Publications by authors named "Martine Aabye"

23 Publications

  • Page 1 of 1

Thermostability of IFN-γ and IP-10 release assays for latent infection with Mycobacterium tuberculosis: A TBnet study.

Tuberculosis (Edinb) 2016 05 15;98:7-12. Epub 2015 May 15.

Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark. Electronic address:

Introduction: Interferon-γ (IFN-γ) inducible protein 10kD (IP-10) and IFN-γ release assays (IGRAs) are immunodiagnostic tests aiming to identify the presence of specific cellular immune responses, interpreted as markers for latent infection with Mycobacterium tuberculosis. Incubation at higher temperatures could affect IFN-γ and IP-10 responsiveness in order to improve the performance of IP-10 release assays and IGRAs.

Aim: The aim of this study was to assess the robustness of whole blood based IP-10 release assay and IGRAs and the effect of hyper-thermic incubation (39 °C) on the diagnostic accuracy of IP-10 release assay and IGRAs.

Results: We included 65 patients with confirmed pulmonary tuberculosis and 160 healthy controls from 6 European centres collaborating in the TBnet. In patients, IP-10 responses increased 1.07 (IQR 0.90-1.36) fold and IFN-γ responses decreased 0.88 (IQR 0.57-1.02) fold, with 39 °C compared to 37 °C incubation temperature. At 37 °C IGRA sensitivity was 85% and IP-10 sensitivity was 82%, whereas specificity was 97% for both tests (p > 0.8). These minor changes observed as a result of hyper-thermic incubation were not sufficient to impact IGRA and IP-10 release assay test performance.

Conclusion: The performance of IGRA and IP-10 release assays is robust despite variations in the incubation temperature between 37 °C and 39 °C.
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http://dx.doi.org/10.1016/j.tube.2015.04.013DOI Listing
May 2016

Increased level of acute phase reactants in patients infected with modern Mycobacterium tuberculosis genotypes in Mwanza, Tanzania.

BMC Infect Dis 2014 Jun 5;14:309. Epub 2014 Jun 5.

Department of Clinical Science, Infection, Faculty of Medicine and Dentristry, University of Bergen, Bergen, Norway.

Background: There is increasing evidence to suggest that different Mycobacterium tuberculosis lineages cause variations in the clinical presentation of tuberculosis (TB). Certain M. tuberculosis genotypes/lineages have been shown to be more likely to cause active TB in human populations from a distinct genetic ancestry. This study describes the genetic biodiversity of M. tuberculosis genotypes in Mwanza city, Tanzania and the clinical presentation of the disease caused by isolates of different lineages.

Methods: Two-hundred-fifty-two isolates from pulmonary TB patients in Mwanza, Tanzania were characterized by spoligotyping, and 45 isolates were further characterized by mycobacterium interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR). The patients' level of the acute phase reactants AGP, CRP and neutrophil counts, in addition to BMI, were measured and compared to the M. tuberculosis lineage of the infectious agent for each patient.

Results: The most frequent genotype was ST59 (48 out of 248 [19.4%]), belonging to the Euro-American lineage LAM11_ZWE, followed by ST21 (CAS_KILI lineage [44 out of 248 [17.7%]). A low degree of diversity (15.7% [39 different ST's out of 248 isolates]) of genotypes, in addition to a high level of mixed M. tuberculosis sub-populations among isolates with an unreported spoligotype pattern (10 out of 20 isolates [50.0%]) and isolates belonging to the ST53 lineage (13 out of 25 [52%]) was observed. Isolates of the 'modern' (TbD1-) Euro-American lineage induced higher levels of α1-acid glycoprotein (β = 0.4, P = 0.02; 95% CI [0.06-0.66]) and neutrophil counts (β = 0.9, P = 0.02; 95% CI [0.12-1.64]) and had lower BMI score (β = -1.0, P = 0.04; 95% CI[-1.89 - (-0.03)]). LAM11_ZWE ('modern') isolates induced higher levels of CRP (β = 24.4, P = 0.05; 95% CI[0.24-48.63]) and neutrophil counts (β = 0.9, P = 0.03; 95% CI[0.09-1.70]).

Conclusion: The low diversity of genotypes may be explained by an evolutionary advantage of the most common lineages over other lineages combined with optimal conditions for transmission, such as overcrowding and inadequate ventilation. The induction of higher levels of acute phase reactants in patients infected by 'modern' lineage isolates compared to 'ancient' lineages may suggest increased virulence among 'modern' lineage isolates.
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http://dx.doi.org/10.1186/1471-2334-14-309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057905PMC
June 2014

Diabetes is associated with lower tuberculosis antigen-specific interferon gamma release in Tanzanian tuberculosis patients and non-tuberculosis controls.

