Plasma levels of C-reactive protein, matrix metalloproteinase-7 and lipopolysaccharide-binding protein distinguish active pulmonary or extrapulmonary tuberculosis from uninfected controls in children

Albuquerque, Victor V. S.; Kumar, Nathella Pavan; Fukutani, Kiyoshi F.; Vasconcelos, Beatriz; Arriaga, María B.; Silveira-Mattos, Paulo S.; Babu, Subash; Andrade, Bruno B.

doi:10.1016/j.cyto.2019.154773

Cited by 19 publications

(14 citation statements)

References 65 publications

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“…Paradoxically, other reports showed that C-reactive protein levels are generally used as a biomarker for systemic inflammation, and higher values are associated with adverse outcomes (34). Albuquerque et al found that C-reactive protein was strong discriminators of active TB and thus could be considered as biomarkers useful in discrimination different TB clinical forms (35). Another study found high C-reactive protein level was associated with sputum smear turn to negative (36).…”

Section: Mortality Risk Factors Of Tb Patients With Respiratory Failure During Icu Treatmentmentioning

confidence: 99%

Prediction model for death in patients with pulmonary tuberculosis accompanied by respiratory failure in ICU: retrospective study

et al. 2020

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Background: The mortality rate of pulmonary tuberculosis (TB) patients with respiratory failure remains high. This study aimed to identify factors contributing to death in these patients, and develop a mortality prediction model for pulmonary TB patients with respiratory failure.Methods: A retrospective study of patients admitted consecutively to the medical intensive care unit (ICU) of Beijing Chest Hospital, (Beijing, China), Chaoyang Fourth Hospital (Chaoyang, China) and Hebi Third People's Hospital (Hebi, China) from May 2018 to May 2019 was conducted. 153 patients with pulmonary TB accompanied by respiratory failure were enrolled. A multivariate analysis was performed to identify risk factors for death. A predictive fatality score was determined. The utility of the score for predicting death was evaluated using receiver operating characteristic (ROC) curve analysis. Results: The patients' median age was 57.82±19.42 years (17.0-87.0 years) and there were 106 males (69.28%). The mortality rate was 39.22% (60 of 153). Independent predictive factors of mortality included the PaO 2 (hazard ratio 0.928, 95% CI: 0.882-0.976, P=0.004), Albumin (hazard ratio 0.881, 95% CI: 0.792-0.980, P=0.019), Apache II score (hazard ratio 1.120, 95% CI: 1.017-1.234, P=0.022) and C-reactive protein (hazard ratio 1.012, 95% CI: 1.004-1.019, P=0.003). Establishing a logistic model of the death risk grade of pulmonary TB with respiratory failure was Y=1.710 − 0.068*PaO 2 −0.163* albumin + 0.215* Apache II +0.012* C-reactive protein. The value was Y=−0.494. If the Y value was greater than or equal to −0.494, the patients belonged to the deceased group, and if less than −0.494 the patients belonged to the survival group. AUC=0.818, The sensitivity was 83.3%; specificity was 73.1%. Conclusions: Pulmonary TB patients with respiratory failure have a high mortality rate and poor prognosis, particularly those with high Apache II scores, high C-reactive protein levels, low PaO 2 admission to ICU and low albumin level. The prediction model will help assess the risk of death in patients with TB and respiratory failure.

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Section: Mortality Risk Factors Of Tb Patients With Respiratory Failure During Icu Treatmentmentioning

confidence: 99%

Prediction model for death in patients with pulmonary tuberculosis accompanied by respiratory failure in ICU: retrospective study

et al. 2020

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“…MMP8 and CXCL1 were not among the TB biomarkers with the highest AUC values reported in humans which were C-reactive protein, transferrin, IFN-γ, interferon (IFN)-γ inducible protein-10 (IP-10), IL-27, and interferon–inducible T Cell Alpha Chemoattractant (ITAC-1) 31-39 . Only one study reported MMP8 performance as a biomarker in children (<25 per diagnostic category) 40 and three studies measured CXCL1 41-43 . A few investigators quantified MMP2, MMP3 and MMP9 (proteins functionally related to MMP8) but did not pursue them further due to missing data 7 , or inconsistent statistical differences 31,39 .…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis biomarkers discovered using Diversity Outbred mice

