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1.
PLoS One ; 14(6): e0218606, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237915

RESUMO

BACKGROUND: Simple methods for the accurate triaging and screening of HIV-associated tuberculosis (TB) are urgently needed. We hypothesized that combining serum antibody with urine lipoarabinomannan (U-LAM) detection can improve the detection of HIV-associated TB. METHODS: We performed a case-control study with sampling from a prospective study of South African HIV-infected subjects who were screened for TB prior to initiating antiretroviral therapy. Sera from all available TB cases (n = 74) and randomly selected non-TB controls (n = 30), all tested for U-LAM, sputum microscopy, GeneXpert, and cultures, were evaluated for antibodies to LAM and arabinomannan (AM). Diagnostic logistic regression models for TB were developed based on the primary test results and the additive effect of antibodies with leave-one-out cross-validation. RESULTS: Antibody responses to LAM and AM correlated strongly (p<0.0001), and IgG and IgM reactivities were significantly higher in TB than non-TB patients (p<0.0001). At 80% specificity, the target specificity for a non-sputum-based simple triage/screening test determined by major TB stakeholders, combining U-LAM with IgG detection significantly increased the sensitivity for HIV-associated TB to 92% compared to 30% for U-LAM alone (p<0.001). Sputum microscopy combined with IgG detection increased sensitivity to 88% compared to 31% for microscopy alone, and Xpert with IgG increased sensitivity to 96% and 99% compared to 57% for testing one, and 70% for testing two sputa with Xpert alone, respectively. CONCLUSION: Combining U-LAM with serum antibody detection could provide a simple low-cost method that meets the requirements for a non-sputum-based test for the screening of HIV-associated TB.


Assuntos
Infecções por HIV/complicações , Lipopolissacarídeos/imunologia , Testes Sorológicos/métodos , Tuberculose/diagnóstico , Adulto , Anticorpos Antibacterianos/sangue , Feminino , Humanos , Lipopolissacarídeos/urina , Masculino , Sensibilidade e Especificidade , África do Sul , Tuberculose/sangue , Tuberculose/etiologia , Tuberculose/urina
2.
PLoS Med ; 16(4): e1002792, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31039161

RESUMO

BACKGROUND: Current guidelines recommend the use of the lateral flow urine lipoarabinomannan assay (LAM) in HIV-positive, ambulatory patients with signs and symptoms of tuberculosis (TB) only if they are seriously ill or have CD4 count ≤ 100 cells/µl. We assessed the diagnostic yield of including LAM in TB diagnostic algorithms in HIV-positive, ambulatory patients with CD4 < 200 cells/µl, as well as the risk of mortality in LAM-positive patients who were not diagnosed using other diagnostic tools and not treated for TB. METHODS AND FINDINGS: We conducted a prospective observational study including HIV-positive adult patients with signs and symptoms of TB and CD4 < 200 cells/µl attending 6 health facilities in Malawi and Mozambique. Patients were included consecutively from 18 September 2015 to 27 October 2016 in Malawi and from 3 December 2014 to 22 August 2016 in Mozambique. All patients had a clinical exam and LAM, chest X-ray, sputum microscopy, and Xpert MTB/RIF assay (Xpert) requested. Culture in sputum was done for a subset of patients. The diagnostic yield was defined as the proportion of patients with a positive assay result among those with laboratory-confirmed TB. For the 456 patients included in the study, the median age was 36 years (IQR 31-43) and the median CD4 count was 50 cells/µl (IQR 21-108). Forty-five percent (205/456) of the patients had laboratory-confirmed TB. The diagnostic yields of LAM, microscopy, and Xpert were 82.4% (169/205), 33.7% (69/205), and 40.0% (84/205), respectively. In total, 50.2% (103/205) of the patients with laboratory-confirmed TB were diagnosed only through LAM. Overall, the use of LAM in diagnostic algorithms increased the yield of algorithms with microscopy and with Xpert by 38.0% (78/205) and 34.6% (71/205), respectively, and, specifically among patients with CD4 100-199 cells/µl, by 27.5% (14/51) and 29.4% (15/51), respectively. LAM-positive patients not diagnosed through other tools and not treated for TB had a significantly higher risk of mortality than LAM-positive patients who received treatment (adjusted risk ratio 2.57, 95% CI 1.27-5.19, p = 0.009). Although the TB diagnostic conditions in the study sites were similar to those in other resource-limited settings, the added value of LAM may depend on the availability of microscopy or Xpert results. CONCLUSIONS: LAM has diagnostic value for identifying TB in HIV-positive patients with signs and symptoms of TB and advanced immunodeficiency, including those with a CD4 count of 100-199 cells/µl. In this study, the use of LAM enabled the diagnosis of TB in half of the patients with confirmed TB disease; without LAM, these patients would have been missed. The rapid identification and treatment of TB enabled by LAM may decrease overall mortality risk for these patients.


