The level of bacterial activity is only poorly defined during asymptomatic Mycobacterium tuberculosis (MTB) infection. The objective was to study the capacity of a new biomarker, the expression of the T cell maturation marker CD27 on MTB-specific CD4 T cells, to identify active tuberculosis (TB) disease in subjects from a MTB and HIV endemic region. The frequency and CD27 expression of circulating MTB-specific CD4 T cells was determined in 96 study participants after stimulation with purified protein derivative (PPD) using intracellular cytokine staining for IFNgamma (IFNγ). Subjects were then stratified by their TB and HIV status. Within PPD responders, a CD27− phenotype was associated with active TB in HIV− (p = 0.0003) and HIV+ (p = 0.057) subjects, respectively. In addition, loss of CD27 expression preceded development of active TB in one HIV seroconverter. Interestingly, in contrast to HIV− subjects, MTB-specific CD4 T cell populations from HIV+ TB-asymptomatic subjects were often dominated by CD27− cells. These data indicate that down-regulation of CD27 on MTB-specific CD4 T cell could be used as a biomarker of active TB, potentially preceding clinical TB disease. Furthermore, these data are consistent with the hypothesis that late, chronic HIV infection is frequently associated with increased mycobacterial activity in vivo. The analysis of T cell maturation and activation markers might thus be a useful tool to monitor TB disease progression.
Identification and evaluation of diagnostic biomarkers that predict TB disease progression are elaborate and complicated undertakings, since the number of incident cases even in high risk study populations is usually low and the definition of latent M.tb infection through a positive TST or IGRA test result is inaccurate. Using a retrospective case–control study approach embedded in the Amsterdam Cohort Studies on HIV infection and AIDS (Van Den Hoek et al., 1988Van Den Hoek J.A. Coutinho R.A. Van Haastrecht H.J. Van Zadelhoff A.W. Goudsmit J. Prevalence and risk factors of HIV infections among drug users and drug-using prostitutes in Amsterdam.AIDS. 1988; 2: 55-60Crossref PubMed Scopus (198) Google Scholar), Sloot et al., in pressSloot R. Van Der Loeff M.F.S. Vanzwet E.W. Haks M.C. Keizer S.T. Scholing M. Ottenhoff T.H.M. Borgdorff M.W. Joosten S.A. Biomarkers can identify pulmonary tuberculosis in HIV-infected drug users months prior to clinical diagnosis.EBioMed. 2015; (in press)https://doi.org/10.1016/j.ebiom.2014.12.001Summary Full Text Full Text PDF Scopus (29) Google Scholar identify a transcriptional signature within Peripheral Blood Mononuclear Cells, which identifies HIV-positive subjects who are later diagnosed with active TB disease. 55 to 250 days prior to TB diagnosis, IL13 transcription was detected in six out of 14 TB progressors and linked to differential expression of 50 additional genes, including type I IFN signature genes, while no subject in the control group expressed IL13. It can be assumed that this signature is part of an early host immune response to mycobacterial replication in vivo. Whether it is a hallmark of deficient immunological control of the pathogen invariably linked to progressive disease or rather reflective of pathogen activity independent of subsequent disease progression remains unclear.The study by Sloot et al. supports the concept that a diagnostic approach based on host biomarkers cannot only improve the diagnosis of active TB in populations where a conventional sputum-based diagnosis is difficult (e.g. in children, HIV-positives, extra-pulmonary TB), but might further allow identification of subjects with sub-clinically active M.tb replication. Other recent articles also highlighted the potential of host biomarkers based on transcriptional (Anderson et al., 2014Anderson S.T. Kaforou M. Brent A.J. Wright V.J. Banwell C.M. Chagaluka G. Crampin A.C. Dockrell H.M. French N. Hamilton M.S. Hibberd M.L. Kern F. Langford P.R. Ling L. Mlotha R. Ottenhoff T.H. Pienaar S. Pillay V. Scott J.A. Twahir H. Wilkinson R.J. Coin L.J. Heyderman R.S. Levin M. Eley B. Consortium I. Group K.T.S. Diagnosis of childhood tuberculosis and host RNA expression in Africa.N. Engl. J. Med. 2014; 370: 1712-1723Crossref PubMed Scopus (230) Google Scholar, Joosten et al., 2012Joosten S.A. Goeman J.J. Sutherland J.S. Opmeer L. De Boer K.G. Jacobsen M. Kaufmann S.H. Finos L. Magis-Escurra C. Ota M.O. Ottenhoff T.H. Haks M.C. Identification of biomarkers for tuberculosis disease using a novel dual-color RT-MLPA assay.Genes Immunol. 