Scand J Infect Dis 2014 May 12;46(5):384-91. Epub 2014 Mar 12.

Department of Nutrition, Exercise and Sports, University of Copenhagen , Denmark.

Background: Diabetes is increasingly common in TB endemic regions and plays a role as a possible risk factor for increased progression from latent TB infection (LTBI) to active TB disease. Although the pathophysiological mechanisms are not fully understood, the immune system is weakened in diabetes patients and therefore the validity of interferon gamma release assays (IGRA) may be compromised. The aim of the present study was to assess the association between diabetes and Mycobacterium tuberculosis (Mtb) antigen-specific interferon gamma (IFN-γ) release in a TB endemic area among culture-confirmed TB patients and non-TB controls.

Methods: Culture-confirmed pulmonary TB patients (n = 187) and healthy non-TB neighbourhood controls (n = 190) from Mwanza, Tanzania were tested for the presence of circulating T cells recognizing Mtb antigens using an IGRA. The diabetes status of all participants was assessed using a standard oral glucose tolerance test. The impact of diabetes on the performance of the IGRA was estimated using robust linear and logistic regression.

Results: Compared to normal glucose tolerance, diabetes was associated with reduced levels of Mtb-specific IFN-γ. Increasing levels of fasting blood glucose (B - 0.3, 95% confidence interval - 0.6 to - 0.03, p = 0.033) was negatively associated with IFN-γ. Although TB patients had higher specific and lower unspecific mitogen IFN-γ responses compared to non-TB controls, the association between diabetes and IFN-γ did not depend on TB status.

Conclusion: Diabetes is associated with lower levels of Mtb antigen-specific IFN-γ, and the validity of IFN- γ tests for LTBI may be questionable in individuals with diabetes.
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http://dx.doi.org/10.3109/00365548.2014.885657DOI Listing
May 2014

The prevalence of latent Mycobacterium tuberculosis infection based on an interferon-γ release assay: a cross-sectional survey among urban adults in Mwanza, Tanzania.

PLoS One 2013 21;8(5):e64008. Epub 2013 May 21.

Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.

Introduction: One third of the world's population is estimated to be latently infected with Mycobacterium tuberculosis (LTBI). Surveys of LTBI are rarely performed in resource poor TB high endemic countries like Tanzania although low-income countries harbor the largest burden of the worlds LTBI. The primary objective was to estimate the prevalence of LTBI in household contacts of pulmonary TB cases and a group of apparently healthy neighborhood controls in an urban setting of such a country. Secondly we assessed potential impact of LTBI on inflammation by quantitating circulating levels of an acute phase reactant: alpha-1-acid glycoprotein (AGP) in neighborhood controls.

Methods: The study was nested within the framework of two nutrition studies among TB patients in Mwanza, Tanzania. Household contacts- and neighborhood controls were invited to participate. The study involved a questionnaire, BMI determination and blood samples to measure AGP, HIV testing and a Quantiferon Gold In tube (QFN-IT) test to detect signs of LTBI.

Results: 245 household contacts and 192 neighborhood controls had available QFN-IT data. Among household contacts, the proportion of QFT-IT positive was 59% compared to 41% in the neighborhood controls (p = 0.001). In a linear regression model adjusted for sex, age, CD4 and HIV, a QFT-IT positive test was associated with a 10% higher level of alpha-1-acid glycoprotein(AGP) (10(B) 1.10, 95% CI 1.01; 1.20, p = 0.03), compared to individuals with a QFT-IT negative test.

Conclusion: LTBI is highly prevalent among apparently healthy urban Tanzanians even without known exposure to TB in the household. LTBI was found to be associated with elevated levels of AGP. The implications of this observation merit further studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064008PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660306PMC
November 2013

Diabetes is a strong predictor of mortality during tuberculosis treatment: a prospective cohort study among tuberculosis patients from Mwanza, Tanzania.

Trop Med Int Health 2013 Jul 6;18(7):822-9. Epub 2013 May 6.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg, Denmark.

Objective: Strong evidence suggests diabetes may be associated with tuberculosis (TB) and could influence TB treatment outcomes. We assessed the role of diabetes on sputum culture conversion and mortality among patients undergoing TB treatment.

Methods: A total of 1250 Tanzanian TB patients were followed prospectively during TB treatment with sputum culture after 2 and 5 months. Survival status was assessed at least 1 year after initiation of treatment. At baseline, all participants underwent testing for diabetes and HIV, and the serum concentration of the acute phase reactant alpha-1 glycoprotein (AGP) was determined.

