Abstract
According to World Health Organization estimates, tuberculosis (TB) and lower respiratory tract infections (LRTIs) are both among the top 10 global causes of death. TB and community-acquired ...pneumonia (CAP), if mortality estimates are combined, would rank as the third most common cause of death globally. It is estimated that each year there are approximately 10 million new cases of TB that are associated with approximately 1.2 million deaths, and almost 450 million new episodes of LRTI (synonymous with CAP) with approximately 4 million associated deaths. Globally,
Streptococcus pneumoniae
remains the most common cause of CAP. However, although well documented, it is not widely appreciated that in several parts of the world, including sub-Saharan Africa, Asia, and South America,
Mycobacterium tuberculosis
is an important cause of CAP, if not the most common organism isolated in such settings. Thus, CAP due to
M. tuberculosis
is not uncommon in some parts of the world with up to a third of cases being attributable to
M. tuberculosis
. Consequently, TB remains an important clinical entity in the intensive care unit in these settings. Despite its frequency and importance, there are very limited data about TB CAP. In this review we discussed the epidemiology, immunopathogenesis, clinical presentation, diagnosis, management, prognosis, and prevention of TB CAP. The utility of newer diagnostic approaches is highlighted.
Globally, Xpert MTB/RIF (Xpert) is the most widely used PCR test for the diagnosis of tuberculosis (TB). Positive results in previously treated patients, which are due to old DNA or active disease, ...are a diagnostic dilemma. We prospectively retested sputum from 238 patients, irrespective of current symptoms, who were previously diagnosed to be Xpert positive and treated successfully. Patients who retested as Xpert positive and culture negative were exhaustively investigated (repeat culture, chest radiography, bronchoscopy with bronchoalveolar lavage, long-term clinical follow-up). We evaluated whether the duration since previous treatment completion, mycobacterial burden (the Xpert cycle threshold
value), and reclassification of Xpert-positive results with a very low semiquantitation level to Xpert-negative results reduced the rate of false positivity. A total of 229/238 (96%) of patients were culture negative. Sixteen of 229 (7%) were Xpert positive a median of 11 months (interquartile range, 5 to 19 months) after treatment completion. The specificity was 93% (95% confidence interval CI, 89 to 96%). Nine of 15 (40%) Xpert-positive, culture-negative patients reverted to Xpert negative after 2 to 3 months (1 patient declined further participation). Patients with false-positive Xpert results had a lower mycobacterial burden than patients with true-positive Xpert results (
, 28.7 95% CI, 27.2 to 30.4 versus 17.6 95% CI, 16.9 to 18.2;
< 0.001), an increased likelihood of a chest radiograph not compatible with active TB (5/15 patients versus 0/5 patients;
= 0.026), and less-viscous sputum (15/16 patients versus 2/5 patients whose sputum was graded as mucoid or less;
= 0.038). All patients who initially retested as Xpert positive and culture negative ("Xpert false positive") were clinically well without treatment after follow-up. The duration since the previous treatment poorly predicted false-positive results (a duration of ≤2 years identified only 66% of patients with false-positive results). Reclassifying Xpert-positive results with a very low semiquantitation level to Xpert negative improved the specificity (+3% 95% CI, +2 to +5%) but reduced the sensitivity (-10% 95% CI, -4 to -15%). Patients with previous TB retested with Xpert can have false-positive results and thus not require treatment. These data inform clinical practice by highlighting the challenges in interpreting Xpert-positive results, underscore the need for culture, and have implications for next-generation ultrasensitive tests.
A randomized, phase 2 trial compared the NVX-CoV2373 nanoparticle vaccine with placebo in participants in South Africa, including 30% who were seropositive at baseline. Overall vaccine efficacy was ...49.4%, with the B.1.351 variant identified in more than 90% of isolates.
Background. Patients with previous tuberculosis may have residual DNA in sputum that confounds nucleic acid amplification tests such as Xpert MTB/RIF. Little is known about the frequency of ...Xpert-positive, culture-negative ("false positive") results in retreatment patients, whether these are distinguishable from true positives, and whether Xpert's automated filter-based wash step reduces false positivity by removing residual DNA associated with nonintact cells. Methods. Pretreatment patients (n = 2889) with symptoms of tuberculosis from Cape Town, South Africa, underwent a sputum-based liquid culture and Xpert. We also compared Xpert result from dilutions of intact or heat-lysed and mechanically lysed bacilli. Results. Retreatment cases were more likely to be Xpert false-positive (45/321 Xpert-positive retreatment cases were false-positive) than new cases (40/461) (14% 95% confidence interval {CI}, 10%-18% vs 8% 95% CI, 6%–12%; P = .018). Fewer years since treatment completion (adjusted odds ratio aOR, 0.85 95% CI, .73–.99), less mycobacterial DNA (aOR, 1.14 95% CI, 1.03–1.27 per cycle threshold CT), and a chest radiograph not suggestive of active tuberculosis (aOR, 0.22 95% CI, .06–.82) were associated with false positivity. CT had suboptimal accuracy for false positivity: 46% of Xpert-positives with CT > 30 would be false positive, although 70% of false positives would be missed. CT's predictive ability (area under the curve, 0.83 95% CI, .76–.90) was not improved by additional variables. Xpert detected nonviable, nonintact bacilli without a change in CT vs controls. Conclusions. One in 7 Xpert-positive retreatment patients were culture negative and potentially false positive. False positivity was associated with recent previous tuberculosis, high CT, and a chest radiograph not suggestive of active tuberculosis. Clinicians may consider awaiting confirmatory testing in retreatment patients with CT > 30; however, most false positives fall below this cut-point. Xpert can detect DNA from nonviable, nonintact bacilli.