2012; 13: 71-82Crossref PubMed Scopus (80) Google Scholar) or novel T cell signatures (Portevin et al., 2014Portevin D. Moukambi F. Clowes P. Bauer A. Chachage M. Ntinginya N.E. Mfinanga E. Said K. Haraka F. Rachow A. Saathoff E. Mpina M. Jugheli L. Lwilla F. Marais B.J. Hoelscher M. Daubenberger C. Reither K. Geldmacher C. Assessment of the novel T-cell activation marker-tuberculosis assay for diagnosis of active tuberculosis in children: a prospective proof-of-concept study.Lancet Infect. Dis. 2014; 14: 931-938Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar, Harari et al., 2011Harari A. Rozot V. Enders F.B. Perreau M. Stalder J.M. Nicod L.P. Cavassini M. Calandra T. Blanchet C.L. Jaton K. Faouzi M. Day C.L. Hanekom W.A. Bart P.A. Pantaleo G. Dominant TNF-alpha + Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease.Nat. Med. 2011; 17: 372-376Crossref PubMed Scopus (302) Google Scholar, Schuetz et al., 2011Schuetz A. Haule A. Reither K. Ngwenyama N. Rachow A. Meyerhans A. Maboko L. Koup R.A. Hoelscher M. Geldmacher C. Monitoring CD27 expression to evaluate mycobacterium tuberculosis activity in HIV-1 infected individuals in vivo.PLoS One. 2011; 6: e27284Crossref PubMed Scopus (39) Google Scholar) to improve diagnosis of active TB and possibly also allow early detection of TB disease progression. It is widely accepted that often a substantial time interval exists between infection with M.tb, and diagnosis of symptomatic disease. Individuals who develop active TB disease after primary infection frequently do so within the first two years (Marais et al., 2004Marais B.J. Gie R.P. Schaaf H.S. Hesseling A.C. Obihara C.C. Starke J.J. Enarson D.A. Donald P.R. Beyers N. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era.Int. J. Tuberc. Lung Dis. 2004; 8: 392-402PubMed Google Scholar). This specific characteristic of M.tb infection provides a window of opportunity for more accurate identification of individuals currently progressing to active TB using such novel biomarkers and to target them for early therapeutic intervention. Particularly in high risk populations such as HIV-positives, TB-contacts or IFN-gamma release assay converters (or TST skin-test converters) this approach might be more attractive than the current suboptimal algorithms with very limited specificity to trigger isoniazid preventive treatment, which likely result in overtreatment (American Thoracic Society, 2000American Thoracic Society Targeted tuberculin testing and treatment of latent tuberculosis infection.MMWR Recomm. Rep. 2000; 49: 1-51Google Scholar). The use of novel host biomarkers in such a strategy would not only help to significantly reduce TB disease morbidity by detection of those subjects with the highest risk of active TB development in a “pre-clinical” stadium and motivating them and the treating medical staff to adhere to preventive treatment, but could also help to abrogate the MTB transmission chain and hence contribute to the EndTB Strategy by WHO and to the vision of a world free of TB in 2050 (WHO, 2014WHO http://www.who.int/tb/features_archive/researchforTBelimination_meeting/en/Date: 2014Google Scholar).Future research in the field of host biomarkers predictive of TB disease should be aiming at simplifying current diagnostic approaches into affordable products applicable on a large scale. Simultaneously, prospective large scale studies on early detection of progressive TB disease will be necessary (even though complicated to conduct) to further confirm the diagnostic accuracy and feasibility of these