Assuntos
Infecções por HIV/urina , Soropositividade para HIV/urina , Lipopolissacarídeos/urina , Tuberculose/diagnóstico , Adulto , Instituições de Assistência Ambulatorial , Contagem de Linfócito CD4 , Coinfecção/diagnóstico , Coinfecção/urina , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Soropositividade para HIV/sangue , Soropositividade para HIV/complicações , Recursos em Saúde , Humanos , Malaui , Masculino , Moçambique , Sistemas Automatizados de Assistência Junto ao Leito , Áreas de Pobreza , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Tuberculose/sangue , Tuberculose/complicações , Tuberculose/urina , Urinálise/economia , Urinálise/métodos
3.
PLoS One ; 14(4): e0215443, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30998715

RESUMO

BACKGROUND: Tuberculosis (TB) infection was responsible for an estimated 1.3 million deaths in 2017. Better diagnostic tools are urgently needed. We sought to determine whether accurate TB antigen detection in blood or urine has the potential to meet the WHO target product profiles for detection of active TB. MATERIALS AND METHODS: We developed Electrochemiluminescence (ECL) immunoassays for Lipoarabinomannan (LAM) and ESAT-6 detection with detection limits in the pg/ml range and used them to compare the concentrations of the two antigens in the urine and serum of 81 HIV-negative and -positive individuals with presumptive TB enrolled across diverse geographic sites. RESULTS: LAM and ESAT-6 overall sensitivities in urine were 93% and 65% respectively. LAM and ESAT-6 overall sensitivities in serum were 55% and 46% respectively. Overall specificity was ≥97% in all assays. Sensitivities were higher in HIV-positive compared to HIV-negative patients for both antigens and both sample types, with signals roughly 10-fold higher on average in urine than in serum. The two antigens showed similar concentration ranges within the same sample type and correlated. CONCLUSIONS: LAM and ESAT-6 can be detected in the urine and serum of TB patients, regardless of the HIV status and further gains in clinical sensitivity may be achievable through assay and reagent optimization. Accuracy in urine was higher with current methods and has the potential to meet the WHO accuracy target if the findings can be transferred to a point-of-care TB test.


Assuntos
Antígenos de Bactérias , Proteínas de Bactérias , Técnicas Eletroquímicas , Lipopolissacarídeos , Medições Luminescentes , Mycobacterium tuberculosis , Tuberculose , Adolescente , Adulto , Antígenos de Bactérias/sangue , Antígenos de Bactérias/urina , Proteínas de Bactérias/sangue , Proteínas de Bactérias/urina , Feminino , Humanos , Imunoensaio , Lipopolissacarídeos/sangue , Lipopolissacarídeos/urina , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tuberculose/sangue , Tuberculose/urina
4.
PLoS Med ; 16(4): e1002776, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951533

RESUMO

BACKGROUND: The prevalence of and mortality from HIV-associated tuberculosis (HIV/TB) in hospital inpatients in Africa remains unacceptably high. Currently, there is a lack of tools to identify those at high risk of early mortality who may benefit from adjunctive interventions. We therefore aimed to develop and validate a simple clinical risk score to predict mortality in high-burden, low-resource settings. METHODS AND FINDINGS: A cohort of HIV-positive adults with laboratory-confirmed TB from the STAMP TB screening trial (Malawi and South Africa) was used to derive a clinical risk score using multivariable predictive modelling, considering factors at hospital admission (including urine lipoarabinomannan [LAM] detection) thought to be associated with 2-month mortality. Performance was evaluated internally and then externally validated using independent cohorts from 2 other studies (LAM-RCT and a Médecins Sans Frontières [MSF] cohort) from South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. The derivation cohort included 315 patients enrolled from October 2015 and September 2017. Their median age was 36 years (IQR 30-43), 45.4% were female, median CD4 cell count at admission was 76 cells/µl (IQR 23-206), and 80.2% (210/262) of those who knew they were HIV-positive at hospital admission were taking antiretroviral therapy (ART). Two-month mortality was 30% (94/315), and mortality was associated with the following factors included in the score: age 55 years or older, male sex, being ART experienced, having severe anaemia (haemoglobin < 80 g/l), being unable to walk unaided, and having a positive urinary Determine TB LAM Ag test (Alere). The score identified patients with a 46.4% (95% CI 37.8%-55.2%) mortality risk in the high-risk group compared to 12.5% (95% CI 5.7%-25.4%) in the low-risk group (p < 0.001). The odds ratio (OR) for mortality was 6.1 (95% CI 2.4-15.2) in high-risk patients compared to low-risk patients (p < 0.001). Discrimination (c-statistic 0.70, 95% CI 0.63-0.76) and calibration (Hosmer-Lemeshow statistic, p = 0.78) were good in the derivation cohort, and similar in the external validation cohort (complete cases n = 372, c-statistic 0.68 [95% CI 0.61-0.74]). The validation cohort included 644 patients between January 2013 and August 2015. Median age was 36 years, 48.9% were female, and median CD4 count at admission was 61 (IQR 21-145). OR for mortality was 5.3 (95% CI 2.2-9.5) for high compared to low-risk patients (complete cases n = 372, p < 0.001). The score also predicted patients at higher risk of death both pre- and post-discharge. A simplified score (any 3 or more of the predictors) performed equally well. The main limitations of the scores were their imperfect accuracy, the need for access to urine LAM testing, modest study size, and not measuring all potential predictors of mortality (e.g., tuberculosis drug resistance). CONCLUSIONS: This risk score is capable of identifying patients who could benefit from enhanced clinical care, follow-up, and/or adjunctive interventions, although further prospective validation studies are necessary. Given the scale of HIV/TB morbidity and mortality in African hospitals, better prognostic tools along with interventions could contribute towards global targets to reduce tuberculosis mortality.


