Potential Utility of C-reactive Protein for Tuberculosis Risk Stratification Among Patients With Non-Meningitic Symptoms at HIV Diagnosis in Low- and Middle-income Countries.

Background: The World Health Organization recommends initiating same-day antiretroviral therapy (ART) while tuberculosis (TB) testing is under way for patients with non-meningitic symptoms at HIV diagnosis, though safety data are limited. C-reactive protein (CRP) testing may improve TB risk stratification in this population. Methods: In this baseline analysis of 498 adults (>18 years) with TB symptoms at HIV diagnosis who were enrolled in a trial of rapid ART initiation in Haiti, we describe test characteristics of varying CRP thresholds in the diagnosis of TB. We also assessed predictors of high CRP as a continuous variable using generalized linear models. Results: Eighty-seven (17.5%) participants were diagnosed with baseline TB. The median CRP was 33.0 mg/L (interquartile range: 5.1, 85.5) in those with TB, and 2.6 mg/L (interquartile range: 0.8, 11.7) in those without TB. As the CRP threshold increased from ≥1 mg/L to ≥10 mg/L, the positive predictive value for TB increased from 22.4% to 35.4% and negative predictive value decreased from 96.9% to 92.3%. With CRP thresholds varying from <1 to <10 mg/L, a range from 25.5% to 64.9% of the cohort would have been eligible for same-day ART and 0.8% to 5.0% would have untreated TB at ART initiation. Conclusions: CRP concentrations can be used to improve TB risk stratification, facilitating same-day decisions about ART initiation. Depending on the CRP threshold, one-quarter to two-thirds of patients could be eligible for same-day ART, with a reduction of 3- to 20-fold in the proportion with untreated TB, compared with a strategy of same-day ART while awaiting TB test results.

Same-day testing with initiation of antiretroviral therapy or tuberculosis treatment versus standard care for persons presenting with tuberculosis symptoms at HIV diagnosis: A randomized open-label trial from Haiti.

BACKGROUND: Same-day HIV testing and antiretroviral therapy (ART) initiation is being widely implemented. However, the optimal timing of ART among patients with tuberculosis (TB) symptoms is unknown. We hypothesized that same-day treatment (TB treatment for those diagnosed with TB; ART for those not diagnosed with TB) would be superior to standard care in this population. METHODS AND FINDINGS: We conducted an open-label trial among adults with TB symptoms at initial HIV diagnosis at GHESKIO in Haiti; participants were recruited and randomized on the same day. Participants were randomized in a 1:1 ratio to same-day treatment (same-day TB testing with same-day TB treatment if TB diagnosed; same-day ART if TB not diagnosed) versus standard care (initiating TB treatment within 7 days and delaying ART to day 7 if TB not diagnosed). In both groups, ART was initiated 2 weeks after TB treatment. The primary outcome was retention in care with 48-week HIV-1 RNA <200 copies/mL, with intention to treat (ITT) analysis. From November 6, 2017 to January 16, 2020, 500 participants were randomized (250/group); the final study visit occurred on March 1, 2021. Baseline TB was diagnosed in 40 (16.0%) in the standard and 48 (19.2%) in the same-day group; all initiated TB treatment. In the standard group, 245 (98.0%) initiated ART at median of 9 days; 6 (2.4%) died, 15 (6.0%) missed the 48-week visit, and 229 (91.6%) attended the 48-week visit. Among all who were randomized, 220 (88.0%) received 48-week HIV-1 RNA testing; 168 had <200 copies/mL (among randomized: 67.2%; among tested: 76.4%). In the same-day group, 249 (99.6%) initiated ART at median of 0 days; 9 (3.6%) died, 23 (9.2%) missed the 48-week visit, and 218 (87.2%) attended the 48-week visit. Among all who were randomized, 211 (84.4%) received 48-week HIV-1 RNA; 152 had <200 copies/mL (among randomized: 60.8%; among tested: 72.0%). There was no difference between groups in the primary outcome (60.8% versus 67.2%; risk difference: -0.06; 95% CI [-0.15, 0.02]; p = 0.14). Two new grade 3 or 4 events were reported per group; none were judged to be related to the intervention. The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain. CONCLUSIONS: In patients with TB symptoms at HIV diagnosis, we found that same-day treatment was not associated with superior retention and viral suppression. In this study, a short delay in ART initiation did not appear to compromise outcomes. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov NCT03154320.