Results: There were no differences between participants with and without diabetes regarding the proportion of positive cultures at 2 (3.8% vs. 5.8%) and 5 (1.3% vs. 0.9%) months (P > 0.46). However, among patients with a positive TB culture, relatively more patients with diabetes died before the 5-month follow-up. Within the initial 100 days of TB treatment, diabetes was associated with a fivefold increased risk of mortality (RR 5.09, 95% CI 2.36; 11.02, P < 0.001) among HIV uninfected, and a twofold increase among HIV co-infected patient (RR 2.33 95% CI 1.20; 4.53, P = 0.012), while diabetes was not associated with long-term mortality. Further adjustment with AGP did not change the estimates.

Conclusion: Diabetes considerably increases risk of early mortality during TB treatment. The effect may not be explained by increased severity of TB, but could be due to impaired TB treatment response. Research is needed to clarify the mechanism and to assess whether glycaemic control improves survival.
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http://dx.doi.org/10.1111/tmi.12120DOI Listing
July 2013

Sex, smoking, and socioeconomic status are associated with body composition among tuberculosis patients in a deuterium dilution cross-sectional study in Mwanza, Tanzania.

J Nutr 2013 May 20;143(5):735-41. Epub 2013 Mar 20.

National Institute for Medical Research, Mwanza Centre, Tanzania.

Underweight is common among tuberculosis (TB) patients. However, there is little information on determinants of body composition at TB treatment initiation in high-TB-burdened countries. This study aimed to determine factors associated with body composition at commencement of TB treatment in Mwanza, Tanzania. A cross-sectional study was conducted from 2007 to 2008 among newly diagnosed TB patients. Fat and fat-free mass were determined using a deuterium dilution technique and fat and fat-free mass indices were computed. Correlates were assessed using multiple regression analysis. A total of 201 pulmonary TB patients were recruited; of these, 37.8% (76) were female, 51.7% (104) were HIV infected, 65.3% (126) had sputum-positive TB, and 24.4% (49) were current smokers. In multiple regressions analysis, males had a 2.2-kg/m(2) [(95% CI = 1.6, 2.9); P < 0.0001] lower fat mass index but 1.5 kg/m(2) [(95% CI = 0.9, 2.0); P < 0.0001] higher fat-free mass index compared with females. Sputum-positive TB was associated with a lower fat mass index among HIV-uninfected patients [-1.4 kg (95% CI = -2.5, -0.4); P = 0.006] but not among HIV-infected patients (P-interaction = 0.09). Current smokers had a 0.7-kg/m(2) [(95% CI = 0.02, 1.5); P = 0.045] lower fat mass index, but smoking did not affect fat-free mass. High socioeconomic status (SES) was associated with higher fat as well as fat-free mass. HIV infection, cluster of differentiation 4 count, and antiretroviral therapy were not correlates. Sex, smoking, and SES were associated with body composition of TB patients at treatment commencement. Prospective studies are needed to determine the role of these factors on weight gain, functional recovery, and survival during and after treatment.
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http://dx.doi.org/10.3945/jn.112.168997DOI Listing
May 2013

Inflammatory markers in the second trimester prior to clinical onset of preeclampsia, intrauterine growth restriction, and spontaneous preterm birth.

Inflammation 2013 Aug;36(4):907-13

Department of Obstetrics and Gynaecology, Hvidovre Hospital, University of Copenhagen, Kettegaard Allé 30, 2650 Hvidovre, Denmark.

Low-grade inflammation has been associated with pregnancy complications including preeclampsia (PE), intrauterine growth restriction (IUGR), and spontaneous preterm birth (SPB). In an unmatched, nested case-control study, we assessed the possible predictive association of maternal C-reactive protein (CRP), interferon-γ-inducible protein 10 (IP-10), and soluble urokinase plasminogen activator receptor (suPAR) in second trimester plasma samples in relation to later development of PE (n = 29), IUGR (n = 53), and SPB (n = 9). Inflammatory marker levels in these groups were compared to normotensive healthy pregnant controls (n = 127). We found no statistically significant difference in CRP, IP-10, or suPAR in second trimester plasma samples from pregnant women with later PE, IUGR, and SPB when compared to normotensive healthy controls. Second trimester plasma samples of CRP, IP-10, and suPAR cannot be used as a prognostic marker for PE, IUGR, and SPB.
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http://dx.doi.org/10.1007/s10753-013-9619-xDOI Listing
August 2013

Dried plasma spots in the diagnosis of tuberculosis: IP-10 release assay on filter paper.

Eur Respir J 2013 Aug 24;42(2):495-503. Epub 2013 Jan 24.

Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.