Koyuncu

Niazi

Tavolara

et al. 2021

Preprint

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BackgroundBiomarker discovery for pulmonary tuberculosis (TB) may be accelerated by modeling human genotypic diversity and phenotypic responses to Mycobacterium tuberculosis (Mtb). To meet these objectives, we use the Diversity Outbred (DO) mouse population and apply novel classifiers to identify informative biomarkers from multidimensional data sets.MethodTo identify biomarkers, we infected DO mice with aerosolized Mtb confirmed a human-like spectrum of phenotypes, examined gene expression, and inflammatory and immune mediators in the lungs. We measured 11 proteins in 453 Mtb-infected and 29 non-infected mice. We have searched all combinations of six classification algorithms and 239 biomarker subsets and independently validated the selected classifiers. Finally, we selected two mouse lung biomarkers to test as candidate biomarkers of active TB, measuring their diagnostic performance in human sera acquired from the Foundation for Innovative New Diagnostics.FindingsDO mice discovered two translationally relevant biomarkers, CXCL1 and MMP8 that accurately diagnosed active TB in humans with > 90% sensitivity and specificity compared to controls. We identified them through the two classifiers that accurately diagnosed supersusceptible DO mice with early-onset TB: Logistic Regression using MMP8 as a single biomarker, and Gradient Tree Boosting using a panel of 4 biomarkers (CXCL1, CXCL2, TNF, IL-10).InterpretationThis work confirms that the DO population models human responses and can accelerate discovery of translationally relevant TB biomarkers.FundingSupport was provided by NIH R21 AI115038; NIH R01 HL145411; NIH UL1-TR001430; and the American Lung Association Biomedical Research Grant RG-349504.

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“…Exploration of multiple host proteins as surrogates of TB disease is often used for the immunodiagnosis of TB (10) and monitoring of treatment responses (25). Several exploratory inflammatory (26) and metabolic (27) markers have been used to identify disease signatures among children. Among these, the use of serum biomarkers and CRP alone (28) or in combination with other proteins (24,26) resulted in good accuracy in discriminating TB and monitoring responses after anti-TB treatment (25).…”

Section: Discussionmentioning

confidence: 99%

“…Several exploratory inflammatory (26) and metabolic (27) markers have been used to identify disease signatures among children. Among these, the use of serum biomarkers and CRP alone (28) or in combination with other proteins (24,26) resulted in good accuracy in discriminating TB and monitoring responses after anti-TB treatment (25). We also observed CRP and ferritin as discriminatory serum biomarkers of disease in children compared to controls.…”

Section: Discussionmentioning

confidence: 99%

Antibody-Secreting Cells To Diagnose Mycobacterium tuberculosis Infection in Children in Pakistan

Iqbal

Ahmed

Qamar

et al. 2020

mSphere

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Reliance on microbiologic methods to diagnose Mycobacterium tuberculosis infection is a suboptimal approach for children due in part to the paucibacillary nature of the disease. A blood-based biomarker assay, such as the mycobacterial-antibody-secreting cell (MASC) assay, could be a major advance for the field of study of pediatric tuberculosis (TB). Children <15 years of age with clinical concern for TB and age-matched children with no concern for TB were enrolled from outpatient clinics in Karachi, Pakistan. MASC, ferritin, and C-reactive protein (CRP) assays were performed, and results were compared among cases and controls, as well as among children with a case definition of “confirmed TB,” “probable TB,” or “possible TB.” MASC responses were significantly higher among children with TB than among controls (0.41 optical density [OD] versus 0.28 OD, respectively, P < 0.001), and the differences were largely driven by the data from children with confirmed TB (P = 0.002). Ferritin and CRP values were significantly higher among those with confirmed TB than among those with the other disease states and controls (P = 0.004 and P = 0.019, respectively). The use of the MASC assay as a blood-based biomarker for TB disease shows some promise among children with microbiologically confirmed disease; however, the performance characteristics for the majority of young children with unconfirmed TB were suboptimal in this cohort. IMPORTANCE Tuberculosis (TB) in children represents a missed opportunity for diagnosis and preventive therapy. The magnitude or burden of disease in children is not fully understood due to our limitations with respect to exploring sensitive diagnostic algorithms. In a setting of TB endemicity in Pakistan, we carried out a proof-of-concept study to evaluate for the first time the performance of B cell analyses by the use of well-defined diagnostic criteria and NIH consensus guidelines as “culture-confirmed,” “probable,” and “possible” TB groups. In contrast to detection of serum antibody, we focused on mycobacterial-antibody-secreting cell (MASC) detection as a marker of active disease in children with a strong suspicion of TB. Further work exploring a larger panel of inflammatory biomarkers and enrichment of B cells with the objective of increasing the sensitivity of the current MASC assay would lead to the development of a field-friendly assay for timely diagnosis of childhood TB.

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Plasma levels of C-reactive protein, matrix metalloproteinase-7 and lipopolysaccharide-binding protein distinguish active pulmonary or extrapulmonary tuberculosis from uninfected controls in children

Cited by 19 publications

References 65 publications

Prediction model for death in patients with pulmonary tuberculosis accompanied by respiratory failure in ICU: retrospective study

Prediction model for death in patients with pulmonary tuberculosis accompanied by respiratory failure in ICU: retrospective study

Tuberculosis biomarkers discovered using Diversity Outbred mice

Antibody-Secreting Cells To Diagnose Mycobacterium tuberculosis Infection in Children in Pakistan

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