IntroductionInfectious spondylodiscitis is a rare infection of the intervertebral disc and the ad... more IntroductionInfectious spondylodiscitis is a rare infection of the intervertebral disc and the adjacent vertebral bodies that often disseminates and requires long-term antibiotic therapy. Immunologic profiling of patients with infectious spondylodiscitis could allow for a personalized medicine strategy. We aimed to examine the induced immune response in patients with infectious spondylodiscitis during and after antibiotic therapy. Furthermore, we explored potential differences in the induced immune response depending on the causative pathogen and the dissemination of the disease.MethodsThis was a prospective observational cohort study that enrolled patients with infectious spondylodiscitis between February 2018 and August 2020. A blood sample was collected at baseline, after four to six weeks of antibiotic therapy (during antibiotic therapy), and three to seven months after end of antibiotic therapy (post-infection). The induced immune response was assessed using the standardized fu...
Infection with Mycobacterium chimaera has globally been linked to cardiac surgery using cardiopul... more Infection with Mycobacterium chimaera has globally been linked to cardiac surgery using cardiopulmonary bypass devices with contaminated heater-cooler units (HCU). This is a case report of M. chimaera infection linked to HCU in Denmark in which we show, how difficult the diagnosis can be. A 67-year-old man had an aortic graft and valvular replacement using HCU. Post-operatively he developed progressing symptoms of intermittent fever, malaise and endocarditis with septic embolic events, and despite extensive diagnostic work-up, he remained undiagnosed for 16 months following surgery.
Active transmission of Mycobacterium tuberculosis (Mt) continues at surprisingly high rates in De... more Active transmission of Mycobacterium tuberculosis (Mt) continues at surprisingly high rates in Denmark. The transmission is particularly observed in specific high risk segments of the population with social problems such as homelessness, alcohol, and/or drug abuse. The patients are infected with the "Danish Cluster 2" Mt outbreak strain, and the transmission is attributed to delayed diagnosis. This situation demands increased focus on early tuberculosis diagnosis, control of transmission, and improved actions calls for prioritising the prevention and control of tuberculosis politically and economically.
The performance of two commercially-available Interferon Gamma Release Assays, QuantiFERON-TB-Gol... more The performance of two commercially-available Interferon Gamma Release Assays, QuantiFERON-TB-Gold and T-SPOT-TB, is reviewed. The tests can indirectly detect M. tuberculosis infection based on T-cell recognition of specific proteins which are not present in the BCG vaccine M. avium, or most other environmental mycobacteria.The sensitivity (76-88%) of the IGRAs is not optimal for a diagnostic test for active tuberculosis. However, the specificity is high (92-97%), and the IGRAs may play an important role in the investigation for active tuberculosis and screening for latent tuberculosis infection in BCG vaccinated populations and immunosuppressed patients.
In search for a serological marker, which may be used to monitor treatment efficacy in patients w... more In search for a serological marker, which may be used to monitor treatment efficacy in patients with extra-pulmonary mycobacterial infections, serum samples were collected prospectively from patients during a 6-months treatment period. The levels of soluble urokinase-type plasminogen activator receptor (suPAR) and soluble tumour necrosis factor receptor II (sTNFrII) were measured and compared with erythrocyte sedimentation rate (SR) and C-reactive protein levels (CRP). sTNFrII levels were elevated at the time of diagnosis and declined in parallel with traditional inflammation markers (SR and CRP). suPAR levels were elevated to more than double (median 7.7 ng/ml, range 5.6-25.8) compared to levels previously reported for patients with pulmonary tuberculosis. The serum suPAR levels however remained high during the entire treatment period. This may reflect that significant inflammatory activity is continuing for more than 6 months in patients with extrapulmonary mycobacterial infections, despite adequate anti-tuberculosis treatment.