Interferon (IFN)-γ release assays (IGRAs) are probably the most accurate tests for the detection of latent Mycobacterium tuberculosis infection, but IGRAs are labour intensive and the transport of samples over longer distances is difficult. IFN-γ-induced protein (IP)-10 is expressed at 100-fold higher levels than IFN-γ, and IP-10 release assays have comparable performance to IGRAs. The aim of this study was to explore the diagnostic potential of a novel IP-10 release assay based on dried plasma spots (DPS). The presence of IP-10 and IFN-γ was determined in plasma and in DPS by ELISA. Diagnostic algorithms for plasma and DPS tests for IP-10 were developed on a training cohort comprising 60 tuberculosis (TB) patients and 59 healthy controls. Diagnostic accuracy was assessed in a validation cohort comprising 78 TB patients and 98 healthy controls. Plasma was measured in Spain and DPS samples were sent to Denmark using the conventional postal service for analysis. IP-10 was readily detectable in both plasma and DPS, and correlation was excellent (r(2) = 0.95). QuantiFERON-TB Gold In-Tube (QFT-TB) and IP-10 in DPS and plasma rendered comparable sensitivity (78%, 82% and 84%, respectively), specificity (100%, 97% and 97%, respectively) and indeterminate rates (p>0.55). The DPS-based IP-10 test has comparable diagnostic accuracy to the QFT-TB and samples can be sent via conventional mail over long distances for analysis without affecting the results.
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http://dx.doi.org/10.1183/09031936.00129412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729975PMC
August 2013

Negative effect of smoking on the performance of the QuantiFERON TB gold in tube test.

BMC Infect Dis 2012 Dec 27;12:379. Epub 2012 Dec 27.

Clinical Research Centre, Copenhagen University Hospital Hvidovre, Kettegårds Alle 30, 2650, Hvidovre, Denmark.

Background: False negative and indeterminate Interferon Gamma Release Assay (IGRA) results are a well documented problem. Cigarette smoking is known to increase the risk of tuberculosis (TB) and to impair Interferon-gamma (IFN-γ) responses to antigenic challenge, but the impact of smoking on IGRA performance is not known. The aim of this study was to evaluate the effect of smoking on IGRA performance in TB patients in a low and high TB prevalence setting respectively.

Methods: Patients with confirmed TB from Denmark (DK, n = 34; 20 smokers) and Tanzania (TZ, n = 172; 23 smokers) were tested with the QuantiFERON-TB Gold In tube (QFT). Median IFN-γ level in smokers and non smokers were compared and smoking was analysed as a risk factor for false negative and indeterminate QFT results.

Results: Smokers from both DK and TZ had lower IFN-γ antigen responses (median 0.9 vs. 4.2 IU/ml, p = 0.04 and 0.4 vs. 1.6, p < 0.01), less positive (50 vs. 86%, p = 0.03 and 48 vs. 75%, p < 0.01) and more false negative (45 vs. 0%, p < 0.01 and 26 vs. 11%, p = 0.04) QFT results. In Tanzanian patients, logistic regression analysis adjusted for sex, age, HIV and alcohol consumption showed an association of smoking with false negative (OR 17.1, CI: 3.0-99.1, p < 0.01) and indeterminate QFT results (OR 5.1, CI: 1.2-21.3, p = 0.02).

Conclusions: Cigarette smoking was associated with false negative and indeterminate IGRA results in both a high and a low TB endemic setting independent of HIV status.
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http://dx.doi.org/10.1186/1471-2334-12-379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546031PMC
December 2012

[Research training is inadequate among future medical doctors].

Ugeskr Laeger 2012 Oct;174(43):2624-7

PUFF, c/o Studenterhuset Panum, Nørre Allé 8, Copenhagen.

This questionnaire survey investigated interest and activity in pregraduate research among 643 medical students at the Faculty of Health and Medical Sciences at the University of Copenhagen. We find, that although the students show great interest and motivation for research, very few have actual research experience. The students described suboptimal research training, lack of tutoring and facilitation as well as of career counselling. Also, conditions for pregraduate research activities are unequal among the faculties of health sciences in Denmark.
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October 2012

BCG protects against tuberculosis irrespective of HIV status: a matched case-control study in Mwanza, Tanzania.

Thorax 2013 Mar 24;68(3):288-9. Epub 2012 Aug 24.

