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  • 1.
    Abate, Ebba
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Belayneh, Meseret
    University of Addis Ababa, Ethiopia .
    Gelaw, Aschalew
    University of Gondar, Ethiopia .
    Idh, Jonna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    The Impact of Asymptomatic Helminth Co-Infection in Patients with Newly Diagnosed Tuberculosis in North-West Ethiopia2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 8Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 2.
    Abate, Ebba
    et al.
    Gondar College of Medical and Health Sciences, Gondar University, Gondar, Ethiopia; Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Idh, Jonna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Impact of helminth infection on the clinical presentation 1 of pulmonary tuberculosis2013Manuskript (preprint) (Annet vitenskapelig)
    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.

  • 3.
    Eklund, Daniel
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Persson, Hans Lennart
    Linköpings universitet, Institutionen för medicin och hälsa, Lungmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Lungmedicinska kliniken US.
    Larsson, Marie C.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Welin, Amanda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Idh, Jonna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Paues, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fransson, Sven-Göran
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Stendahl, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Lerm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Vitamin D enhances IL-1β secretion and restricts growth of Mycobacterium tuberculosis in macrophages from TB patients2013Inngår i: International Journal of Mycobacteriology, ISSN 2212-5531, Vol. 2, nr 1, s. 18-25Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 4.
    Idh, Jonna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    The Role of Nitric Oxide in Host Defence Against Mycobacterium tuberculosis: Clinical and Experimental Studies2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), responsible for significant morbidity and mortality worldwide, especially in low-income countries. Considering aggravating factors, such as HIV co-infection and emerging drug resistance, new therapeutic interventions are urgently needed. Following exposure to M. tuberculosis, surprisingly few individuals will actually develop active disease, indicating effective defence mechanisms. One such candidate is nitric oxide (NO). The role of NO in human TB is not fully elucidated, but has been shown to have a vital role in controlling TB in animal models.

    The general aim of this thesis was to investigate the role of NO in the immune defence against M. tuberculosis, by combining clinical and experimental studies. In pulmonary TB patients, we found low levels of NO in exhaled air, and low levels of NO metabolites in urine. HIV coinfection decreased levels of exhaled NO even further, reflecting a locally impaired NO production in the lung. Low levels of exhaled NO were associated with a decreased cure rate in HIV-positive TB patients. Household contacts to sputum smear positive TB patient presented the highest levels of both urinary NO metabolites and exhaled NO. Malnutrition, a common condition in TB, may lead to deficiencies of important nutrients such as the amino acid L-arginine, essential for NO production. We therefore assessed the effect of an argininerich food supplement (peanuts) in a clinical trial including pulmonary TB patients, and found that peanut supplementation increased cure rate in HIV-positive TB patients.

    We also investigated NO susceptibility of clinical strains of M. tuberculosis, and its association to clinical outcome and antibiotic resistance. Patients infected with strains of M. tuberculosis with reduced susceptibility to NO in vitro, showed a tendency towards lower rate of weight gain during treatment. Moreover, there was a clear variability between strains in the susceptibility to NO, and in intracellular survival within NO-producing macrophages. A novel finding, that can be of importance in understanding drug resistance and for drug development, was that reduced susceptibility to NO was associated with resistance to firstline TB drugs, in particular isoniazid and mutations in inhA.

    Taken together, the data presented here show that NO plays a vital role  in human immune defence against TB, and although larger multicentre studies are warranted, arginine-rich food supplementation can be recommended to malnourished HIV co-infected patients on TB treatment.

    Delarbeid
    1. Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection
    Åpne denne publikasjonen i ny fane eller vindu >>Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection
    Vise andre…
    2008 (engelsk)Inngår i: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 8, nr 146Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Nitric oxide (NO) is essential for host defense in rodents, but the role of NO during tuberculosis (TB) in man remains controversial. However, earlier observations that arginine supplementation facilitates anti-TB treatment, supports the hypothesis that NO is important in the host defense against TB. Local production of NO measured in fractional exhaled air (FeNO) in TB patients with and without HIV co-infection has not been reported previously. Thus, our aim was to investigate levels of FeNO in relation to clinical symptoms and urinary NO metabolites (uNO).

    Methods: In a cross sectional study, FeNO and uNO were measured and clinical symptoms, chest x-ray, together with serum levels of arginine, tumor necrosis factor alpha (TNF-alpha) and interleukin 12 (IL-12) were evaluated in sputum smear positive TB patients (HIV+/TB, n = 36, HIV-/TB, n = 59), their household contacts (n = 17) and blood donors (n = 46) from Gondar University Hospital, Ethiopia.