Potential Utility of C-reactive Protein for Tuberculosis Risk Stratification among Patients with Non-Meningitic Symptoms at HIV Diagnosis in Low- and Middle-Income Countries.

Article Summary: We assessed the association between C-reactive protein (CRP) and Mycobacterium tuberculosis (TB) diagnosis in symptomatic patients at HIV diagnosis. We found that CRP concentrations can improve tuberculosis risk stratification, facilitating decision making about whether (specific) tuberculosis testing is indicated before antiretroviral therapy initiation. Background: The World Health Organization recommends initiating same-day ART while tuberculosis testing is underway for patients with non-meningitic symptoms at HIV diagnosis, though safety data are limited. C-reactive protein (CRP) testing may improve tuberculosis risk stratification in this population. Methods: In this baseline analysis of 498 adults (>18 years) with tuberculosis symptoms at HIV diagnosis who were enrolled in a trial of rapid ART initiation in Haiti, we describe test characteristics of varying CRP thresholds in the diagnosis of TB. We also assessed predictors of high CRP (≥3 mg/dL) using generalized linear models. Results: Eighty-seven (17.5%) patients were diagnosed with baseline TB. The median CRP was 33.0 mg/L (IQR: 5.1, 85.5) in those with TB, and 2.6 mg/L (IQR: 0.8, 11.7) in those without TB. As the CRP threshold increased from ≥1 mg/L to ≥10 mg/L, the positive predictive value for TB increased from 22.4% to 35.4%, and negative predictive value decreased from 96.9% to 92.3%. With CRP thresholds varying from <1 to <10 mg/L, a range from 25.5% to 64.9% of the cohort would have been eligible for same-day ART, and 0.8% to 5.0% would have untreated TB at ART initiation. Conclusions: CRP concentrations can be used to improve TB risk stratification, facilitating same-day decisions about ART initiation. Depending on the CRP threshold, one-quarter to two-thirds of patients could be eligible for same-day ART, with a reduction of 3-fold to 20-fold in the proportion with untreated TB, compared with a strategy of same-day ART while awaiting TB test results.

Lifetime burden of disease due to incident tuberculosis: a global reappraisal including post-tuberculosis sequelae.

BACKGROUND: Many individuals who survive tuberculosis disease face ongoing disability and elevated mortality risks. However, the impact of post-tuberculosis sequelae is generally omitted from policy analyses and disease burden estimates. We therefore estimated the global burden of tuberculosis, inclusive of post-tuberculosis morbidity and mortality. METHODS: We constructed a hypothetical cohort of individuals developing tuberculosis in 2019, including pulmonary and extrapulmonary disease. We simulated lifetime health outcomes for this cohort, stratified by country, age, sex, HIV status, and treatment status. We used disability-adjusted life-years (DALYs) to summarise fatal and non-fatal health losses attributable to tuberculosis, during the disease episode and afterwards. We estimated post-tuberculosis mortality and morbidity based on the decreased lung function caused by pulmonary tuberculosis disease. FINDINGS: Globally, we estimated 122 (95% uncertainty interval [UI] 98-151) million DALYs due to incident tuberculosis disease in 2019, with 58 (38-83) million DALYs attributed to post-tuberculosis sequelae, representing 47% (95% UI 37-57) of the total burden estimate. The increase in burden from post-tuberculosis varied substantially across countries and regions, driven largely by differences in estimated case fatality for the disease episode. We estimated 12·1 DALYs (95% UI 10·0-14·9) per incident tuberculosis case, of which 6·3 DALYs (5·6-7·0) were from the disease episode and 5·8 DALYs (3·8-8·3) were from post-tuberculosis. Per-case post-tuberculosis burden estimates were greater for younger individuals, and in countries with high incidence rates. The burden of post-tuberculosis was spread over the remaining lifetime of tuberculosis survivors, with almost a third of total DALYs (28%, 95% UI 23-34) accruing 15 or more years after incident tuberculosis. INTERPRETATION: Post-tuberculosis sequelae add substantially to the overall disease burden caused by tuberculosis. This hitherto unquantified burden has been omitted from most previous policy analyses. Future policy analyses and burden estimates should take better account of post-tuberculosis, to avoid the potential misallocation of funding, political attention, and research effort resulting from continued neglect of this issue. FUNDING: National Institutes of Health.

Burden of non-communicable diseases from infectious causes in 2017: a modelling study.