Assuntos
Infecções por HIV/diagnóstico , Infecções por HIV/mortalidade , Lipopolissacarídeos/urina , Tuberculose/diagnóstico , Tuberculose/mortalidade , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Infecções Oportunistas Relacionadas com a AIDS/urina , Adulto , África ao Sul do Saara/epidemiologia , Estudos de Coortes , Feminino , HIV , Infecções por HIV/complicações , Infecções por HIV/urina , Hospitalização , Humanos , Pacientes Internados , Masculino , Programas de Rastreamento/métodos , Prognóstico , Projetos de Pesquisa , Fatores de Risco , Análise de Sobrevida , Tuberculose/urina , Urinálise
5.
J Acquir Immune Defic Syndr ; 81(1): e10-e14, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30865176

RESUMO

BACKGROUND: The urine lipoarabinomannan (LAM) lateral flow assay is a point-of-care test to diagnose HIV-associated tuberculosis (TB). We assessed the performance of urine LAM in HIV-positive patients presenting to the emergency center and evaluated the interobserver agreement between emergency center physicians and laboratory technologists. SETTING: A cross-sectional diagnostic study was performed at the emergency center of a district hospital in a high HIV-prevalence community in South Africa. METHODS: Consecutive HIV-positive adults presenting with ≥1 WHO TB symptom were enrolled over a 16-month period. A urine LAM test was performed at point-of-care by an emergency physician and interpreted independently by 2 physicians. A second test was performed in the laboratory and interpreted independently by 2 laboratory technologists. The reference standard was a positive TB culture or Xpert MTB/RIF test on sputum or appropriate extrapulmonary samples. We compared diagnostic accuracy and reproducibility of urine LAM between point-of-care readers and laboratory readers. RESULTS: One thousand three hundred eighty-eight samples (median, 3 samples/participant) were sent for TB microbiology tests in 411 participants; 170 had confirmed TB (41.4%). Point-of-care and laboratory-performed urine LAM had similar sensitivity (41.8% vs 42.0%, P = 1.0) and specificity (90.5% vs 87.5%, P = 0.23). Moderate agreement was found between point-of-care and laboratory testing (κ = 0.62), but there was strong agreement between point-of-care readers (κ = 0.95) and between laboratory readers (κ = 0.94). Positive percent agreement between point-of-care and laboratory readers was 68% and negative percent agreement 92%. CONCLUSION: There is no diagnostic accuracy advantage in laboratory-performed versus point-of-care-performed urine LAM tests in emergency care centers in high-burden settings.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/urina , Serviço Hospitalar de Emergência , Lipopolissacarídeos/urina , Tuberculose Pulmonar/urina , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Adulto , Estudos Transversais , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Humanos , Masculino , Variações Dependentes do Observador , Testes Imediatos , Sensibilidade e Especificidade , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/etiologia
6.
PLoS One ; 14(3): e0214161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913250

RESUMO

BACKGROUND: Timely diagnosis of tuberculosis disease is critical for positive patient outcomes, yet potentially millions go undiagnosed or unreported each year. Sputum is widely used as the testing input, but limited by its complexity, heterogeneity, and sourcing problems. Finding methods to interrogate noninvasive, non-sputum clinical specimens is indispensable to improving access to tuberculosis diagnosis and care. In this work, economical plasmonic gratings were used to analyze tuberculosis biomarker lipoarabinomannan (LAM) from clinical urine samples by single molecule fluorescence assay (FLISA) and compared with gold standard sputum GeneXpert MTB/ RIF, culture, and reference ELISA testing results. METHODS AND FINDINGS: In this study, twenty sputum and urine sample sets were selected retrospectively from a repository of HIV-negative patient samples collected before initiation of anti-tuberculosis therapy. GeneXpert MTB/RIF and culture testing of patient sputum confirmed the presence or absence of pulmonary tuberculosis while all patient urines were reference ELISA LAM-negative. Plasmonic gratings produced by low-cost soft lithography were bound with anti-LAM capture antibody, incubated with patient urine samples, and biotinylated detection antibody. Fluorescently labeled streptavidin revealed single molecule emission by epifluorescence microscope. Using a 1 fg/mL baseline for limit of detection, single molecule FLISA demonstrated good qualitative agreement with gold standard tests on 19 of 20 patients, including accurately predicting the gold-standard-negative patients, while one gold-standard-positive patient produced no observable LAM in urine. CONCLUSIONS: Single molecule FLISA by plasmonic grating demonstrated the ability to quantify tuberculosis LAM from complex urine samples of patients from a high endemic setting with negligible interference from the complex media itself. Moreover, agreement with patient diagnoses by gold standard testing suggests that single molecule FLISA could be used as a highly sensitive test to diagnose tuberculosis noninvasively.