    Results: The proportion of HIV-/TB patients with an increased FeNO level (> 25 ppb) was significantly higher as compared to HIV+/TB patients, but HIV+/TB patients had significantly higher uNO than HIV-/TB patients. HIV+ and HIV-/TB patients both had lower levels of FeNO compared to blood donors and household contacts. The highest levels of both uNO and FeNO were found in household contacts. Less advanced findings on chest x-ray, as well as higher sedimentation rate were observed in HIV+/TB patients as compared to HIV-/TB patients. However, no significant correlation was found between FeNO and uNO, chest x-ray grading, clinical symptoms, TNF-alpha, IL-12, arginine levels or sedimentation rate.

    Conclusion: In both HIV negative and HIV co infected TB patients, low levels of exhaled NO compared to blood donors and household were observed. Future studies are needed to confirm whether low levels of exhaled NO could be a risk factor in acquiring TB and the relative importance of NO in human TB.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-16238 (URN)10.1186/1471-2334-8-146 (DOI)
    Merknad
    Original Publication: Jonna Idh, Anna Westman, Daniel Elias, Feleke Moges, Assefa Getachew, Aschalew Gelaw, Tommy Sundqvist, Tony Forslund, Addis Alemu, Belete Ayele, Ermias Diro, Endalkachew Melese, Yared Wondmikun, Sven Britton, Olle Stendahl and Thomas Schoen, Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection, 2008, BMC INFECTIOUS DISEASES, (8), 146. http://dx.doi.org/10.1186/1471-2334-8-146 Publisher: BioMed Central http://www.biomedcentral.com/Tilgjengelig fra: 2009-01-16 Laget: 2009-01-09 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    2. Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis - A randomised trial
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis - A randomised trial
    Vise andre…
    2011 (engelsk)Inngår i: Tuberculosis, ISSN 1472-9792, E-ISSN 1873-281X, Vol. 91, nr 5, s. 370-377Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    sted, utgiver, år, opplag, sider
    Elsevier, 2011
    Emneord
    Nitric oxide, Arginine, Nutritional supplementation, Tuberculosis, Interleukin 10
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-71556 (URN)10.1016/j.tube.2011.06.002 (DOI)000295462300004 ()
    Merknad
    Funding Agencies|Swedish Heart and Lung Foundation||Swedish SAREC/SIDA foundation||Swedish Research Council||Tilgjengelig fra: 2011-10-21 Laget: 2011-10-21 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    3. Resistance to First-Line Anti-TB Drugs is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis
    Åpne denne publikasjonen i ny fane eller vindu >>Resistance to First-Line Anti-TB Drugs is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis
    Vise andre…
    2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 1, s. e39891-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background and objective: The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug resistance and clinical outcome is not known.

    Methods: In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO.

    Results: Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (>10% survival after exposure to 1mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters, but a tendency towards lower rate of weight gain after two months of treatment.

    Conclusion: There is a correlation between resistance to first-line anti-TB drugs and reduced NO susceptibility in clinical strains of M. tuberculosis. Further studies including the mechanisms of reduced NO susceptibility are warranted and could identify targets for new therapeutic interventions.

    sted, utgiver, år, opplag, sider
    Public Library of Science, 2012
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-77129 (URN)10.1371/journal.pone.0039891 (DOI)000305892100124 ()
    Tilgjengelig fra: 2012-05-07 Laget: 2012-05-07 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    4. Susceptibility of Clinical Strains of Mycobacterium tuberculosis to Reactive Nitrogen Species in Activated Macrophages
    Åpne denne publikasjonen i ny fane eller vindu >>Susceptibility of Clinical Strains of Mycobacterium tuberculosis to Reactive Nitrogen Species in Activated Macrophages
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Nitric oxide (NO) is produced in macrophages by the inducible NO synthase (iNOS) upon activation by pro-inflammatory cytokines. NO has been shown to be essential for the control of Mycobacterium tuberculosis infection in murine models whereas its importance in man is not as clear. There is a lack of studies regarding the susceptibility to reactive nitrogen species (RNS) in clinical strains of M. tuberculosis and the relation to first-line drug resistance, such as to isoniazid (INH). The aim of this study was to explore susceptibility to RNS and intracellular survival of clinical strains of M. tuberculosis, with or without INH resistance.

    Method: Seven clinical strains of M. tuberculosis were transformed with the pSMT1-plasmid encoding Vibrio harveyi luciferase. Survival was analysed by luminometry following exposure to the NO donor DETA/NO or peroxynitrite (SIN-1). Intracellular killing was studied in murine macrophages (RAW 264.7) activated with interferon gamma (IFN-γ) and lipopolysaccharide (LPS).