We have developed monoclonal antibodies (MoAb) reactive with a protein from Mycobacterium tubercu... more We have developed monoclonal antibodies (MoAb) reactive with a protein from Mycobacterium tuberculosis of apparent molecular mass 24 kDa, This protein was shown lo he identical with MPB M (Harboe et al., [1]), The MoAb bound to four different epitopes of which two were restricted to the tuberculosis complex” and two were also found in mycobacteria not belonging to the “tuberculosis complex”, The cross‐reactive MoAb demonstrate that MPB M is present in more mycobacterial species than previously assumed. MPB 64 was show n lo induce strong delayed type hypersensitivity (Dth) reactions in out bred guinea pigs immunized with M tuberculosis and M. hovis bacille Calmette‐Guérin (BCG), No reaction was observed m animals immunized with mycobacteria not belonging to the “tuberculosis complex”, The Dth‐inducing capacity of MPB 64 was compared with that of another 24 kDa protein purified from W. merciless and of the previously described 38 kDa protein. The Dth responses lo these three antigens ...
PurposeMost HIV‐infected patients develop immunodeficiency without treatment. However, Long‐Term ... more PurposeMost HIV‐infected patients develop immunodeficiency without treatment. However, Long‐Term Non Progressors (LTNP) and Viremic Controllers (VC) maintain normal CD4 counts and do not progress in the absence of treatment. While VC are able to control viral replication LTNP are not. Thus, lack of viral replication cannot explain non‐progression in LTNP. Therefore we hypothesized that the immunological mechanism responsible for preserved CD4 counts in LTNP is different from that in VC.Methods69 treatment naïve HIV‐infected patients were included in a cross‐sectional study. A total of 14 LTNP (viral load, VL>5000 copies/ml, CD4+ cell count>350 cells/ul, infected>10 years), 30 VC (VL<5000 copies/ml, CD4 count>350 cells/ul), and 25 progressors (PR) (VL>5.000 copies/ml, CD4 count>350 cells/ul) were included. Immune activation (CD4+ and CD8+cells co‐expressing CD38+HLA‐DR+), apoptosis (CD8+CD28‐CD95+), Th17 cells (CD4+CD161+), and regulatory T cells (Tregs, CD4+CD25...
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2014
HIV-infected controllers control viral replication and maintain normal CD4 T cell counts. Long-te... more HIV-infected controllers control viral replication and maintain normal CD4 T cell counts. Long-term nonprogressors (LTNPs) also maintain normal CD4 T cell counts but have ongoing viral replication. We hypothesized that immunoregulatory mechanisms are involved in preserved CD4 T cell counts in controllers and in LTNPs. Twenty HIV-infected viremic controllers, 5 elite controllers (ECs), and 14 LTNPs were included in this cross-sectional study. For comparison, 25 progressors and 34 healthy controls were included. Regulatory T cells (Tregs), Treg subpopulations, CD161+Th17 cells, and CD3+CD8+CD161(high)Tc17 cells in peripheral blood were measured using flow cytometry. Tregs in lymphoid tissue were determined in tonsil biopsies and evaluated using immunolabeling. The production of transforming growth factor beta (TGF-β), interleukin (IL)-10, and IL-17 upon stimulation with phytohemagglutinin in peripheral blood was determined by Luminex. All groups of HIV-infected patients displayed similar percentages of Tregs in both peripheral blood and lymphoid tissue. However, a larger percentage of Tregs in ECs and LTNPs were activated compared with that in controls, progressors, and viremic controllers. Further, ECs as the only group of HIV-infected patients, displayed elevated percentages of CD161+Th17 cells, preserved CD3+CD8+CD161(high)Tc17 cells, and preserved IL-10 production. Overall, Treg percentage was similar in both blood and lymphoid tissue in all groups of patients and controls. However, both ECs and LTNPs displayed a large proportion of activated Tregs suggesting immunoregulatory mechanisms to be involved in preserving CD4 T cell counts in HIV-infected nonprogressors.