Assuntos
Técnicas Biossensoriais , Soronegatividade para HIV , HIV-1 , Lipopolissacarídeos/urina , Tuberculose/urina , Adulto , Feminino , Humanos , Pessoa de Meia-Idade
7.
Am J Respir Crit Care Med ; 199(5): 643-650, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30192649

RESUMO

RATIONALE: The recommended tuberculosis (TB) intensified case finding (ICF) algorithm for people living with HIV (symptom-based screening followed by Xpert MTB/RIF [Xpert] testing) is insufficiently sensitive and results in unnecessary Xpert testing. OBJECTIVES: To evaluate whether novel ICF algorithms combining C-reactive protein (CRP)-based screening with urine Determine TB-LAM (TB-LAM), sputum Xpert, and/or sputum culture could improve ICF yield and efficiency. METHODS: We compared the yield and efficiency of novel ICF algorithms inclusive of point-of-care CRP-based TB screening and confirmatory testing with urine TB-LAM (if CD4 count ≤100 cells/µl), sputum Xpert, and/or a single sputum culture among consecutive people living with HIV with CD4 counts less than or equal to 350 cells/µl initiating antiretroviral therapy in Uganda. MEASUREMENTS AND MAIN RESULTS: Of 1,245 people living with HIV, 203 (16%) had culture-confirmed TB including 101 (49%) patients with CD4 counts less than or equal to 100 cells/µl. Compared with the current ICF algorithm, point-of-care CRP-based TB screening followed by Xpert testing had similar yield (56% [95% confidence interval, 49-63] vs. 59% [95% confidence interval, 51-65]) but consumed less than half as many Xpert assays per TB case detected (9 vs. 4). Addition of TB-LAM did not significantly increase diagnostic yield relative to the current ICF algorithm but provided same-day diagnosis for 26% of TB patients with advanced HIV. Addition of a single culture to TB-LAM and Xpert substantially improved ICF yield, identifying 78% of all TB cases. CONCLUSIONS: Point-of-care CRP-based screening can improve ICF efficiency among people living with HIV. Addition of TB-LAM and a single culture to Xpert confirmatory testing could enable HIV programs to increase the speed of TB diagnosis and ICF yield.


Assuntos
Coinfecção/diagnóstico , Infecções por HIV/complicações , Tuberculose Pulmonar/diagnóstico , Adulto , Algoritmos , Proteína C-Reativa/análise , Contagem de Linfócito CD4 , Coinfecção/microbiologia , Coinfecção/virologia , Feminino , Infecções por HIV/microbiologia , Custos de Cuidados de Saúde , Humanos , Lipopolissacarídeos/urina , Masculino , Programas de Rastreamento/instrumentação , Programas de Rastreamento/métodos , Sistemas Automatizados de Assistência Junto ao Leito/economia , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/economia , Tuberculose Pulmonar/virologia
8.
Int J Infect Dis ; 79: 37-43, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30292891

RESUMO

BACKGROUND: The World Health Organization (WHO) recommends the use of adjunctive urine lipopolysaccharide lipoarabinomannan (LAM) testing in hospitalized HIV-infected persons with suspected tuberculosis (TB) and a CD4 count <100cells/ml. However, the recommendation is conditional, and uptake by individual treatment programmes depends on perceived additional benefit. The aim of this study was to determine whether adjunctive LAM testing has additional clinical benefits including a reduction in healthcare-related use of resources. METHODS: A post hoc analysis was performed of a published multicentre, multi-country, randomized controlled trial that showed an approximate 20% mortality benefit in HIV-infected hospitalized patients who underwent adjunctive LAM testing as part of their diagnostic workup. In that parent study, adult HIV-infected hospitalized patients with suspected TB (n=2528) were randomly allocated to either routine diagnostics (smear microscopy, Xpert MTB/RIF, and culture; n=1271), or routine diagnostics plus adjunctive urine LAM testing (n=1257). Data were further analyzed to determine whether there were other potential benefits of LAM usage based on CD4 count and illness severity. Aspects evaluated included: (1) the reduction in number of diagnostic sputum samples tested, (2) the utilization of additional imaging, (3) disease resolution based on follow-up signs and symptoms of illness severity, and (4) the reduction in hospital readmission. RESULTS: Adjuvant LAM did not reduce the number of diagnostic sputum samples requested, the need for additional imaging, or the hospital readmission rate. However, adjunctive LAM was associated with a more rapid rate of disease resolution (dyspnoea) in the severely ill subgroup. Higher LAM grade (grades 4 and 5), compared to lower grade positivity (≤3), was associated with lower use of ultrasound, lower Karnofsky performance score, lower CD4 cell count, and shorter time to culture positivity. CONCLUSIONS: Although, adjunct LAM was associated with a mortality benefit in the parent study, no benefit could be demonstrated in the secondary analysis with respect to the number of diagnostic sputum samples requested, the use of additional imaging, or hospital readmission rates. However, given the limitations of the present study, further appropriately designed studies are required to determine the effect of adjunct urine LAM on the utilization of healthcare resources.


