared. This information is necessary for assessing in vitro activity and setting breakpoints for future anti-tuberculosis agents. (C) 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  • 48.
    Schön, Thomas
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Pando, R. H.
    Experimental Pathology Laboratory, Dept of Pathology, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City.
    Negesse, Y.
    AHRI, Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Leekassa, R.
    ALERT, All Africa Leprosy Relief and Training Hospital, Addis Ababa, Ethiopia.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Britton, Sven
    AHRI, Armauer Hansen Research Institute, Addis Ababa, Ethiopia and Department of Infectious Diseases, Karolinska Hospital, Stockholm, Sweden.
    Expression of inducible nitric oxide synthase and nitrotyrosine in borderline leprosy lesions2001In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 145, no 5, p. 809-815Article in journal (Refereed)
    Abstract [en]

    Background In the response to T-helper cell (Th1)-type cytokines and interactions with pathogens, high levels of nitric oxide (NO) are produced by activated macrophages expressing the inducible NO synthase (iNOS). The role and importance of reactive nitrogen intermediates (RNIs) such as NO and peroxynitrite in the host response to diseases caused by intracellular pathogens such as Mycobacterium leprae and M. tuberculosis is unclear.

    Objectives The aim of this study was to investigate the presence of local production of NO and peroxynitrite in borderline leprosy by using antibodies against iNOS and the product of peroxynitrite, nitrotyrosine (NT).

    Methods We detected the presence of iNOS and NT in skin biopsies from borderline leprosy patients, with and without reversal reaction (RR), by immunohistochemistry (n = 26).

    Results In general, the granulomas from borderline leprosy lesions with and without RR showed high and specific expression of iNOS and NT. Moreover, strong immunoreactivity to iNOS and NT was observed in granulomas surrounding and infiltrating dermal nerves. The expression of iNOS and NT was also strong in keratinocytes, fibroblasts and endothelial cells in close relation to the granulomatous reaction. In contrast, normal human skin showed no expression of iNOS and NT in these cells.

    Conclusions We conclude that iNOS and NT are expressed in granulomas from borderline leprosy patients with and without RR and propose that RNIs might be involved in the nerve damage following RR in leprosy.

  • 49.
    Schön, Thomas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Wolday, Dawit
    Elias, Daniel
    Melese, Endalkachew
    Mogens, Feleke
    Tessema, Tesfaye
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Sundqvist, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Britton, Sven
    Kinetics of sedimentation rate, viral load and TNF-α in relation to HIV co-infection in tuberculosis2006In: Transactions of the Royal Society of Tropical Medicine and Hygiene, ISSN 0035-9203, E-ISSN 1878-3503, Vol. 100, no 5, p. 483-488Article in journal (Refereed)
    Abstract [en]

    The kinetics of potential surrogate markers in HIV-positive (HIV+) and HIV-negative (HIV-), smear-positive tuberculosis (Tb+) patients in Gondar, Ethiopia (n = 60) was investigated. Clinical symptoms, sputum conversion, sedimentation rate (SR), HIV viral load and serum levels of TNF-α were determined before and 8 weeks after treatment initiation. The co-infection rate of HIV was 45%. There were significantly higher initial levels of SR and TNF-α in HIV+/Tb+ patients (79 ± 29 mm/h and 13.5 ± 7.6 pg/ml), than in HIV-/Tb+ patients (60 ± 23 mm/h and 6.8 ± 5.9 pg/ml, P < 0.001). In HIV-/Tb+ patients, there was a marked decrease in SR compared with co-infected patients (46% [33 ± 24 mm/h at week 8] vs. 24% [61 ± 27 mm/h at week 8]). The HIV viral load (4.99 [range 3.70-5.92] to 4.90 [range 3.96-5.78] log10 copies/ml from week 0 to 8) and TNF-α (13.5 ± 7.6 to 12.0 ± 6.0 pg/ml) remained high in HIV+/Tb+ patients. In Tb patients, SR was significantly increased in HIV+ compared with HIV- patients. Additionally, TNF-α and HIV viral load remained elevated in HIV+/ Tb+ patients following treatment despite clinical improvement comparable to HIV-/Tb+ patients. © 2005 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

  • 50.
    Singh, Susmita K.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    HIV Interferes with the Dendritic Cell-T Cell Axis of Macrophage Activation by Shifting Mycobacterium tuberculosis-Specific CD4 T Cells into a Dysfunctional Phenotype2019In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 202, no 3, p. 816-826Article in journal (Refereed)
    Abstract [en]

    HIV coinfection is the greatest risk factor for transition of latent Mycobacterium tuberculosis infection into active tuberculosis (TB). Epidemiological data reveal both the reduction and the impairment of M. tuberculosis-specific CD4 T cells, although the cellular link and actual mechanisms resulting in immune impairment/suppression need further characterization. M. tuberculosis-specific CD4 T cells play a central role in development of protective immunity against TB, in which they participate in the activation of macrophages through the dendritic cell (DC)-T cell axis. Using an in vitro priming system for generating Ag-specific T cells, we explored if HIV-M. tuberculosis-infected (coinfected) human DCs can dysregulate the M. tuberculosis-specific CD4 T cell phenotype and functionality and subsequently mediate the failure to control M. tuberculosis infection in macrophages. After coculture with coinfected DCs, M. tuberculosis Ag-specific CD4 T cells lost their ability to enhance control of M. tuberculosis infection in infected macrophages. Coinfection of DCs reduced proliferation of M. tuberculosis Ag-specific CD4 T cells without affecting their viability, led to increased expression of coinhibitory factors CTLA-4, PD-1, and Blimp-1, and decreased expression of costimulatory molecules CD40L, CD28, and ICOS on the T cells. Expression of the regulatory T cell markers FOXP3 and CD25, together with the immunosuppressive cytokines TGF-beta and IL-10, was also significantly increased by coinfection compared with M. tuberculosis single infection. Our data suggest a pattern in which HIV, through its effect on DCs, impairs the ability of M. tuberculosis-specific CD4 T cells to maintain a latent TB within human macrophages, which could play an early role in the subsequent development of TB.

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