While BCG vaccine protects against severe tuberculosis (TB) in children, its effect against adult TB is questionable. Furthermore, it is not known if HIV co-infection modifies the effect of BCG. Among 352 pairs of Tanzanian TB cases and matched controls, the BCG scar was associated with a reduced risk of TB (OR 0.3, 95% CI 0.2 to 0.7, p=0.005), irrespective of HIV status (interaction, p=0.623). BCG vaccination considerably reduced the risk of TB, both among individuals with and without HIV infection.
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http://dx.doi.org/10.1136/thoraxjnl-2012-201971DOI Listing
March 2013

The role of diabetes co-morbidity for tuberculosis treatment outcomes: a prospective cohort study from Mwanza, Tanzania.

BMC Infect Dis 2012 Jul 27;12:165. Epub 2012 Jul 27.

Department of Human Nutrition, University of Copenhagen, Frederiksberg, Denmark.

Background: Due to the association between diabetes and pulmonary tuberculosis (TB), diabetes may threaten the control of TB. In a prospective cohort study nested in a nutrition trial, we investigated the role of diabetes on changes in anthropometry, grip strength, and clinical parameters over a five months follow-up period.

Methods: Among pulmonary TB patients with known diabetes status, we assessed anthropometry and clinical parameters (e.g. haemoglobin) at baseline and after two and five months of TB treatment. A linear mixed-effects model (repeated measurements) was used to investigate the role of diabetes during recovery.

Results: Of 1205 TB patients, the mean (standard deviation) age was 36.6 (13.0) years, 40.9% were females, 48.9% were HIV co-infected, and 16.3% had diabetes. TB patients with diabetes co-morbidity experienced a lower weight gain at two (1.3 kg, CI95% 0.5; 2.0, p = 0.001) and five months (1.0 kg, CI95% 0.3; 1.7, p = 0.007). Similarly, the increase in the level of haemoglobin was lower among TB patients with diabetes co-morbidity after two (Δ 0.6 g/dL, CI95% 0.3; 0.9 p < 0.001) and five months (Δ 0.5 g/dL, CI95% 0.2; 0.9 p = 0.004) of TB treatment, respectively.

Conclusion: TB patients initiating TB treatment with diabetes co-morbidity experience delayed recovery of body mass and haemoglobin, which are important for the functional recovery from disease.
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http://dx.doi.org/10.1186/1471-2334-12-165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462148PMC
July 2012

A simple method to quantitate IP-10 in dried blood and plasma spots.

PLoS One 2012 27;7(6):e39228. Epub 2012 Jun 27.

Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.

Background: Antigen specific release of IP-10 is an established marker for infection with M.tuberculosis. Compared to IFN-γ, IP-10 is released in 100-fold higher concentrations enabling the development of novel assays for detection. Dried blood spots are a convenient sample for high throughput newborn screening.

Aim: To develop a robust and sensitive ELISA-based assay for IP-10 detection in plasma, dried blood spots (DBS) and dried plasma spots (DPS); to validate the ELISA in clinically relevant samples; and to assess the performance of the assay for detection of Cytomegalovirus (CMV) and M.tuberculosis specific immune responses.

Method: We raised mice and rat monoclonal antibodies against human IP-10 and developed an ELISA. The assay was validated and applied to the detection of CMV and M.tuberculosis specific responses in 18 patients with immune reactivity towards M.tuberculosis and 32 healthy controls of which 22 had immune reactivity towards CMV and none towards M.tuberculosis. We compared the performance of this new assay to IFN-γ.

Results: The ELISA was reliable for IP-10 detection in both plasma and filter paper samples. The linear range of the ELISA was 2.5-600 pg/ml. IFN-γ was not readily detectable in DPS samples. IP-10 was stabile in filter paper samples for at least 4 weeks at 37 °C. The correlation between IP-10 detected in plasma, DPS and DBS samples was excellent (r(2)>0.97).

Conclusions: This newly developed assay is reliable for IP-10 quantification in plasma, DBS and DPS samples from antigen stimulated and non-stimulated whole blood. The filter paper assays enable easy sample acquisition and transport at ambient temperature e.g. via the postal system. The system can potentially simplify diagnostic assays for M.tuberculosis and CMV infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384664PMC
March 2013

The role of diabetes on the clinical manifestations of pulmonary tuberculosis.

Trop Med Int Health 2012 Jul 11;17(7):877-83. Epub 2012 May 11.

Department of Human Nutrition, University of Copenhagen, Frederiksberg, Denmark.

Objective: Diabetes is associated with pulmonary tuberculosis (TB), possibly due to impaired immunity, and diabetes may exacerbate the clinical manifestations of TB. Our aim was to assess the role of diabetes in the clinical manifestations of TB.

Methods: We studied 1250 patients with pulmonary TB in an urban population in a cross-sectional study in Tanzania. All participants were tested for diabetes and HIV co-infection, and TB culture intensity was assessed. Levels of white blood cells, haemoglobin, acute phase reactants, CD4 count and HIV viral load were measured, and a qualitative morbidity questionnaire was used to identify the prevalence of disease-related symptoms.