Assuntos
Coinfecção , Infecções por HIV/complicações , Lipopolissacarídeos/urina , Tuberculose/diagnóstico , Adulto , Contagem de Linfócito CD4 , Utilização de Instalações e Serviços , Hospitalização , Humanos , Tuberculose/complicações , Tuberculose/diagnóstico por imagem , Tuberculose/mortalidade
9.
ACS Sens ; 3(10): 2079-2086, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30269480

RESUMO

Tuberculosis (TB) is the leading global cause of death from a single infectious agent. Registered incidence rates are low, especially in low-resource countries with weak health systems, due to the disadvantages of current diagnostic techniques. A major effort is directed to develop a point-of-care (POC) platform to reduce TB deaths with a prompt and reliable low-cost technique. In the frame of the European POCKET Project, a novel POC platform for the direct and noninvasive detection of TB in human urine was developed. The photonic sensor chip is integrated in a disposable cartridge and is based on a highly sensitive Mach-Zehnder Interferometer (MZI) transducer combined with an on-chip spectral filter. The required elements for the readout are integrated in an instrument prototype, which allows real-time monitoring and data processing. In this work, the novel POC platform has been employed for the direct detection of lipoarabinomannan (LAM), a lipopolysaccharide found in the mycobacterium cell wall. After the optimization of several parameters, a limit of detection of 475 pg/mL (27.14 pM) was achieved using a direct immunoassay in undiluted human urine in less than 15 min. A final validation of the technique was performed using 20 clinical samples from TB patients and healthy donors, allowing the detection of TB in people regardless of HIV coinfection. The results show excellent correlation to those obtained with standard techniques. These promising results demonstrate the high sensitivity, specificity and applicability of our novel POC platform, which could be used during routine check-ups in developing countries.


Assuntos
Imunoensaio/métodos , Lipopolissacarídeos/urina , Tuberculose/diagnóstico , Anticorpos Imobilizados/química , Anticorpos Imobilizados/imunologia , Humanos , Limite de Detecção , Lipopolissacarídeos/imunologia , Mycobacterium tuberculosis/metabolismo , Sistemas Automatizados de Assistência Junto ao Leito
10.
Int J Tuberc Lung Dis ; 22(11): 1366-1373, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30355418

RESUMO

SETTING: Four ambulatory clinics in Durban, South Africa. OBJECTIVE: To test the relationships of patient characteristics, time to mycobacterial culture positivity, and mortality with urinary lipoarabinomannan (LAM) grade category. DESIGN: Newly diagnosed human immunodeficiency virus (HIV) infected adults were screened for tuberculosis (TB) using sputum culture, tested for urinary LAM, and followed for up to 12 months. We performed multivariable ordinal logistic regression of risk factors for low (1 or 2) or high (3, 4, or 5) LAM grade. We used adjusted Cox regression models to determine the hazard ratios of time to culture positivity and death. RESULTS: Among 683 HIV-infected adults, median CD4 count was 215 cells/mm³ (interquartile range 86-361 cells/mm³), 17% had culture-confirmed TB, and 11% died during follow-up. Smoking, tachycardia (pulse > 100 beats/minute), CD4 count < 100 cells/mm³, and TB culture positivity were each associated with higher LAM grade. In multivariate models, a high urine LAM grade was associated with four-fold increased hazard of culture positivity (P = 0.001) and two-fold increased hazard of mortality (P = 0.02). Among patients treated for TB, these associations were no longer statistically significant. CONCLUSION: In this population, a higher urine LAM grade was associated with shorter time to culture positivity and mortality; however, these associations were not present for those starting anti-tuberculosis treatment.


Assuntos
Infecções por HIV/complicações , Lipopolissacarídeos/urina , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/mortalidade , Adulto , Contagem de Linfócito CD4 , Feminino , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Pacientes Ambulatoriais , Estudos Prospectivos , Fatores de Risco , Sensibilidade e Especificidade , África do Sul/epidemiologia , Escarro/microbiologia
11.
Int J Tuberc Lung Dis ; 22(9): 1082-1087, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30092876

RESUMO

INTRODUCTION: The World Health Organization recommends point-of-care (POC) lateral flow urine lipoarabinomannan (LF-LAM) for tuberculosis (TB) diagnosis in selected human immunodeficiency virus (HIV) positive people. South Africa had 438 000 new TB episodes in 2016, 58.9% of which were contributed by HIV-positive people. LF-LAM is being considered for scale-up in South Africa. METHODS: We estimated the costs of using LF-LAM in HIV-positive adults with CD4 counts  150 cells/µl enrolled in the TB Fast Track Trial in South Africa. We also estimated costs of POC haemoglobin (Hb), as this was used in the study algorithm. Data on clinic-level (10 intervention clinics) and above-clinic-level costs were collected. RESULTS: A total of 1307 LF-LAM tests were performed at 10 clinics over 24 months. The mean clinic-level costs were US$12.80 per patient for LF-LAM and POC Hb; LF-LAM costs were US$11.49 per patient. The mean above-clinic-level unit costs for LF-LAM were US$12.06 for clinic preparation, training, coordination and mentoring. The mean total cost of LF-LAM was US$23.55 per patient. CONCLUSION: At clinic level, the cost of LF-LAM was comparable to other TB diagnostics in South Africa. It is important to consider above-clinic-level costs for POC tests, as these may be required to support roll-out and ensure successful implementation.