novel biomarkers in the field. Especially, the specificity for progressive versus non-progressive/latent M.tb infection needs to be assessed, as well as the biomarkers ability to distinguish between TB and other inflammatory diseases. An assessment of host biomarkers would require validation work in patient populations with different genetic backgrounds, as ethnicity can influence the composition of the host response, making such studies even larger. Significant effort is still required until the application of such novel diagnostic strategies on a large scale could be achieved. Nonetheless, new diagnostic host markers for early identification of progressive TB disease might herald a new era in TB diagnosis and early treatment.Conflicts of interestThe authors declared no conflicts of interest. Identification and evaluation of diagnostic biomarkers that predict TB disease progression are elaborate and complicated undertakings, since the number of incident cases even in high risk study populations is usually low and the definition of latent M.tb infection through a positive TST or IGRA test result is inaccurate. Using a retrospective case–control study approach embedded in the Amsterdam Cohort Studies on HIV infection and AIDS (Van Den Hoek et al., 1988Van Den Hoek J.A. Coutinho R.A. Van Haastrecht H.J. Van Zadelhoff A.W. Goudsmit J. Prevalence and risk factors of HIV infections among drug users and drug-using prostitutes in Amsterdam.AIDS. 1988; 2: 55-60Crossref PubMed Scopus (198) Google Scholar), Sloot et al., in pressSloot R. Van Der Loeff M.F.S. Vanzwet E.W. Haks M.C. Keizer S.T. Scholing M. Ottenhoff T.H.M. Borgdorff M.W. Joosten S.A. Biomarkers can identify pulmonary tuberculosis in HIV-infected drug users months prior to clinical diagnosis.EBioMed. 2015; (in press)https://doi.org/10.1016/j.ebiom.2014.12.001Summary Full Text Full Text PDF Scopus (29) Google Scholar identify a transcriptional signature within Peripheral Blood Mononuclear Cells, which identifies HIV-positive subjects who are later diagnosed with active TB disease. 55 to 250 days prior to TB diagnosis, IL13 transcription was detected in six out of 14 TB progressors and linked to differential expression of 50 additional genes, including type I IFN signature genes, while no subject in the control group expressed IL13. It can be assumed that this signature is part of an early host immune response to mycobacterial replication in vivo. Whether it is a hallmark of deficient immunological control of the pathogen invariably linked to progressive disease or rather reflective of pathogen activity independent of subsequent disease progression remains unclear. The study by Sloot et al. supports the concept that a diagnostic approach based on host biomarkers cannot only improve the diagnosis of active TB in populations where a conventional sputum-based diagnosis is difficult (e.g. in children, HIV-positives, extra-pulmonary TB), but might further allow identification of subjects with sub-clinically active M.tb replication. Other recent articles also highlighted the potential of host biomarkers based on transcriptional (Anderson et al., 2014Anderson S.T. Kaforou M. Brent A.J. Wright V.J. Banwell C.M. Chagaluka G. Crampin A.C. Dockrell H.M. French N. Hamilton M.S. Hibberd M.L. Kern F. Langford P.R. Ling L. Mlotha R. Ottenhoff T.H. Pienaar S. Pillay V. Scott J.A. Twahir H. Wilkinson R.J. Coin L.J. Heyderman R.S. Levin M. Eley B. Consortium I. Group K.T.S. Diagnosis of childhood tuberculosis and host RNA expression in Africa.N. Engl. J. Med. 2014; 370: 1712-1723Crossref PubMed Scopus (230) Google Scholar, Joosten et al., 2012Joosten S.A. Goeman J.J. Sutherland J.S. Opmeer L. De Boer K.G. Jacobsen M. Kaufmann S.H. Finos L. Magis-Escurra C. Ota M.O. Ottenhoff T.H. Haks M.C. Identification of biomarkers for tuberculosis disease using a novel dual-color RT-MLPA assay.Genes Immunol. 