BACKGROUND: Non-communicable diseases (NCDs) cause a large burden of disease globally. Some infectious diseases cause an increased risk of developing specific NCDs. Although the NCD burden from some infectious causes has been quantified, in this study, we aimed to more comprehensively quantify the global burden of NCDs from infectious causes. METHODS: In this modelling study, we identified NCDs with established infectious risk factors and infectious diseases with long-term non-communicable sequelae, and did narrative reviews between April 11, 2018, and June 10, 2020, to obtain relative risks (RRs) or population attributable fractions (PAFs) from studies quantifying the contribution of infectious causes to NCDs. To determine infection-attributable burden for the year 2017, we applied estimates of PAFs to estimates of disease burden from the Global Burden of Disease Study (GBD) 2017 for pairs of infectious causes and NCDs, or used estimates of attributable burden directly from GBD 2017. Morbidity and mortality burden from these conditions was summarised with age-standardised rates of disability-adjusted life-years (DALYs), for geographical regions as defined by the GBD. Estimates of NCD burden attributable to infectious causes were compared with attributable burden for the groups of risk factors with the highest PAFs from GBD 2017. FINDINGS: Globally, we quantified 130 million DALYs from NCDs attributable to infection, comprising 8·4% of all NCD DALYs. The infection-NCD pairs with the largest burden were gastric cancer due to H pylori (14·6 million DALYs), cirrhosis and other chronic liver diseases due to hepatitis B virus (12·2 million) and hepatitis C virus (10·4 million), liver cancer due to hepatitis B virus (9·4 million), rheumatic heart disease due to streptococcal infection (9·4 million), and cervical cancer due to HPV (8·0 million). Age-standardised rates of infection-attributable NCD burden were highest in Oceania (3564 DALYs per 100 000 of the population) and central sub-Saharan Africa (2988 DALYs per 100 000) followed by the other sub-Saharan African regions, and lowest in Australia and New Zealand (803 DALYs per 100 000) followed by other high-income regions. In sub-Saharan Africa, the proportion of crude NCD burden attributable to infectious causes was 11·7%, which was higher than the proportion of burden attributable to each of several common risk factors of NCDs (tobacco, alcohol use, high systolic blood pressure, dietary risks, high fasting plasma glucose, air pollution, and high LDL cholesterol). In other broad regions, infectious causes ranked between fifth and eighth in terms of crude attributable proportions among the nine risks compared. The age-standardised attributable proportion for infectious risks remained highest in sub-Saharan Africa of the broad regions, but age-standardisation caused infectious risks to fall below dietary risks, high systolic blood pressure, and fasting plasma glucose in ranked attributable proportions within the region. INTERPRETATION: Infectious conditions cause substantial NCD burden with clear regional variation, and estimates of this burden are likely to increase as evidence that can be used for quantification expands. To comprehensively avert NCD burden, particularly in low-income and middle-income countries, the availability, coverage, and quality of cost-effective interventions for key infectious conditions need to be strengthened. Efforts to promote universal health coverage must address infectious risks leading to NCDs, particularly in populations with high rates of these infectious conditions, to reduce existing regional disparities in rates of NCD burden. FUNDING: Leona M and Harry B Helmsley Charitable Trust.

Use of GeneXpert MTB/RIF on a single pooled sputum specimen to exclude pulmonary tuberculosis among hospital inpatients placed in respiratory isolation.

BACKGROUND: Patients with suspected pulmonary tuberculosis (PTB) are usually placed in respiratory isolation awaiting three sputum smear microscopy results for acid-fast bacilli (3AFB). GeneXpert MTB/RIF (Xpert) on a pooled sample from two sputa may allow for more rapid de-isolation. OBJECTIVES: To compare the sensitivity and negative predictive value (NPV) of Xpert performed on a single pooled sputum sample ('pooled Xpert') to 3AFB, in order to exclude PTB in patients placed in respiratory isolation. METHODS: Hospital inpatients in respiratory isolation for possible PTB were enrolled prospectively. Three expectorated sputum samples were obtained for smear microscopy. Two of the same samples had 0.5 ml removed from each and pooled for pooled Xpert. The diagnostic accuracy of pooled Xpert and 3AFB were assessed and compared to liquid culture at 8 weeks as the reference standard. RESULTS: Of 56 participants, nine (16.1%) were diagnosed with PTB. Compared to liquid culture, pooled Xpert had a sensitivity of 88.9% (95% confidence interval (CI) 57-99%) and NPV of 97.9% (95% CI 89-99%). 3AFB had a sensitivity of 66.7% (95% CI 35-88%) and NPV of 93.5% (95% CI 83-98%). CONCLUSIONS: A single pooled Xpert was non-inferior to 3AFB, with a strong trend towards greater sensitivity and better NPV. These findings support the use of a single pooled Xpert as an effective rapid screening approach for ruling out PTB in low incidence settings. Its value in high incidence settings and optimal combination with smear microscopy and culture warrant further evaluation.