ABSTRACTIn a cohort study of children <4 years of age in Greenland, mannose-binding lectin (MB... more ABSTRACTIn a cohort study of children <4 years of age in Greenland, mannose-binding lectin (MBL2) genotypes and Epstein-Barr virus (EBV) antibody levels were determined. EBV seropositivity was significantly lower and time to seroconversion increased in MBL-insufficient compared with MBL-sufficient children, indicating that MBL may be involved in primary EBV infection in infancy.
A case of hepatic actinomycosis contracted one year after removal of an intrauterine device durin... more A case of hepatic actinomycosis contracted one year after removal of an intrauterine device during ongoing Actinomyces cervicitis is reported. During active disease, lymphocytes from the apparently fully immunocompetent patient were able to proliferate but not to produce the proinflammatory lymphokine γ‐interferon in response to Actinomyces antigen. This ability was only partly restored during antibiotic therapy.
Tumour necrosis factor-alpha (TNF-α) inhibitors have been introduced in the treatment of refracto... more Tumour necrosis factor-alpha (TNF-α) inhibitors have been introduced in the treatment of refractory sarcoidosis. These biologics may reactivate latent tuberculosis infection (LTBI). Despite its known limitations, the tuberculin skin test (TST) is currently used for the diagnosis of LTBI in Danish sarcoidosis patients. We report the results of a screening using the interferon-gamma release assay (IGRA) QuantiFERON TB Gold (QFN) for the diagnosis of LTBI. We aimed to assess whether the QFN is reliable for diagnosing LTBI among sarcoidosis patients and if results are influenced by disease activity or immunosuppressive treatment. A prospective study was performed from 2005 to 2007 among sarcoidosis patients who were candidates for TNF-α inhibitor treatment. Information on immunosuppressive treatment was obtained from the medical records. Disease activity was assessed by biochemistry, chest roentgenograms and pulmonary function tests. The predictive value of QFN results was evaluated by follow-up in the Danish National Tuberculosis Registry. A total of 44 sarcoidosis patients (22 men) with a median age of 39 y (range 25-59 y) were enrolled; 93% had a negative QFN test result and 7% had an indeterminate result. Forty-three percent had disease activity and 57% (n = 25) received immunosuppressive treatment. There was no significant difference in QFN interferon-γ response between subjects with or without disease activity (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.4) and between treated vs non-treated patients (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.5). At follow-up using the Danish tuberculosis registry, there was no occurrence of tuberculosis among study participants. The predictive value of the QFN seems good among Danish sarcoidosis patients and the results appear to be unaffected by sarcoidosis disease activity and immunosuppressive treatment.
Tuberculosis (TB) remains a public health emergency worldwide. WHO recommends low-incidence count... more Tuberculosis (TB) remains a public health emergency worldwide. WHO recommends low-incidence countries to increase awareness of latent tuberculosis infection (LTBI) as part of a national preventive strategy. This review focuses on the burden of TB in Denmark, which might be reduced, if more focus was paid on diagnosing LTBI in relevant patients, and treatment to prevent future active TB cases was initiated. LTBI testing should be considered in persons at risk of TB disease, who will benefit from LTBI treatment, e.g. recently infected persons or persons having undergone organ transplantation or having comorbidity such as HIV, dialyses, and immunosuppression.
Despite an increase in the total number of tuberculosis (TB) patients globally, positive trends i... more Despite an increase in the total number of tuberculosis (TB) patients globally, positive trends in reduction of prevalence and mortality are observed. However, high numbers of drug-resistant cases are threatening this trend. Multidrug-resistant and extensively resistant cases constitute an increasing challenge in many parts of the world also within the European region - especially in former Sovjet Republic nations. Point-of-care test systems potentially replacing microscopy and urine antigen detection systems are currently launched in many TB-high endemic countries improving TB detection rates. However, the effect on key indicators like mortality is still waiting to break through.