2012; 13: 71-82Crossref PubMed Scopus (80) Google Scholar) or novel T cell signatures (Portevin et al., 2014Portevin D. Moukambi F. Clowes P. Bauer A. Chachage M. Ntinginya N.E. Mfinanga E. Said K. Haraka F. Rachow A. Saathoff E. Mpina M. Jugheli L. Lwilla F. Marais B.J. Hoelscher M. Daubenberger C. Reither K. Geldmacher C. Assessment of the novel T-cell activation marker-tuberculosis assay for diagnosis of active tuberculosis in children: a prospective proof-of-concept study.Lancet Infect. Dis. 2014; 14: 931-938Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar, Harari et al., 2011Harari A. Rozot V. Enders F.B. Perreau M. Stalder J.M. Nicod L.P. Cavassini M. Calandra T. Blanchet C.L. Jaton K. Faouzi M. Day C.L. Hanekom W.A. Bart P.A. Pantaleo G. Dominant TNF-alpha + Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease.Nat. Med. 2011; 17: 372-376Crossref PubMed Scopus (302) Google Scholar, Schuetz et al., 2011Schuetz A. Haule A. Reither K. Ngwenyama N. Rachow A. Meyerhans A. Maboko L. Koup R.A. Hoelscher M. Geldmacher C. Monitoring CD27 expression to evaluate mycobacterium tuberculosis activity in HIV-1 infected individuals in vivo.PLoS One. 2011; 6: e27284Crossref PubMed Scopus (39) Google Scholar) to improve diagnosis of active TB and possibly also allow early detection of TB disease progression. It is widely accepted that often a substantial time interval exists between infection with M.tb, and diagnosis of symptomatic disease. Individuals who develop active TB disease after primary infection frequently do so within the first two years (Marais et al., 2004Marais B.J. Gie R.P. Schaaf H.S. Hesseling A.C. Obihara C.C. Starke J.J. Enarson D.A. Donald P.R. Beyers N. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era.Int. J. Tuberc. Lung Dis. 2004; 8: 392-402PubMed Google Scholar). This specific characteristic of M.tb infection provides a window of opportunity for more accurate identification of individuals currently progressing to active TB using such novel biomarkers and to target them for early therapeutic intervention. Particularly in high risk populations such as HIV-positives, TB-contacts or IFN-gamma release assay converters (or TST skin-test converters) this approach might be more attractive than the current suboptimal algorithms with very limited specificity to trigger isoniazid preventive treatment, which likely result in overtreatment (American Thoracic Society, 2000American Thoracic Society Targeted tuberculin testing and treatment of latent tuberculosis infection.MMWR Recomm. Rep. 2000; 49: 1-51Google Scholar). The use of novel host biomarkers in such a strategy would not only help to significantly reduce TB disease morbidity by detection of those subjects with the highest risk of active TB development in a “pre-clinical” stadium and motivating them and the treating medical staff to adhere to preventive treatment, but could also help to abrogate the MTB transmission chain and hence contribute to the EndTB Strategy by WHO and to the vision of a world free of TB in 2050 (WHO, 2014WHO http://www.who.int/tb/features_archive/researchforTBelimination_meeting/en/Date: 2014Google Scholar). Future research in the field of host biomarkers predictive of TB disease should be aiming at simplifying current diagnostic approaches into affordable products applicable on a large scale. Simultaneously, prospective large scale studies on early detection of progressive TB disease will be necessary (even though complicated to conduct) to further confirm the diagnostic accuracy and feasibility of these novel biomarkers in the field. Especially, the specificity for progressive versus non-progressive/latent M.tb infection needs to be assessed, as well as the biomarkers ability to distinguish between TB and other inflammatory diseases. An assessment of host biomarkers would require validation work in patient populations with different genetic backgrounds, as ethnicity can influence the composition of the host response, making such studies even larger. Significant effort is still required until the application of such novel diagnostic strategies on a large scale could be achieved. Nonetheless, new diagnostic host markers for early identification of progressive TB disease might herald a new era in TB diagnosis and early treatment. Conflicts of interestThe authors declared no conflicts of interest. The authors declared no conflicts of interest. Biomarkers Can Identify Pulmonary Tuberculosis in HIV-infected Drug Users Months Prior to Clinical DiagnosisWe here demonstrated that biomarkers, such as IL13-AIRE, can identify individuals that progress to TB within a high risk population, months prior to clinical diagnosis. Full-Text PDF Open Access