Assuntos
Custos e Análise de Custo/estatística & dados numéricos , Infecções por HIV/tratamento farmacológico , Lipopolissacarídeos/urina , Testes Imediatos/economia , Tuberculose/diagnóstico , Instituições de Assistência Ambulatorial , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Coinfecção/economia , Infecções por HIV/complicações , Humanos , Sensibilidade e Especificidade , África do Sul , Tuberculose/complicações , Tuberculose/economia
12.
Int J Infect Dis ; 75: 67-73, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30125689

RESUMO

BACKGROUND: Tuberculosis is a major cause of mortality among HIV-infected inpatients, and the World Health Organization (WHO) recommends an algorithm to improve diagnosis. The urine lateral flow lipoarabinomannan (LAM) and sputum Xpert MTB/RIF tests are promising tools, but the optimal diagnostic algorithm is unclear. METHODS: This prospective cohort study enrolled HIV-positive inpatients with cough and WHO danger signs. The Xpert MTB/RIF test and mycobacterial culture were performed on sputum using sputum induction when necessary, and the LAM test was performed on stored urine. Tuberculosis was diagnosed by culture from any site. The diagnostic accuracy and costs of testing were determined for single and combined tests. RESULTS: Tuberculosis was confirmed in 169 of 332 patients (50.9%). The yield of LAM, Xpert MTB/RIF on spontaneous sputum (Xpert Spot), and Xpert MTB/RIF on spontaneous or induced sputum (Xpert SI) was 35.5%, 23.1%, and 90.5%, respectively. When LAM was placed before Xpert Spot and Xpert SI in an algorithm, the yield was 50.9% and 92.3%, respectively. Adding culture to Xpert MTB/RIF only increased the yield by 1.2% and 2.7%, respectively. Use of the LAM test reduced costs. CONCLUSIONS: Sputum induction is important to increase the yield of Xpert MTB/RIF for seriously ill patients with HIV and cough. LAM testing has little effect on yield when sputum induction is available, but reduces costs and may have other benefits.


Assuntos
Técnicas e Procedimentos Diagnósticos/economia , Infecções por HIV/complicações , Lipopolissacarídeos/urina , Escarro/química , Tuberculose/diagnóstico , Adulto , Algoritmos , Feminino , Humanos , Lipopolissacarídeos/economia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/fisiologia , Estudos Prospectivos , Escarro/microbiologia , Tuberculose/economia , Tuberculose/etiologia , Tuberculose/microbiologia
13.
Tuberculosis (Edinb) ; 111: 178-187, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30029905

RESUMO

TB diagnosis and treatment monitoring in resource limited regions rely heavily on serial sputum smear microscopy and bacterial culture. These microbiological methods are time-consuming, expensive and lack adequate sensitivity. The WHO states that improved TB diagnosis and treatment is imperative to achieve an end to the TB epidemic by 2030. Commercially available lipoarabinomannan (LAM) detection tools perform at low sensitivity that are highly dependent on the underlying immunological status of the patient; those with advanced HIV infection perform well. In this study, we have applied two novel strategies towards the sensitive diagnosis of TB infection based on LAM: Capture ELISA to detect LAM in paired urine and serum samples using murine and human monoclonal antibodies, essentially relying on LAM as an 'immuno-marker'; and, secondly, detection of α-d-arabinofuranose and tuberculostearic acid (TBSA)- 'chemical-markers' unique to mycobacterial cell wall polysaccharides/lipoglycans by our recently developed gas chromatography/mass spectrometry (GC/MS) method. Blinded urine specimens, with microbiologically confirmed active pulmonary TB or non TB (HIV+/HIV-) were tested by the aforementioned assays. LAM in patient urine was detected in a concentration range of 3-28 ng/mL based on GC/MS detection of the two LAM-surrogates, d-arabinose and tuberculostearic acid (TBSA) correctly classifying TB status with sensitivity > 99% and specificity = 84%. The ELISA assay had high sensitivity (98%) and specificity (92%) and the results were in agreement with GC/MS analysis. Both tests performed well in their present form particularly for HIV-negative/TB-positive urine samples. Among the HIV+/TB+ samples, 52% were found to have >10 ng/mL urinary LAM. The detected amounts of LAM present in the urine samples also appears to be associated with the gradation of the sputum smear, linking elevated LAM levels with higher mycobacterial burden (odds ratio = 1.08-1.43; p = 0.002). In this small set, ELISA was also applied to parallel serum samples confirming that serum could be an additional reservoir for developing a LAM-based immunoassay for diagnosis of TB.


Assuntos
Anticorpos Monoclonais/imunologia , Coinfecção , Ensaio de Imunoadsorção Enzimática/métodos , Cromatografia Gasosa-Espectrometria de Massas , Infecções por HIV/diagnóstico , Lipopolissacarídeos/sangue , Lipopolissacarídeos/urina , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/urina , Especificidade de Anticorpos , Biomarcadores/sangue , Biomarcadores/urina , Infecções por HIV/sangue , Infecções por HIV/urina , Humanos , Lipopolissacarídeos/imunologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/microbiologia , Urinálise
14.
BMC Pulm Med ; 18(1): 67, 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739378