Results: Tuberculosis patients with diabetes had a higher neutrophil count (B 0.5 × 10(9) cells/l, 95% CI 0.2; 0.9, P = 0.001) than non-diabetic TB patients. Serum C-reactive protein (B 18.8 mg/l, CI 95% 8.2; 29.4, P = 0.001) and alpha-1-acid glycoprotein (B 0.2 g/l, CI 95% 0.03; 0.3, P = 0.02) were similarly higher in patients with diabetes. Diabetes did not affect culture intensity or HIV status, but self-reported fever was three times higher among participants with diabetes than in those without diabetes (OR 2.9, CI 95% 1.5; 5.7, P = 0.002).

Conclusion: Diabetes is associated with small changes in the manifestations of TB, but may have little clinical significance.
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http://dx.doi.org/10.1111/j.1365-3156.2012.03002.xDOI Listing
July 2012

IP-10 release assays in the diagnosis of tuberculosis infection: current status and future directions.

Expert Rev Mol Diagn 2012 Mar;12(2):175-87

Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.

The current state-of-the-art tests for infection with Mycobacterium tuberculosis - the IFN-γ release assays - rely on accurate measurement of the cytokine IFN-γ. Many other potential biomarkers are expressed in concert with IFN-γ, and IP-10 in particular has shown promising results. IP-10 is produced in large amounts, allowing for the development of new and simplified test platforms, such as lateral flow. In this review, we summarize the results of 22 clinical studies exploring the use of IP-10 as an alternative marker to IFN-γ. The studies report that diagnostic accuracy of IP-10 is on par with IFN-γ, but also that IP-10 may be more robust in young children and in HIV-infected individuals with low CD4 cell counts. We conclude the review by presenting limitations of the published works and outline recent developments and future directions.
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http://dx.doi.org/10.1586/erm.11.97DOI Listing
March 2012

Diabetes is a risk factor for pulmonary tuberculosis: a case-control study from Mwanza, Tanzania.

PLoS One 2011 30;6(8):e24215. Epub 2011 Aug 30.

Department of Human Nutrition, University of Copenhagen, Frederiksberg, Denmark.

Background: Diabetes and TB are associated, and diabetes is increasingly common in low-income countries where tuberculosis (TB) is highly endemic. However, the role of diabetes for TB has not been assessed in populations where HIV is prevalent.

Methods: A case-control study was conducted in an urban population in Tanzania among culture-confirmed pulmonary TB patients and non-TB neighbourhood controls. Participants were tested for diabetes according to WHO guidelines and serum concentrations of acute phase reactants were measured. The association between diabetes and TB, and the role of HIV as an effect modifier, were examined using logistic regression. Since blood glucose levels increase during the acute phase response, we adjusted for elevated serum acute phase reactants.

Results: Among 803 cases and 350 controls the mean (SD) age was 34.8 (11.9) and 33.8 (12.0) years, and the prevalence of diabetes was 16.7% (95% CI: 14.2; 19.4) and 9.4% (6.6; 13.0), respectively. Diabetes was associated with TB (OR 2.2, 95% CI: 1.5; 3.4, p<0.001). However, the association depended on HIV status (interaction, p = 0.01) due to a stronger association among HIV uninfected (OR 4.2, 95% CI: 1.5; 11.6, p = 0.01) compared to HIV infected (OR 0.1, 95% CI: 0.01; 1.8, p = 0.13) after adjusting for age, sex, demographic factors and elevated serum acute phase reactants.

Conclusion: Diabetes is a risk factor for TB in HIV uninfected, whereas the association in HIV infected patients needs further study. The increasing diabetes prevalence may be a threat to TB control.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024215PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166171PMC
December 2011

The effect of energy-protein supplementation on weight, body composition and handgrip strength among pulmonary tuberculosis HIV-co-infected patients: randomised controlled trial in Mwanza, Tanzania.

Br J Nutr 2012 Jan 6;107(2):263-71. Epub 2011 Jul 6.

National Institute for Medical Research, Mwanza Centre, Box 1462, Mwanza, Tanzania.