To control the global HIV epidemic, targeted interventions to reduce the incidence of HIV infections are urgently needed until an effective HIV vaccine is available. This study describes HIV-1 incidence and associated risk factors in a general population cohort of adults from Mbeya region, Tanzania, who participated in a vaccine preparedness study.We conducted a closed prospective cohort study with 6-monthly follow-up from 2002 to 2006 enrolling adults from the general population. HIV-1 incidence and risk factors for HIV-1 acquisition were analyzed using Cox regression.We observed 2578 seronegative participants for a mean period of 3.06 person years (PY) (7471 PY in total). Overall HIV-1 incidence was 1.35 per 100 PY (95% confidence interval [CI], 1.10-1.64/100 PY). The highest overall HIV-1 incidence was found in females from Itende village (1.55 per 100 PY; 95% CI, 0.99-2.30/100 PY); the highest age-specific incidence was observed in semiurban males aged 30 to 34 years (2.75 per 100 PY; 95% CI, 0.75-7.04). HIV-1 acquisition was independently associated with female gender (hazard ratio [HR], 1.64; 95% CI, 1.05-2.57), younger age at enrollment (age 18-19 versus 35-39 years: HR, 0.29; 95% CI, 0.11-0.75), alcohol consumption (almost daily versus none: HR, 2.01; 95% CI, 1.00-4.07), education level (secondary school versus none: HR, 0.39; 95% CI, 0.17-0.89), and number of lifetime sex partners (more than five versus one: HR, 2.22; 95% CI, 1.13-4.36).A high incidence of HIV was observed in this cohort, and incident infection was strongly associated with young age, alcohol consumption, low school education level, and number of sex partners. Targeted interventions are needed to address the elevated risk associated with these factors.
Abstract Background Noninfectious comorbid diseases (NCDs) contribute to morbidity and mortality in human immunodeficiency virus (HIV)–infected populations in resource-rich countries. With antiretroviral therapy (ART) scale-up in Africa, understanding burden NCD informs public health strategy. Methods At enrollment, participants at 11 HIV clinics in Kenya, Uganda, Tanzania, and Nigeria underwent medical history, physical, laboratory, and neuropsychological assessments to identify elevated blood pressure, hypercholesterolemia, dysglycemia, renal insufficiency, and cognitive impairment. Poisson regression models estimated adjusted relative risks (ARRs) and 95% confidence intervals (CIs) for the number of NCDs associated with factors of interest. Logistic regression was used to evaluate each NCD separately among HIV-infected participants. Results Among 2720 participants with complete NCD data, 2159 (79.4%) were HIV-infected. Of those, 1426 (66.0%) were taking ART and 813 (37.7%) had at least 1 NCD. HIV infection was associated with more NCDs, especially with ART (ARR, 1.42; 95% CI, 1.22–1.66). In addition to age, body mass index, and program site, ART usage was associated with more NCDs (ARR, 1.50; 95% CI, 1.27–1.78 for virologically suppressed and ARR, 1.38; 95% CI, 1.13–1.68 for viremic) among HIV-infected participants. In participants taking ART, CD4 nadir below 200 cells/mm3 was associated with more NCDs (ARR, 1.43; 95% CI, 1.06–1.93). ART use was independently associated with hypercholesterolemia and dysglycemia. Program site was significantly associated with all comorbidities except renal insufficiency. Conclusions HIV infection was a risk for NCDs, which were common in HIV-infected participants, geographically variable, and largely consistent with metabolic complications of first-line ART.