RESUMO

BACKGROUND: The inherent risk of developing tuberculosis (TB) in HIV- infected individuals is further enhanced by hypovitaminosis D. Interventions that offset HIV-associated immune deterioration potentially arrest disease progression and incidence of opportunistic infections including TB. Despite conflicting reports on association between vitamin D deficiency (VDD) and risk of TB, vitamin D (VD) supplementation remains a promising intervention. METHODS: We conducted a comparative cross-sectional study on 145 HIV+/pulmonary TB+ (PTB) and 139 HIV+/PTB- hospitalised patients to investigate association of vitamin D status and risk of PTB. Stratified random sampling was used to select archived serum specimens from participants enrolled in a randomised controlled trial (RCT) conducted to investigate the impact of using a point-of-care urine lipoarabinomannan strip test for TB diagnosis. PTB status was confirmed using sputum smear microscopy, culture or GeneXpert MTB/RIF. Serum 25-hydroxyvitamin D [25(OH) D] concentrations were assayed by competitive chemiluminescent immunoassay prior to commencement of anti-TB treatment. Effect of VD status on duration of hospital stay and patient outcomes on follow up at 8 weeks were also investigated. Median serum 25(OH) D concentrations were compared using Mann-Whitney test and covariates of serum VD status were assessed using logistic regression analysis. RESULTS: Overall VDD prevalence in the cohort was 40.9% (95% CI: 35.1-46.8). Median serum 25(OH)D concentrations were significantly higher in HIV+/PTB+ group (25.3 ng/ml, IQR:18.0-33.7) compared to the HIV+/PTB- group (20.4 ng/ml, IQR:14.6-26.9), p = 0.0003. Patients with serum 25(OH) D concentration ≥ 30 ng/ml were 1.9 times more likely to be PTB+ compared to those with serum 25(OH) D concentrations < 30 ng/ml (odds ratio (OR) 1.91; 95% CI 1.1-3.2). PTB-related death was associated with higher odds of having 25(OH) D levels≥30 ng/ml. Age, gender, CD4+ count, combination antiretroviral therapy (cART) status, efavirenz based cART regimen and length of hospital stay were not associated with vitamin D status. CONCLUSIONS: The finding of an association between higher serum 25(OH) D concentrations and active PTB and TB-related mortality among hospitalised HIV-infected patients in the present study is at variance with the commonly reported association of hypovitaminosis and susceptibility to TB. Our findings though, are in concordance with a small pool of reports from other settings.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV , Tuberculose Pulmonar , Deficiência de Vitamina D , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , Adulto , Estudos Transversais , Progressão da Doença , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/terapia , Humanos , Incidência , Tempo de Internação/estatística & dados numéricos , Lipopolissacarídeos/análise , Lipopolissacarídeos/urina , Masculino , Infecções Oportunistas/complicações , Fatores de Risco , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Urinálise/métodos , Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/epidemiologia , Vitaminas/uso terapêutico , Zimbábue/epidemiologia
17.
Enferm Infecc Microbiol Clin ; 36(2): 104-111, 2018 02.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29287920

RESUMO

Mycobacterial culture has a high sensitivity and is the test of choice for the microbiological diagnosis of tuberculosis and nontuberculous mycobacterial infections. However, the results of this culture require at least 2-3 weeks to obtain positivity. Staining is rapid and can be used as a complementary study, although its sensitivity is low. Gene amplification tests have an intermediate sensitivity and obtain results in 1-2 days. These last tests are indicated in cases with moderate or high clinical suspicion. In HIV patients with severe immunodeficiency (<200 CD4), lipoarabinomannan antigen detection in urine may be useful. The identification of isolates from positive cultures is essential to evaluate the clinical significance of the culture results and consider the therapeutic options available. At present, there is a wide range of identification techniques available, which provide results within just 1-4 days. The future of diagnostic techniques in tuberculosis and nontuberculous mycobacterial infections lies in greater development of gene amplification techniques and promoting the search for biomarkers which enable a new approach to the diagnosis of these infections.


Assuntos
Técnicas Bacteriológicas , Infecções por Mycobacterium/diagnóstico , Meios de Cultura , DNA Bacteriano/genética , Previsões , Infecções por HIV/complicações , Humanos , Lipopolissacarídeos/urina , Mycobacterium/crescimento & desenvolvimento , Mycobacterium/isolamento & purificação , Infecções por Mycobacterium/microbiologia , Infecções por Mycobacterium/urina , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Manejo de Espécimes , Coloração e Rotulagem/métodos , Fatores de Tempo
18.
BMC Infect Dis ; 17(1): 803, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29282005

RESUMO

BACKGROUND: Up to one third of HIV-infected individuals with suspected TB are sputum-scarce. The Alere Determine™ TB LAM Ag lateral flow strip test can be used to diagnose TB in HIV-infected patients with advanced immunosuppression. However, how urine LAM testing should be incorporated into testing algorithms and in the context of specific patient sub-groups remains unclear. METHODS: This study represents a post hoc sub-group analysis of data from a randomized multi-center parent study. The study population consisted of hospitalized HIV-infected patients with suspected TB who were unable to produce sputum and who underwent urine LAM testing. The diagnostic utility of urine LAM for TB in this group was compared to the performance of urine LAM in patients who did produce a sputum sample in the parent study. RESULTS: There were a total of 187 and 2341 patients in the sputum-scarce and sputum-producing cohorts, respectively. 80 of the sputum-scarce patients underwent testing with urine LAM. In comparison to those who did produce sputum, sputum-scarce patients had a younger age, a lower Karnofsky performance score, and a lower weight and BMI at admission. A greater proportion of sputum-scarce patients were urine LAM positive, compared to those who were able to produce sputum (31% vs. 21%, p = 0.04). A higher proportion of sputum-scarce patients died within 8 weeks of admission (32% vs. 24%, p = 0.013). We inferred that 19% of HIV-infected sputum-scarce patients suspected of TB were diagnosed with tuberculosis by urine LAM testing, with an estimated positive predictive value of 63% (95% CI 43-82%). CONCLUSIONS: Urine LAM testing can effectively identify tuberculosis in HIV-infected patients who are at a higher risk of mortality yet are unable to generate a sputum sample for diagnostic testing. Our findings support the use of urine LAM testing in sputum-scarce hospitalized HIV-infected patients, and its incorporation into diagnostic algorithms for this patient population.