IntroductionInfectious spondylodiscitis is a rare infection of the intervertebral disc and the ad... more IntroductionInfectious spondylodiscitis is a rare infection of the intervertebral disc and the adjacent vertebral bodies that often disseminates and requires long-term antibiotic therapy. Immunologic profiling of patients with infectious spondylodiscitis could allow for a personalized medicine strategy. We aimed to examine the induced immune response in patients with infectious spondylodiscitis during and after antibiotic therapy. Furthermore, we explored potential differences in the induced immune response depending on the causative pathogen and the dissemination of the disease.MethodsThis was a prospective observational cohort study that enrolled patients with infectious spondylodiscitis between February 2018 and August 2020. A blood sample was collected at baseline, after four to six weeks of antibiotic therapy (during antibiotic therapy), and three to seven months after end of antibiotic therapy (post-infection). The induced immune response was assessed using the standardized fu...
Infection with Mycobacterium chimaera has globally been linked to cardiac surgery using cardiopul... more Infection with Mycobacterium chimaera has globally been linked to cardiac surgery using cardiopulmonary bypass devices with contaminated heater-cooler units (HCU). This is a case report of M. chimaera infection linked to HCU in Denmark in which we show, how difficult the diagnosis can be. A 67-year-old man had an aortic graft and valvular replacement using HCU. Post-operatively he developed progressing symptoms of intermittent fever, malaise and endocarditis with septic embolic events, and despite extensive diagnostic work-up, he remained undiagnosed for 16 months following surgery.
Active transmission of Mycobacterium tuberculosis (Mt) continues at surprisingly high rates in De... more Active transmission of Mycobacterium tuberculosis (Mt) continues at surprisingly high rates in Denmark. The transmission is particularly observed in specific high risk segments of the population with social problems such as homelessness, alcohol, and/or drug abuse. The patients are infected with the "Danish Cluster 2" Mt outbreak strain, and the transmission is attributed to delayed diagnosis. This situation demands increased focus on early tuberculosis diagnosis, control of transmission, and improved actions calls for prioritising the prevention and control of tuberculosis politically and economically.
The performance of two commercially-available Interferon Gamma Release Assays, QuantiFERON-TB-Gol... more The performance of two commercially-available Interferon Gamma Release Assays, QuantiFERON-TB-Gold and T-SPOT-TB, is reviewed. The tests can indirectly detect M. tuberculosis infection based on T-cell recognition of specific proteins which are not present in the BCG vaccine M. avium, or most other environmental mycobacteria.The sensitivity (76-88%) of the IGRAs is not optimal for a diagnostic test for active tuberculosis. However, the specificity is high (92-97%), and the IGRAs may play an important role in the investigation for active tuberculosis and screening for latent tuberculosis infection in BCG vaccinated populations and immunosuppressed patients.
In search for a serological marker, which may be used to monitor treatment efficacy in patients w... more In search for a serological marker, which may be used to monitor treatment efficacy in patients with extra-pulmonary mycobacterial infections, serum samples were collected prospectively from patients during a 6-months treatment period. The levels of soluble urokinase-type plasminogen activator receptor (suPAR) and soluble tumour necrosis factor receptor II (sTNFrII) were measured and compared with erythrocyte sedimentation rate (SR) and C-reactive protein levels (CRP). sTNFrII levels were elevated at the time of diagnosis and declined in parallel with traditional inflammation markers (SR and CRP). suPAR levels were elevated to more than double (median 7.7 ng/ml, range 5.6-25.8) compared to levels previously reported for patients with pulmonary tuberculosis. The serum suPAR levels however remained high during the entire treatment period. This may reflect that significant inflammatory activity is continuing for more than 6 months in patients with extrapulmonary mycobacterial infections, despite adequate anti-tuberculosis treatment.