Abstract Despite intensive research since the emergence of SARS-CoV-2, it has remained unclear precisely which components of the early immune response protect against the development of severe COVID-19. Here, we perform a comprehensive immunogenetic and virologic analysis of nasopharyngeal and peripheral blood samples obtained during the acute phase of infection with SARS-CoV-2. We find that soluble and transcriptional markers of systemic inflammation peak during the first week after symptom onset and correlate directly with upper airways viral loads (UA-VLs), whereas the contemporaneous frequencies of circulating viral nucleocapsid (NC)-specific CD4 + and CD8 + T cells correlate inversely with various inflammatory markers and UA-VLs. In addition, we show that high frequencies of activated CD4 + and CD8 + T cells are present in acutely infected nasopharyngeal tissue, many of which express genes encoding various effector molecules, such as cytotoxic proteins and IFN-γ. The presence of IFNG mRNA-expressing CD4 + and CD8 + T cells in the infected epithelium is further linked with common patterns of gene expression among virus-susceptible target cells and better local control of SARS-CoV-2. Collectively, these results identify an immune correlate of protection against SARS-CoV-2, which could inform the development of more effective vaccines to combat the acute and chronic illnesses attributable to COVID-19.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant of concern (VOC) resists neutralization by major classes of antibodies from COVID-19 patients and vaccinated individuals. In this study, serum of Beta-infected patients revealed reduced cross-neutralization of wild-type virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of VOC-specific clonotypes and accommodation of mutations present in Beta and Omicron into a major antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with wild type-elicited antibodies, including a public VH1-58 clonotype that targets the RBD ridge. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift, with implications for design of next-generation vaccines and therapeutics.
Population-based serological studies allow to estimate prevalence of SARS-CoV-2 infections despite a substantial number of mild or asymptomatic disease courses. This became even more relevant for decision making after vaccination started. The KoCo19 cohort tracks the pandemic progress in the Munich general population for over two years, setting it apart in Europe.Recruitment occurred during the initial pandemic wave, including 5313 participants above 13 years from private households in Munich. Four follow-ups were held at crucial times of the pandemic, with response rates of at least 70%. Participants filled questionnaires on socio-demographics and potential risk factors of infection. From Follow-up 2, information on SARS-CoV-2 vaccination was added. SARS-CoV-2 antibody status was measured using the Roche Elecsys® Anti-SARS-CoV-2 anti-N assay (indicating previous infection) and the Roche Elecsys® Anti-SARS-CoV-2 anti-S assay (indicating previous infection and/or vaccination). This allowed us to distinguish between sources of acquired antibodies.The SARS-CoV-2 estimated cumulative sero-prevalence increased from 1.6% (1.1-2.1%) in May 2020 to 14.5% (12.7-16.2%) in November 2021. Underreporting with respect to official numbers fluctuated with testing policies and capacities, becoming a factor of more than two during the second half of 2021. Simultaneously, the vaccination campaign against the SARS-CoV-2 virus increased the percentage of the Munich population having antibodies, with 86.8% (85.5-87.9%) having developed anti-S and/or anti-N in November 2021. Incidence rates for infections after (BTI) and without previous vaccination (INS) differed (ratio INS/BTI of 2.1, 0.7-3.6). However, the prevalence of infections was higher in the non-vaccinated population than in the vaccinated one. Considering the whole follow-up time, being born outside Germany, working in a high-risk job and living area per inhabitant were identified as risk factors for infection, while other socio-demographic and health-related variables were not. Although we obtained significant within-household clustering of SARS-CoV-2 cases, no further geospatial clustering was found.Vaccination increased the coverage of the Munich population presenting SARS-CoV-2 antibodies, but breakthrough infections contribute to community spread. As underreporting stays relevant over time, infections can go undetected, so non-pharmaceutical measures are crucial, particularly for highly contagious strains like Omicron.