Assuntos
Infecções por HIV/diagnóstico , Lipopolissacarídeos/urina , Escarro/microbiologia , Tuberculose/diagnóstico , Adulto , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/complicações , Infecções por HIV/patologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose/complicações
19.
Sci Transl Med ; 9(420)2017 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-29237757

RESUMO

An accurate urine test for pulmonary tuberculosis (TB), affecting 9.6 million patients worldwide, is critically needed for surveillance and treatment management. Past attempts failed to reliably detect the mycobacterial glycan antigen lipoarabinomannan (LAM), a marker of active TB, in HIV-negative, pulmonary TB-infected patients' urine (85% of 9.6 million patients). We apply a copper complex dye within a hydrogel nanocage that captures LAM with very high affinity, displacing interfering urine proteins. The technology was applied to study pretreatment urine from 48 Peruvian patients, all negative for HIV, with microbiologically confirmed active pulmonary TB. LAM was quantitatively measured in the urine with a sensitivity of >95% and a specificity of >80% (n = 101) in a concentration range of 14 to 2000 picograms per milliliter, as compared to non-TB, healthy and diseased, age-matched controls (evaluated by receiver operating characteristic analysis; area under the curve, 0.95; 95% confidence interval, 0.9005 to 0.9957). Urinary LAM was elevated in patients with a higher mycobacterial burden (n = 42), a higher proportion of weight loss (n = 37), or cough (n = 50). The technology can be configured in a variety of formats to detect a panel of previously undetectable very-low-abundance TB urinary analytes. Eight of nine patients who were smear-negative and culture-positive for TB tested positive for urinary LAM. This technology has broad implications for pulmonary TB screening, transmission control, and treatment management for HIV-negative patients.


Assuntos
Infecções por HIV/complicações , Infecções por HIV/urina , Lipopolissacarídeos/urina , Índice de Gravidade de Doença , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/urina , Adulto , Anticorpos Antibacterianos/metabolismo , Antígenos de Bactérias/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Corantes , Cobre , Efeitos Psicossociais da Doença , Citocinas/metabolismo , Feminino , Infecções por HIV/patologia , Humanos , Imunoensaio , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Adulto Jovem
20.
Clin Infect Dis ; 65(11): 1878-1883, 2017 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-29020319

RESUMO

Background: Tuberculosis is a major health concern in several countries, and effective diagnostic algorithms for use in human immunodeficiency virus (HIV)-positive patients are urgently needed. Methods: At prescription of antiretroviral therapy, all patients in 3 Mozambican health centers were screened for tuberculosis, with a combined approach: World Health Organization (WHO) 4-symptom screening (fever, cough, night sweats, and weight loss), a rapid test detecting mycobacterial lipoarabinomannan in urine (Determine TB LAM), and a molecular assay performed on a sputum sample (Xpert MTB/RIF; repeated if first result was negative). Patients with positive LAM or Xpert MTB/RIF results were referred for tuberculosis treatment. Results: Among 972 patients with a complete diagnostic algorithm (58.5% female; median CD4 cell count, 278/µL; WHO HIV stage I, 66.8%), 98 (10.1%) tested positive with Xpert (90, 9.3%) or LAM (34, 3.5%) assays. Compared with a single-test Xpert strategy, dual Xpert tests improved case finding by 21.6%, LAM testing alone improved it by 13.5%, and dual Xpert tests plus LAM testing improved it by 32.4%. Rifampicin resistance in Xpert-positive patients was infrequent (2.5%). Among patients with positive results, 22 of 98 (22.4%) had no symptoms at WHO 4-symptom screening. Patients with tuberculosis diagnosed had significantly lower CD4 cell counts and hemoglobin levels, more advanced WHO stage, and higher HIV RNA levels. Fifteen (15.3%) did not start tuberculosis treatment, mostly owing to rapidly deteriorating clinical conditions or logistical constraints. The median interval between start of the diagnostic algorithm and start of tuberculosis treatment was 7 days. Conclusions: The prevalence of tuberculosis among Mozambican HIV-positive patients starting antiretroviral therapy was 10%, with limited rifampicin resistance. Use of combined point-of-care tests increased case finding, with a short time to treatment. Interventions are needed to remove logistical barriers and prevent presentation in very advanced HIV/tuberculosis disease.


Assuntos
Infecções por HIV/tratamento farmacológico , Técnicas de Diagnóstico Molecular , Sistemas Automatizados de Assistência Junto ao Leito , Testes Imediatos , Tuberculose Pulmonar/diagnóstico , Adulto , Algoritmos , Terapia Antirretroviral de Alta Atividade/estatística & dados numéricos , Antituberculosos/uso terapêutico , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/microbiologia , Soropositividade para HIV , Humanos , Lipopolissacarídeos/urina , Masculino , Moçambique/epidemiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Prevalência , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia
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