    Results: There was a significant effect on growth control of M. tuberculosis strains upon macrophage activation, which showed variability among clinical isolates. In the cell-free system, all strains showed a dose-dependent susceptibility to DETA/NO and SIN-1, and clinical strains were in general more resistant than H37Rv to DETA/NO. INH-resistant strains with an inhA mutation were significantly more tolerant to DETA/NO than inhA wild type.

    Conclusion: Reactive nitrogen species inhibited growth of clinical M. tuberculosis isolates both in an intra- and extracellular model with significant difference between strains. Increased tolerance to NO was associated with isoniazid resistance mediated by inhA.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-77131 (URN)
    Tilgjengelig fra: 2012-05-07 Laget: 2012-05-07 Sist oppdatert: 2012-05-07bibliografisk kontrollert
  • 5.
    Idh, Jonna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    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 disease2010Inngår i: Scandinavian journal of infectious diseases, ISSN 1651-1980, Vol. 42, nr 9, s. 650-657Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 6.
    Idh, Jonna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Lerm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Raffetseder, Johanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Eklund, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Larsson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Pienaar, Elsje
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Forslund, Tony
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Werngren, Jim
    Department of Preparedness, Unit of Highly Pathogenic Microorganisms, Swedish Institute for Communicable Disease Control, Sweden.
    Juréen, Pontus
    Department of Preparedness, Swedish Institute for Communicable Disease Control, Sweden.
    Ängeby, Kristian
    Department of Clinical Microbiology, Karolinska Institute, Karolinska University Hospital, Sweden.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Stendahl, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Schön, Thomas
    Department of Infectious Diseases and Clinical Microbiology, Kalmar County Hospital, Sweden.
    Susceptibility of Clinical Strains of Mycobacterium tuberculosis to Reactive Nitrogen Species in Activated MacrophagesManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Nitric oxide (NO) is produced in macrophages by the inducible NO synthase (iNOS) upon activation by pro-inflammatory cytokines. NO has been shown to be essential for the control of Mycobacterium tuberculosis infection in murine models whereas its importance in man is not as clear. There is a lack of studies regarding the susceptibility to reactive nitrogen species (RNS) in clinical strains of M. tuberculosis and the relation to first-line drug resistance, such as to isoniazid (INH). The aim of this study was to explore susceptibility to RNS and intracellular survival of clinical strains of M. tuberculosis, with or without INH resistance.

    Method: Seven clinical strains of M. tuberculosis were transformed with the pSMT1-plasmid encoding Vibrio harveyi luciferase. Survival was analysed by luminometry following exposure to the NO donor DETA/NO or peroxynitrite (SIN-1). Intracellular killing was studied in murine macrophages (RAW 264.7) activated with interferon gamma (IFN-γ) and lipopolysaccharide (LPS).

    Results: There was a significant effect on growth control of M. tuberculosis strains upon macrophage activation, which showed variability among clinical isolates. In the cell-free system, all strains showed a dose-dependent susceptibility to DETA/NO and SIN-1, and clinical strains were in general more resistant than H37Rv to DETA/NO. INH-resistant strains with an inhA mutation were significantly more tolerant to DETA/NO than inhA wild type.

    Conclusion: Reactive nitrogen species inhibited growth of clinical M. tuberculosis isolates both in an intra- and extracellular model with significant difference between strains. Increased tolerance to NO was associated with isoniazid resistance mediated by inhA.

  • 7.
    Idh, Jonna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Mekonnen, M.
    Department of Microbiology, Immunology and Parasitology, Addis Ababa University, Ethiopia.
    Abate, E.
    Armauer Hansen Research Institute, Ethiopia.
    Wedajo, W.
    Armauer Hansen Research Institute, Ethiopia.
    Werngren, J.
    Department of Preparedness, Unit of Highly Pathogenic Microorganisms, Swedish Institute for Communicable Disease Control, Sweden.
    Ängeby, K.
    Clinical Microbiology, MTC, Karolinska Institute, Karolinska University Hospital, Sweden.
    Lerm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Elias, D.
    University of Southern Denmark, Institute of Molecular Medicine, Department of Cancer and Inflammation, Denmark.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Aseffa, A.
    Armauer Hansen Research Institute, Ethiopia.
    Stendahl, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Schön, T.
    Department of Infectious Diseases and Department of Clinical Microbiology, Kalmar County Hospital, Sweden.
    Resistance to First-Line Anti-TB Drugs is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 1, s. e39891-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and objective: The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug resistance and clinical outcome is not known.

    Methods: In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO.

    Results: Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (>10% survival after exposure to 1mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters, but a tendency towards lower rate of weight gain after two months of treatment.

    Conclusion: There is a correlation between resistance to first-line anti-TB drugs and reduced NO susceptibility in clinical strains of M. tuberculosis. Further studies including the mechanisms of reduced NO susceptibility are warranted and could identify targets for new therapeutic interventions.