Asthma and atopy prevalence are not reduced among former tuberculosis patients compared with controls in Lima, Peru.

BACKGROUND: Although there are theoretical reasons for believing that asthma and atopy may be negatively correlated with tuberculosis, epidemiological studies have had conflicting findings. OBJECTIVE: To determine if people with confirmed tuberculosis were less likely to be atopic and less likely to have atopic disease including asthma compared to those with no previous tuberculosis. METHODS: Patients in Lima, Peru with a prior history of tuberculosis were identified from clinic records in this cohort study. A representative sample of individuals without a prior tuberculosis diagnosis was recruited from the same community. Allergen skin prick testing was performed to classify atopic status. Allergic rhinitis was identified by history. Asthma was defined by symptoms and spirometry. Eosinophilic airway inflammation was measured using exhaled nitric oxide levels. RESULTS: We evaluated 177 patients with, and 161 individuals without, previous tuberculosis. There was a lower prevalence of atopy among people with prior tuberculosis on univariate analysis (odds ratio 0.57; 95% confidence interval 0.37-0.88) but, after adjustment for potential confounders, this was no longer statistically significant (aOR 0.64, 95% CI 0.41-1.01). The prevalence of allergic rhinitis (aOR 0.76, 95% CI 0.47 to 1.24 and asthma (aOR 1.18, 95% CI 0.69 to 2.00) did not differ significantly between the two groups. We also found no significant difference in the prevalence of elevated exhaled nitric oxide (aOR 1.30, 95% CI 0.78 to 2.17) or a combined index of atopic disease (aOR 0.86, 95% CI 0.54 to 1.36). CONCLUSION: In this urban environment in a middle-income country, prior tuberculosis may be associated with a reduced risk of atopy but does not protect against asthma and atopic disease.

Better than a pound of cure: preventing the development of multidrug-resistant tuberculosis.

Diagnostic and treatment delays contribute to increased death and disability among the 490,000 adults and children who develop multidrug-resistant (MDR) tuberculosis every year. Since the treatment of MDR tuberculosis is complex, costly and often toxic, tuberculosis control programs should prioritize strategies to prevent drug-resistant tuberculosis. Opportunities to limit transmission and prevent disease progression in close contacts of MDR tuberculosis cases are often neglected. Effective MDR tuberculosis preventive strategies could minimize the costs for patients and healthcare systems. This review characterizes the biological basis for the development of MDR tuberculosis, outlines the evidence for strategies to reduce transmission and highlights programmatic approaches to the management of patients infected with drug-resistant strains of Mycobacterium tuberculosis.

Decentralized care for multidrug-resistant tuberculosis: a systematic review and meta-analysis.

OBJECTIVE: To assess the effectiveness of decentralized treatment and care for patients with multidrug-resistant (MDR) tuberculosis, in comparison with centralized approaches. METHODS: We searched ClinicalTrials.gov, the Cochrane library, Embase®, Google Scholar, LILACS, PubMed®, Web of Science and the World Health Organization's portal of clinical trials for studies reporting treatment outcomes for decentralized and centralized care of MDR tuberculosis. The primary outcome was treatment success. When possible, we also evaluated, death, loss to follow-up, treatment adherence and health-system costs. To obtain pooled relative risk (RR) estimates, we performed random-effects meta-analyses. FINDINGS: Eight studies met the eligibility criteria for review inclusion. Six cohort studies, with 4026 participants in total, reported on treatment outcomes. The pooled RR estimate for decentralized versus centralized care for treatment success was 1.13 (95% CI: 1.01-1.27). The corresponding estimate for loss to follow-up was RR: 0.66 (95% CI: 0.38-1.13), for death RR: 1.01 (95% CI: 0.67-1.52) and for treatment failure was RR: 1.07 (95% CI: 0.48-2.40). Two of three studies evaluating health-care costs reported lower costs for the decentralized models of care than for the centralized models. CONCLUSION: Treatment success was more likely among patients with MDR tuberculosis treated using a decentralized approach. Further studies are required to explore the effectiveness of decentralized MDR tuberculosis care in a range of different settings.