Tuberculosis (TB) is now the biggest infectious disease killer worldwide. Although the estimated incidence of TB has marginally declined over several years, it is out of control in some regions ...including in Africa. The advent of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) threatens to further destabilize control in several regions of the world. Drug-resistant TB constitutes a significant threat because it underpins almost 25% of global TB mortality, is associated with high morbidity, is a threat to healthcare workers and is unsustainably costly to treat. The advent of highly resistant TB with emerging bacillary resistance to newer drugs has raised further concern. Encouragingly, in addition to preventative strategies, several interventions have recently been introduced to curb the drug-resistant TB epidemic, including newer molecular diagnostic tools, new (bedaquiline and delamanid) and repurposed (linezolid and clofazimine) drugs and shorter and individualized treatment regimens. However, there are several controversies that surround the use of new drugs and regimens, including whether, how and to what extent they should be used, and who specifically should be treated so that outcomes are optimally improved without amplifying the burden of drug resistance, and other potential drawbacks, thus sustaining effectiveness of the new drugs. The equipoise surrounding these controversies is discussed and some recommendations are provided.
Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to ∼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant ...tuberculosis (MDR/RR-TB).
To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or aminoglycosides).
Participants were randomly assigned (1:1 ratio) to a ∼6-month all-oral regimen that included levofloxacin, bedaquiline, and linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization (WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drug substitution is counted as an unfavorable outcome) 24 months after treatment initiation. The trial was stopped prematurely when bedaquiline-based therapy became the standard of care in South Africa.
In total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the interventional arm) were included in the modified intention-to-treat analysis; 51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm (51% 25 of 49 vs. 22.7% 10 of 44; risk ratio, 2.2 1.2-4.1;
= 0.006). Toxicity-related drug substitution occurred more frequently in the SOC arm (65.9% 29 of 44 vs. 34.7% 17 of 49;
= 0.001), 82.8% (24 of 29) owing to kanamycin (mainly hearing loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to linezolid (mainly anemia) in the interventional arm. Adverse event-related treatment discontinuation in the safety population was more common in the SOC arm (56.4% 31 of 55 vs. 32.1% 17 of 56;
= 0.007). However, grade 3 adverse events were more common in the interventional arm (55.4% 31 of 56 vs. 32.7 18 of 55;
= 0.022). Culture conversion was significantly better in the intervention arm (hazard ratio, 2.6 1.4-4.9;
= 0.003) after censoring those with bedaquiline replacement in the SOC arm (and this pattern remained consistent after censoring for drug replacement in both arms;
= 0.01).
Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drug substitution). However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB.Clinical trial registered with www.clinicaltrials.gov (NCT02454205).
BackgroundPleural tuberculosis (TB) remains difficult to diagnose. Tests measuring host biomarkers, such as adenosine deaminase (ADA) and unstimulated interferon-gamma, perform better than ...conventional microbiological tests for TB diagnosis using pleural fluid. However, there is no data on the cost-effectiveness of these diagnostic approaches. MethodsA cost-consequence analysis was performed from the South African healthcare provider perspective to determine the cost-effectiveness of the following strategies for the diagnosis of pleural TB: (I) Smear microscopy (SM); (II) Mycobacterial-Growth-In-Tube liquid culture (MGIT); (III) adenosine deaminase (ADA); (IV) Xpert ULTRA (Xpert); (V) unstimulated interferon-gamma using IRISA-TB™ (IRISA-TB). Costs (2019 USD) were derived from national sources and outcomes from published literature. Cost-effectiveness was expressed as the cost per pleural TB case diagnosed and initiated on treatment (per 1,000 patients screened). Sensitivity analyses were performed. ResultsTotal strategy costs ranged from $354,632 (SM) to $390,363 (ADA). Strategies incorporating highly specific tests, including IRISA-TB and Xpert, had the lowest costs associated with unnecessary treatment. In terms of outcomes (per 1,000 screened), IRISA-TB and ADA correctly identified the most pleural TB cases (8.4 and 8.0 cases, respectively), almost double that of MGIT (4.2 cases) and Xpert ULTRA (3.7 cases). IRISA-TB was the most cost-effective strategy, as the cost per pleural TB patient diagnosed and initiated on treatment was $44,084, ~$5,000 less than ADA (the second most cost-effective strategy; $49,065). These values were most sensitive to changes in pleural TB prevalence, treatment costs, and empirical treatment rates. The cost difference, compared to ADA, equated to a potential saving of ~US$45 million per year in South Africa. ConclusionsIRISA-TB offers good value for money and is a potentially more cost-effective alternative to ADA for pleural TB diagnosis.