  • 8.
    Idh, Jonna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Westman, Anna
    Karolinska Hospital.
    Elias, Daniel
    Armauer Hansen Research Institute.
    Moges, Feleke
    Gondar University.
    Getachew, Assefa
    Gondar University.
    Gelaw, Aschalew
    Gondar University.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Forslund, Tony
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Alemu, Addis
    Gondar University.
    Ayele, Belete
    Gondar University.
    Diro, Ermias
    Gondar University.
    Melese, Endalkachew
    Gondar University.
    Wondmikun, Yared
    Gondar University.
    Britton, Sven
    Karolinska Hospital.
    Stendahl, Olle
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi.
    Schön, Thomas
    Kalmar City Hospital.
    Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection2008Inngår i: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 8, nr 146Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Nitric oxide (NO) is essential for host defense in rodents, but the role of NO during tuberculosis (TB) in man remains controversial. However, earlier observations that arginine supplementation facilitates anti-TB treatment, supports the hypothesis that NO is important in the host defense against TB. Local production of NO measured in fractional exhaled air (FeNO) in TB patients with and without HIV co-infection has not been reported previously. Thus, our aim was to investigate levels of FeNO in relation to clinical symptoms and urinary NO metabolites (uNO).

    Methods: In a cross sectional study, FeNO and uNO were measured and clinical symptoms, chest x-ray, together with serum levels of arginine, tumor necrosis factor alpha (TNF-alpha) and interleukin 12 (IL-12) were evaluated in sputum smear positive TB patients (HIV+/TB, n = 36, HIV-/TB, n = 59), their household contacts (n = 17) and blood donors (n = 46) from Gondar University Hospital, Ethiopia.

    Results: The proportion of HIV-/TB patients with an increased FeNO level (> 25 ppb) was significantly higher as compared to HIV+/TB patients, but HIV+/TB patients had significantly higher uNO than HIV-/TB patients. HIV+ and HIV-/TB patients both had lower levels of FeNO compared to blood donors and household contacts. The highest levels of both uNO and FeNO were found in household contacts. Less advanced findings on chest x-ray, as well as higher sedimentation rate were observed in HIV+/TB patients as compared to HIV-/TB patients. However, no significant correlation was found between FeNO and uNO, chest x-ray grading, clinical symptoms, TNF-alpha, IL-12, arginine levels or sedimentation rate.

    Conclusion: In both HIV negative and HIV co infected TB patients, low levels of exhaled NO compared to blood donors and household were observed. Future studies are needed to confirm whether low levels of exhaled NO could be a risk factor in acquiring TB and the relative importance of NO in human TB.

  • 9.
    Janols, Helena
    et al.
    Department of Clinical Sciences, Section for Infectious Diseases, Skåne University Hospital, Lund University, Malmö, Sweden.
    Abate, Ebba
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi.
    Idh, Jonna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi.
    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
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi.
    Schön, Thomas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi.
    Early treatment response evaluated by a clinical scoring system correlates with the prognosis of pulmonary tuberculosis patients in Ethiopia: A prospective follow-up study.2012Inngår i: Scandinavian journal of infectious diseases, ISSN 1651-1980, Vol. 44, nr 11, s. 828-834Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 10.
    Persson, Hans Lennart
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Lungmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Lungmedicinska kliniken US.
    Eklund, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Welin, Amanda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Paues, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet.
    Idh, Jonna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Fransson, Sven-Göran
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Hälsouniversitetet.
    Stendahl, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Lerm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Schön, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Alveolar macrophages from patients with tuberculosis exhibit reduced capacity of restricting growth of Mycobacterium tuberculosis: a pilot study of vitamin D stimulation in vitro2013Inngår i: HOAJ Biology, ISSN 2050-0874Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 11.
    Persson, Hans Lennart
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Jacobson, Petra
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Eklund, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Larsson, Marie C.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Welin, Amanda
    Göteborgs universitet.
    Paues, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Idh, Jonna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Fransson, Sven-Göran
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Stendahl, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Lerm, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Schon, Thomas
    Kalmar länssjukhus.
    Alveolar macrophages from patients with tuberculosis display a reduced capacity to inhibit growth of Mycomacterium tuberculosis2012Konferansepaper (Annet vitenskapelig)
  • 12.
    Schön, Thomas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Idh, Jonna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Getachew, A
    Gondar University.
    Britton, S
    Karolinska Hospital.
    Stendahl, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Sundqvist, Tommy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis - A randomised trial2011Inngår i: Tuberculosis, ISSN 1472-9792, E-ISSN 1873-281X, Vol. 91, nr 5, s. 370-377Artikkel i tidsskrift (Fagfellevurdert)
    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.

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