Chronic airflow obstruction after successful treatment of multidrug-resistant tuberculosis.

Cross-sectional studies reveal an association between tuberculosis (TB) and chronic airflow obstruction, but cannot adequately address confounding. We hypothesised that treated pulmonary TB is an independent risk factor for chronic airflow obstruction. The Pulmones Post TB cohort study enrolled participants from Lima, Peru, aged 10-70 years with a history of drug-susceptible (DS)- or multidrug-resistant (MDR)-TB who had completed treatment and were clinically cured. Unexposed participants without TB were randomly selected from the same districts. We assessed respiratory symptoms, relevant environmental exposures, and spirometric lung function pre- and post-bronchodilator. In total, 144 participants with DS-TB, 33 with MDR-TB and 161 unexposed participants were fully evaluated. Compared with unexposed participants, MDR-TB patients had lower lung volumes (adjusted mean difference in forced vital capacity -370 mL, 95% CI -644- -97) and post-bronchodilator airflow obstruction (adjusted OR 4.89, 95% CI 1.27-18.78). Participants who had recovered from DS-TB did not have lower lung volumes than unexposed participants, but were more likely to have a reduced forced expiratory volume in 1 s/forced vital capacity ratio <0.70 (adjusted OR 2.47, 95% CI 1.01-6.03). Individuals successfully treated for TB may experience long-lasting sequelae. Interventions facilitating earlier TB treatment and management of chronic respiratory disease should be explored.

Tuberculosis and chronic respiratory disease: a systematic review.

BACKGROUND: Chronic respiratory disease causes substantial global morbidity and mortality. The contribution of pulmonary tuberculosis to the aetiology of chronic respiratory disease is rarely considered, but may be important in tuberculosis-endemic areas. METHODS: We performed a systematic literature review to assess the association between a history of tuberculosis and the presence of chronic obstructive pulmonary disease (COPD) or chronic suppurative lung disease (bronchiectasis). Study quality was evaluated using the National Heart Lung and Blood Institute quality assessment tool. Meta-analysis was performed using the DerSimonian and Laird random effects model. RESULTS: We identified 9 eligible studies for COPD and 2 for bronchiectasis. Overall, there was a significant association between a history of tuberculosis and the presence of COPD in adults aged over 40 years (pooled odds ratio 3.05 (95% confidence interval 2.42, 3.85). Among individual COPD studies the strongest associations were found in countries with a high incidence of tuberculosis, as well as among never smokers and younger people. CONCLUSION: In tuberculosis endemic areas, tuberculosis is strongly associated with the presence of chronic respiratory disease in adults. Efforts to improve long-term lung health should be part of tuberculosis care.

Peripheral venous and arterial blood gas analysis in adults: are they comparable? A systematic review and meta-analysis.

Peripheral venous blood gas (PVBG) analysis is increasingly being used as a substitute for arterial blood sampling; however, comparability has not been clearly established. To determine if the pH, PCO2 and PO2 obtained from PVBG analysis is comparable with arterial blood gas (ABG) analysis. A search was conducted of electronic databases as well as hand-searching of journals and reference lists through December 2012 to identify studies comparing PVBG with ABG analysis in adult subjects. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A meta-analysis using a random effects model was used to calculate the average difference (bias) and the limits of agreement for the venous and arterial pH, PCO2 and PO2 . A total of 18 studies comprising 1768 subjects were included in the meta-analysis. There was considerable heterogeneity between studies with I(2) approaching 100%. There was little difference between the pH obtained from the PVBG and the ABG, with the arterial pH typically 0.03 higher than the venous pH (95% confidence interval 0.029-0.038). The venous and arterial PCO2 were not comparable because the 95% prediction interval of the bias for venous PCO2 was unacceptably wide, extending from -10.7 mm Hg to +2.4 mm Hg. The PO2 values compared poorly, the arterial PO2 typically 36.9 mm Hg greater than the venous with significant variability (95% confidence interval from 27.2 to 46.6 mm Hg). PVBG analysis compares well with ABG analysis for pH estimations in adults but not to the PCO2 or PO2 . These differences are sufficiently large to be of clinical significance.