Abstract
Background
Automated radiologic analysis using computer-aided detection software (CAD) could facilitate chest X-ray (CXR) use in tuberculosis diagnosis. There is little to no evidence on the ...accuracy of commercially available deep learning-based CAD in different populations, including patients with smear-negative tuberculosis and people living with human immunodeficiency virus (HIV, PLWH).
Methods
We collected CXRs and individual patient data (IPD) from studies evaluating CAD in patients self-referring for tuberculosis symptoms with culture or nucleic acid amplification testing as the reference. We reanalyzed CXRs with three CAD programs (CAD4TB version (v) 6, Lunit v3.1.0.0, and qXR v2). We estimated sensitivity and specificity within each study and pooled using IPD meta-analysis. We used multivariable meta-regression to identify characteristics modifying accuracy.
Results
We included CXRs and IPD of 3727/3967 participants from 4/7 eligible studies. 17% (621/3727) were PLWH. 17% (645/3727) had microbiologically confirmed tuberculosis. Despite using the same threshold score for classifying CXR in every study, sensitivity and specificity varied from study to study. The software had similar unadjusted accuracy (at 90% pooled sensitivity, pooled specificities were: CAD4TBv6, 56.9% 95% confidence interval {CI}: 51.7–61.9; Lunit, 54.1% 95% CI: 44.6–63.3; qXRv2, 60.5% 95% CI: 51.7–68.6). Adjusted absolute differences in pooled sensitivity between PLWH and HIV-uninfected participants were: CAD4TBv6, −13.4% −21.1, −6.9; Lunit, +2.2% −3.6, +6.3; qXRv2: −13.4% −21.5, −6.6; between smear-negative and smear-positive tuberculosis was: were CAD4TBv6, −12.3% −19.5, −6.1; Lunit, −17.2% −24.6, −10.5; qXRv2, −16.6% −24.4, −9.9. Accuracy was similar to human readers.
Conclusions
For CAD CXR analysis to be implemented as a high-sensitivity tuberculosis rule-out test, users will need threshold scores identified from their own patient populations and stratified by HIV and smear status.
An individual patient data (IPD) meta-analysis found the accuracy of commercially available deep learning-based chest X-ray analysis software for detecting tuberculosis varied between studies and by patient characteristics. Diagnostic heterogeneity poses an implementation challenge for this novel technology.
Two in every five patients with active tuberculosis (TB) remain undiagnosed or unreported. Therefore community-based, active case-finding strategies require urgent implementation. However, whether ...point-of-care (POC), portable battery-operated, molecular diagnostic tools deployed at a community level, compared with conventionally used POC smear microscopy, can shorten time-to-treatment initiation, thus potentially curtailing transmission, remains unclear. To clarify this issue, we performed an open-label, randomized controlled trial in periurban informal settlements of Cape Town, South Africa, where we TB symptom screened 5,274 individuals using a community-based scalable mobile clinic. Some 584 individuals with HIV infection or symptoms of TB underwent targeted diagnostic screening and were randomized (1:1) to same-day smear microscopy (n = 296) or on-site DNA-based molecular diagnosis (n = 288; GeneXpert). The primary aim was to compare time to TB treatment initiation between the arms. Secondary aims included feasibility and detection of probably infectious people. Of participants who underwent targeted screening, 9.9% (58 of 584) had culture-confirmed TB. Time-to-treatment initiation occurred significantly earlier in the Xpert versus the smear-microscopy arm (8 versus 41 d, P = 0.002). However, overall, Xpert detected only 52% of individuals with culture-positive TB. Notably, Xpert detected almost all of the probably infectious patients compared with smear microscopy (94.1% versus 23.5%, P = <0.001). Xpert was associated with a shorter median time to treatment of probably infectious patients (7 versus 24 d, P = 0.02) and a greater proportion of infectious patients were on treatment at 60 d compared with the probably noninfectious patients (76.5% versus 38.2%, P < 0.01). Overall, a greater proportion of POC Xpert-positive participants were on treatment at 60 d compared with all culture-positive participants (100% versus 46.5%, P < 0.01). These findings challenge the traditional paradigm of a passive case-finding, public health strategy and argues for the implementation of portable DNA-based diagnosis with linkage to care as a community-oriented, transmission-interruption strategy. The study was registered with the South African National Clinical Trials Registry (application ID 4367; DOH-27-0317-5367) and ClinicalTrials.gov (NCT03168945).
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