Undernutrition is common among smear-positive pulmonary tuberculosis (PTB+) patients. Micronutrient supplementation may improve treatment outcomes, but it is unclear whether additional energy-protein would be beneficial. The present study aimed to assess the effect of energy-protein supplementation on weight, body composition and handgrip strength against a background of high micronutrient intake during tuberculosis (TB) treatment. A total of 377 PTB+ patients co-infected with HIV were randomly allocated one or six biscuits daily for 60 d during TB treatment. Weight, arm fat area, arm muscle area and handgrip strength were assessed at baseline and 2 and 5 months. There were no effects on any outcome at 2 months, but energy-protein supplementation was associated with a 1·3 (95 % CI - 0·1, 2·8) kg marginally significant gain in handgrip strength at 5 months. However, after 2 months, energy-protein supplementation led to a weight gain of 1·9 (95 % CI 0·1, 3·7) kg among patients with cluster of differentiation 4 (CD4) counts ≥ 350 cells/μl, but not among patients with low CD4 counts ( - 0·2 kg; 95 % CI - 1·3, 0·8, Pinteraction = 0·03). Similarly, at 5 months, energy-protein supplementation led to a 2·3 (95 % CI 0·6, 4·1) kg higher handgrip strength gain among patients with CD4 counts < 350 cells/μl, but not in those with high CD4 counts (Pinteraction = 0·04). In conclusion, energy-protein supplementation to PTB+ HIV-co-infected patients had no overall effects on weight and body composition, but was associated with marginally significant gain in handgrip strength. More research is needed to develop an effective supplement, before it is recommended to TB programmes.
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http://dx.doi.org/10.1017/S0007114511002832DOI Listing
January 2012

Incubation of whole blood at 39°C augments gamma interferon (IFN-γ)-induced protein 10 and IFN-γ responses to Mycobacterium tuberculosis antigens.

Clin Vaccine Immunol 2011 Jul 25;18(7):1150-6. Epub 2011 May 25.

Clinical Research Centre, University of Copenhagen, Hvidovre Hospital, Copenhagen 2650, Denmark.

A rarely challenged dogma in cell-mediated immune (CMI) assays is the incubation temperature, 37°C. Fever augments proinflammatory immune responses in vivo, and the aim of this study was to explore whether incubation at fever-range temperature could increase antigen-specific biomarker responses. We compared CMI responses following incubation of whole blood at 37°C and 39°C. Whole blood was obtained from (i) 34 healthy subjects whose blood was incubated with TB10.4 antigen, present in the Mycobacterium bovis bacillus Calmette-Guérin vaccine and many environmental mycobacteria; (ii) 8 TB patients and 8 controls incubated with Mycobacterium tuberculosis-specific antigens in the QuantiFERON-TB Gold test (QFT-IT); and (iii) from both groups incubated with a T cell mitogen. T cell responses (gamma interferon [IFN-γ]) and responses from antigen-presenting cells (IFN-γ-induced protein 10 [IP-10]) were determined. We further evaluated the effect of adding interleukin-7 (IL-7) and blocking IL-10 during incubation. In TB patients, IFN-γ and IP-10 levels were increased 4.1- and 3.4-fold, respectively, at 39°C incubation (P < 0.001). Similar results were seen after mitogen stimulation. In subjects responding to TB10.4, the effects were less pronounced and significant only for IP-10. Incubation at 39°C increased IP-10 and IFN-γ responsiveness to both antigens and mitogen in persons with baseline or initial low responses. Adding IL-7 and blocking IL-10 augmented the effects in synergy with fever-range temperature. Incubation at fever-range temperature vividly increases CMI responsiveness to antigen stimulation in vitro in tuberculosis patients and may increase the sensitivity of CMI assays.
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http://dx.doi.org/10.1128/CVI.00051-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147319PMC
July 2011

Daily multi-micronutrient supplementation during tuberculosis treatment increases weight and grip strength among HIV-uninfected but not HIV-infected patients in Mwanza, Tanzania.

J Nutr 2011 Apr 23;141(4):685-91. Epub 2011 Feb 23.

National Institute for Medical Research, Mwanza Centre Mwanza, Tanzania.

Undernutrition is common among tuberculosis (TB) patients. The objective of this study was to assess the effect of multi-micronutrient supplementation during TB treatment on weight, body composition, and handgrip strength. A total of 865 patients with smear-positive (PTB+) or -negative (PTB-) pulmonary TB were randomly allocated to receive a daily biscuit with or without multi-micronutrients for 60 d during the intensive phase of TB treatment. Weight, arm fat area, arm muscle area, and handgrip strength were assessed at baseline and after 2 and 5 mo. At 2 mo, the multi-micronutrient supplementation led to a higher handgrip gain (1.22 kg; 95% CI = 0.50, 1.94; P = 0.001) but had no effects on other outcomes. The effects of multi-micronutrient supplementation were modified by HIV infection (P-interaction = 0.002). Among HIV- patients, multi-micronutrient supplementation increased weight gain by 590 g (95% CI = -40, 1210; P = 0.07) and handgrip strength by 1.6 kg (95% CI = 0.78, 2.47; P < 0.001), whereas among HIV+ patients, it reduced weight gain by 1440 g (95% CI = 290, 2590; P = 0.002) and had no effect on handgrip strength (0.07 kg; 95% CI = -1.30, 1.46; P = 0.91). The reduced weight gain among HIV+ patients receiving multi-micronutrient supplementation seemed to be explained by a higher proportion of patients reporting fever. At 5 mo, the effects on weight were sustained, whereas there was no effect on handgrip strength. In conclusion, multi-micronutrient supplementation given as a biscuit is beneficial among HIV- PTB patients and may be recommended to TB programs. More research is needed to develop an effective supplement for HIV+ PTB patients.
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http://dx.doi.org/10.3945/jn.110.131672DOI Listing
April 2011