Background With one quarter of the world population infected, the intestinal nematode Ascaris lumbricoides is one of the most common infectious agents, especially in the tropics and sub-tropics. Infection is caused by oral intake of eggs and can cause respiratory and gastrointestinal problems. To identify high risk areas for intervention, it is necessary to understand the effects of climatic, environmental and socio-demographic conditions on A. lumbricoides infection. Methodology Cross-sectional survey data of 6,366 study participants in the Mbeya region of South-Western Tanzania were used to analyze associations between remotely sensed environmental data and A. lumbricoides infection. Non-linear associations were accounted for by using fractional polynomial regression, and socio-demographic and sanitary data were included as potential confounders. Principal Findings The overall prevalence of A. lumbricoides infection was 6.8%. Our final multivariable model revealed a significant non-linear association between rainfall and A. lumbricoides infection with peak prevalences at 1740 mm of mean annual rainfall. Mean annual land surface temperature during the day was linearly modeled and negatively associated with A. lumbricoides infection (odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.78–0.97). Furthermore, age, which also showed a significant non-linear association (infection maximum at 7.7 years), socio-economic status (OR = 0.82, CI = 0.68–0.97), and latrine coverage around the house (OR = 0.80, CI = 0.67–0.96) remained in the final model. Conclusions A. lumbricoides infection was associated with environmental, socio-demographic and sanitary factors both in uni- and multivariable analysis. Non-linear analysis with fractional polynomials can improve model fit, resulting in a better understanding of the relationship between environmental conditions and helminth infection, and more precise predictions of high prevalence areas. However, socio-demographic determinants and sanitary conditions should also be considered, especially when planning public health interventions on a smaller scale, such as the community level.
Background: The analysis of phenotypic characteristics on Mycobacterium tuberculosis (MTB)-specific T cells is a promising approach for the diagnosis of active tuberculosis (aTB) and for monitoring treatment success. We therefore studied phenotypic changes on MTB-specific CD4 T cells upon anti-tuberculosis treatment initiation in relation to the treatment response as determined by sputum culture. Methods: Peripheral blood mononuclear cells from subjects with latent MTB infection (n=16) and aTB (n=39) at baseline, week 9, 12 and 26 (end of treatment) were analyzed after intracellular interferon gamma staining and overnight stimulation with tuberculin. Liquid sputum cultures were performed weekly until week 12 and during 4 visits until week 26. Results: T cell activation marker expression on MTB-specific CD4 T cells differed significantly between subjects with aTB and latent MTB infection with no overlap for the frequencies of CD38pos and Ki67pos cells (both p<0.0001). At 9 weeks after anti-TB treatment treatment initiation the frequencies of activation marker (CD38, HLA-DR, Ki67) positive MTB-specific, but not total CD4 T cells, were significantly reduced (p<0.0001). Treatment induced phenotypic changes from baseline until week 9 and until week 12 differed substantially between individual aTB patients and correlated with an individual's time to stable sputum culture conversion for expression of CD38 and HLA-DR (both p<0.05). In contrast, the frequencies of maturation marker CD27 positive MTB-specific CD4 T cells remained largely unchanged until week 26 and significantly differed between subjects with treated TB disease and latent MTB infection (p=0.0003). Discussion: Phenotypic changes of MTB-specific T cells are potential surrogate markers for tuberculosis treatment efficacy and can help to discriminate between aTB (profile: CD38pos, CD27low), treated TB (CD38neg, CD27low) and latent MTB infection (CD38neg, CD27high).