We have developed monoclonal antibodies (MoAb) reactive with a protein from Mycobacterium tubercu... more We have developed monoclonal antibodies (MoAb) reactive with a protein from Mycobacterium tuberculosis of apparent molecular mass 24 kDa, This protein was shown lo he identical with MPB M (Harboe et al., [1]), The MoAb bound to four different epitopes of which two were restricted to the tuberculosis complex” and two were also found in mycobacteria not belonging to the “tuberculosis complex”, The cross‐reactive MoAb demonstrate that MPB M is present in more mycobacterial species than previously assumed. MPB 64 was show n lo induce strong delayed type hypersensitivity (Dth) reactions in out bred guinea pigs immunized with M tuberculosis and M. hovis bacille Calmette‐Guérin (BCG), No reaction was observed m animals immunized with mycobacteria not belonging to the “tuberculosis complex”, The Dth‐inducing capacity of MPB 64 was compared with that of another 24 kDa protein purified from W. merciless and of the previously described 38 kDa protein. The Dth responses lo these three antigens ...
PurposeMost HIV‐infected patients develop immunodeficiency without treatment. However, Long‐Term ... more PurposeMost HIV‐infected patients develop immunodeficiency without treatment. However, Long‐Term Non Progressors (LTNP) and Viremic Controllers (VC) maintain normal CD4 counts and do not progress in the absence of treatment. While VC are able to control viral replication LTNP are not. Thus, lack of viral replication cannot explain non‐progression in LTNP. Therefore we hypothesized that the immunological mechanism responsible for preserved CD4 counts in LTNP is different from that in VC.Methods69 treatment naïve HIV‐infected patients were included in a cross‐sectional study. A total of 14 LTNP (viral load, VL>5000 copies/ml, CD4+ cell count>350 cells/ul, infected>10 years), 30 VC (VL<5000 copies/ml, CD4 count>350 cells/ul), and 25 progressors (PR) (VL>5.000 copies/ml, CD4 count>350 cells/ul) were included. Immune activation (CD4+ and CD8+cells co‐expressing CD38+HLA‐DR+), apoptosis (CD8+CD28‐CD95+), Th17 cells (CD4+CD161+), and regulatory T cells (Tregs, CD4+CD25...
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2014
HIV-infected controllers control viral replication and maintain normal CD4 T cell counts. Long-te... more HIV-infected controllers control viral replication and maintain normal CD4 T cell counts. Long-term nonprogressors (LTNPs) also maintain normal CD4 T cell counts but have ongoing viral replication. We hypothesized that immunoregulatory mechanisms are involved in preserved CD4 T cell counts in controllers and in LTNPs. Twenty HIV-infected viremic controllers, 5 elite controllers (ECs), and 14 LTNPs were included in this cross-sectional study. For comparison, 25 progressors and 34 healthy controls were included. Regulatory T cells (Tregs), Treg subpopulations, CD161+Th17 cells, and CD3+CD8+CD161(high)Tc17 cells in peripheral blood were measured using flow cytometry. Tregs in lymphoid tissue were determined in tonsil biopsies and evaluated using immunolabeling. The production of transforming growth factor beta (TGF-β), interleukin (IL)-10, and IL-17 upon stimulation with phytohemagglutinin in peripheral blood was determined by Luminex. All groups of HIV-infected patients displayed similar percentages of Tregs in both peripheral blood and lymphoid tissue. However, a larger percentage of Tregs in ECs and LTNPs were activated compared with that in controls, progressors, and viremic controllers. Further, ECs as the only group of HIV-infected patients, displayed elevated percentages of CD161+Th17 cells, preserved CD3+CD8+CD161(high)Tc17 cells, and preserved IL-10 production. Overall, Treg percentage was similar in both blood and lymphoid tissue in all groups of patients and controls. However, both ECs and LTNPs displayed a large proportion of activated Tregs suggesting immunoregulatory mechanisms to be involved in preserving CD4 T cell counts in HIV-infected nonprogressors.