Weight, body composition and handgrip strength among pulmonary tuberculosis patients: a matched cross-sectional study in Mwanza, Tanzania.

Trans R Soc Trop Med Hyg 2011 Mar 15;105(3):140-7. Epub 2011 Jan 15.

National Institute for Medical Research, Mwanza Centre, P.O. Box 1462, Mwanza, Tanzania.

This study aimed to estimate deficits in weight, arm fat area (AFA), arm muscle area (AMA) and handgrip strength among smear-positive pulmonary TB (PTB+) patients starting treatment. We conducted a cross-sectional study among PTB+ patients and age- and sex-matched neighborhood controls. HIV status, anthropometric measurements and handgrip strength were determined. Deficits in weight, AFA, AMA and handgrip strength associated with PTB+ and HIV were estimated using multiple regression analysis. We recruited 355 pairs of PTB+ patients and controls. PTB+ was associated with deficits of 10.0kg (95% CI 7.3; 12.7) in weight and 6.8kg (95% CI 5.2; 8.3) in handgrip strength among females and 9.1kg (95% CI 7.3; 10.9) in weight and 6.8kg (95% CI 5.2; 8.4) in handgrip strength among males. In both sexes, PTB+ was associated with deficits in AFA and AMA. Among females, HIV was associated with deficits in AMA and handgrip strength, but the deficit in handgrip strength was larger among PTB+ patients (3.2kg 95% CI 1.3; 5.2) than controls (-1.6kg 95% CI -4.8; 1.5) (interaction, P=0.009). These findings suggest that deficits in weight and handgrip strength among patients starting TB treatment are severe. Thus, nutritional support may be necessary to ensure reversal of the deficits, and may improve treatment outcomes.
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http://dx.doi.org/10.1016/j.trstmh.2010.11.009DOI Listing
March 2011

The impact of HIV infection and CD4 cell count on the performance of an interferon gamma release assay in patients with pulmonary tuberculosis.

PLoS One 2009 19;4(1):e4220. Epub 2009 Jan 19.

Department of Infectious Diseases, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.

Background: The performance of the tuberculosis specific Interferon Gamma Release Assays (IGRAs) has not been sufficiently documented in tuberculosis- and HIV-endemic settings. This study evaluated the sensitivity of the QuantiFERON TB-Gold In-Tube (QFT-IT) in patients with culture confirmed pulmonary tuberculosis (PTB) in a TB- and HIV-endemic population and the effect of HIV-infection and CD4 cell count on test performance.

Methodology/principal Findings: 161 patients with sputum culture confirmed PTB were subjected to HIV- and QFT-IT testing and measurement of CD4 cell count. The QFT-IT was positive in 74% (119/161; 95% CI: 67-81%). Sensitivity was higher in HIV-negative (75/93) than in HIV-positive (44/68) patients (81% vs. 65%, p = 0.02) and increased with CD4 cell count in HIV-positive patients (test for trend p = 0.03). 23 patients (14%) had an indeterminate result and this proportion decreased with increasing CD4 cell count in HIV-positive patients (test for trend p = 0.03). Low CD4 cell count (<300 cells/microl) did not account for all QFT-IT indeterminate nor all negative results. Sensitivity when excluding indeterminate results was 86% (95% CI: 81-92%) and did not differ between HIV-negative and HIV-positive patients (88 vs. 83%, p = 0.39).

Conclusions/significance: Sensitivity of the QFT-IT for diagnosing active PTB infection was reasonable when excluding indeterminate results and in HIV-negative patients. However, since the test missed more than 10% of patients, its potential as a rule-out test for active TB disease is limited. Furthermore, test performance is impaired by low CD4 cell count in HIV-positive patients and possibly by other factors as well in both HIV-positive and HIV-negative patients. This might limit the potential of the test in populations where HIV-infection is prevalent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004220PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2626632PMC
May 2009
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