ABSTRACTIn a cohort study of children <4 years of age in Greenland, mannose-binding lectin (MB... more ABSTRACTIn a cohort study of children <4 years of age in Greenland, mannose-binding lectin (MBL2) genotypes and Epstein-Barr virus (EBV) antibody levels were determined. EBV seropositivity was significantly lower and time to seroconversion increased in MBL-insufficient compared with MBL-sufficient children, indicating that MBL may be involved in primary EBV infection in infancy.
A case of hepatic actinomycosis contracted one year after removal of an intrauterine device durin... more A case of hepatic actinomycosis contracted one year after removal of an intrauterine device during ongoing Actinomyces cervicitis is reported. During active disease, lymphocytes from the apparently fully immunocompetent patient were able to proliferate but not to produce the proinflammatory lymphokine γ‐interferon in response to Actinomyces antigen. This ability was only partly restored during antibiotic therapy.
Tumour necrosis factor-alpha (TNF-α) inhibitors have been introduced in the treatment of refracto... more Tumour necrosis factor-alpha (TNF-α) inhibitors have been introduced in the treatment of refractory sarcoidosis. These biologics may reactivate latent tuberculosis infection (LTBI). Despite its known limitations, the tuberculin skin test (TST) is currently used for the diagnosis of LTBI in Danish sarcoidosis patients. We report the results of a screening using the interferon-gamma release assay (IGRA) QuantiFERON TB Gold (QFN) for the diagnosis of LTBI. We aimed to assess whether the QFN is reliable for diagnosing LTBI among sarcoidosis patients and if results are influenced by disease activity or immunosuppressive treatment. A prospective study was performed from 2005 to 2007 among sarcoidosis patients who were candidates for TNF-α inhibitor treatment. Information on immunosuppressive treatment was obtained from the medical records. Disease activity was assessed by biochemistry, chest roentgenograms and pulmonary function tests. The predictive value of QFN results was evaluated by follow-up in the Danish National Tuberculosis Registry. A total of 44 sarcoidosis patients (22 men) with a median age of 39 y (range 25-59 y) were enrolled; 93% had a negative QFN test result and 7% had an indeterminate result. Forty-three percent had disease activity and 57% (n = 25) received immunosuppressive treatment. There was no significant difference in QFN interferon-γ response between subjects with or without disease activity (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.4) and between treated vs non-treated patients (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.5). At follow-up using the Danish tuberculosis registry, there was no occurrence of tuberculosis among study participants. The predictive value of the QFN seems good among Danish sarcoidosis patients and the results appear to be unaffected by sarcoidosis disease activity and immunosuppressive treatment.
Tuberculosis (TB) remains a public health emergency worldwide. WHO recommends low-incidence count... more Tuberculosis (TB) remains a public health emergency worldwide. WHO recommends low-incidence countries to increase awareness of latent tuberculosis infection (LTBI) as part of a national preventive strategy. This review focuses on the burden of TB in Denmark, which might be reduced, if more focus was paid on diagnosing LTBI in relevant patients, and treatment to prevent future active TB cases was initiated. LTBI testing should be considered in persons at risk of TB disease, who will benefit from LTBI treatment, e.g. recently infected persons or persons having undergone organ transplantation or having comorbidity such as HIV, dialyses, and immunosuppression.
Despite an increase in the total number of tuberculosis (TB) patients globally, positive trends i... more Despite an increase in the total number of tuberculosis (TB) patients globally, positive trends in reduction of prevalence and mortality are observed. However, high numbers of drug-resistant cases are threatening this trend. Multidrug-resistant and extensively resistant cases constitute an increasing challenge in many parts of the world also within the European region - especially in former Sovjet Republic nations. Point-of-care test systems potentially replacing microscopy and urine antigen detection systems are currently launched in many TB-high endemic countries improving TB detection rates. However, the effect on key indicators like mortality is still waiting to break through.
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Papers by Åse Andersen