BACKGROUND:To understand how lung pathology relates to symptoms, microbiology, and progression risk in tuberculosis and to advance diagnostic development, we determined the frequency at screening of tuberculosis-consistent lesions in asymptomatic individuals within 5 years of tuberculosis diagnosis using highly sensitive imaging ([18F]-fluorodeoxyglucose PET-CT) and compared with chest x-ray computer-aided detection (CAD). METHODS:We enrolled a prospective longitudinal cohort in Khayelitsha, Cape Town, South Africa, of asymptomatic, HIV-uninfected contacts aged 18-65 years of patients with rifampicin-resistant tuberculosis, a tuberculosis high-risk group not eligible for chemoprophylaxis. Participants underwent baseline PET-CT, chest x-ray, phlebotomy, and intensive sputum collection, and were classified into four PET-CT lung categories: consistent with tuberculosis, inactive tuberculosis, other lesions, and normal. Chest x-ray was processed by three types of CAD software (CAD4TB [version 7.0], qXR [version 3.0.0], and Lunit [version 3.1.4.111]). Follow-up included symptom-agnostic tuberculosis screening (23-38 months) and provincial register review (≤74 months), and a subgroup had repeat PET-CT (5-15 months). Tuberculosis was defined as bacteriologically confirmed or clinically diagnosed. The primary outcome measures were hazard ratio (HR) for tuberculosis diagnosis and treatment by baseline PET-CT lung abnormality category with normal as the reference group, and diagnostic performance of chest x-ray CAD software using area under the receiver operator characteristic curve (AUC). FINDINGS:250 asymptomatic adults were enrolled between March 3, 2015, and Oct 11, 2017, irrespective of tuberculosis history or previous infection, and followed up for 1107 person-years (median 4·7 years [IQR 4·0-5·1]). 18 (7%) participants were treated for tuberculosis (16 [89%] of 18 bacteriologically confirmed). Six of 18 participants were diagnosed at baseline (four requiring induced sputum culture) and 12 of 18 after a median of 32 months (IQR 12-35). By baseline PET-CT category, tuberculosis was diagnosed and treated in 12 (41%) of 29 participants with scans consistent with tuberculosis, two (7%) of 30 with scans consistent with inactive tuberculosis, two (2%) of 83 with scans showing other lesions, and two (2%) of 108 with scans showing normal lungs. Participants with baseline PET-CT scans consistent with tuberculosis had the highest risk of 5-year tuberculosis diagnosis (HR 28·54 [95% CI 6·37-127·81] compared with those with scans showing normal lungs, p<0·0001), with no significant risk for scans consistent with inactive tuberculosis (3·55 [0·50-25·21], p=0·21) or other lung lesions (1·30 [0·18-9·23], p=0·79). 11 (69%) of the 16 participants with bacteriologically confirmed tuberculosis were asymptomatic at bacteriological confirmation, and ten (91%) of 11 had baseline PET-CT scans consistent with tuberculosis. Using baseline PET-CT classification as reference, the AUC for chest x-ray CAD software ranged from 0·86 (95% CI 0·72-0·99) to 0·89 (0·75-1·00) for bacteriologically confirmed tuberculosis. INTERPRETATION:Most adult asymptomatic contacts diagnosed with tuberculosis over 5 years had baseline radiographically evident disease, not radiographically negative incipient tuberculosis. Although PET-CT is not feasible for routine screening, it provides a highly sensitive reference benchmark for diagnostic development, with chest x-ray CAD performing comparatively well. FUNDING:South Africa Medical Research Council, US National Institutes of Health, Gates Foundation, Wellcome, UK Research and Innovation Medical Research Council, and Walter and Eliza Hall Institute of Medical Research.

Introduction There are limited published data on how countries carry out screening for tuberculosis (TB) disease and what the perceived challenges are for implementing screening from a country perspective. Understanding these factors are important to enable better planning and support for the roll-out of appropriate screening interventions.Methods We conducted a cross-sectional survey of national TB programmes from countries reporting >1000 TB cases annually.Results Sixty of 123 countries responded, representing 82% of the global TB burden. Only 35% of countries had a policy to screen for TB in all four key risk groups identified by WHO, 66% carried out all six WHO-recommended steps to implement screening and 39% collected all seven of the WHO-recommended data points for monitoring activity. Although 68% of countries planned to increase CXR-based screening, 90% reported at least one significant barrier to implementing this, and 20% were not aware of computer-aided detection (CAD) software technology.Conclusion Although chest X-ray and CAD use are expanding and hold promise as tools to find people with TB, many programmes do not have adequate access to them. While global policy is in place that recommends the use of these tools, efforts should be made to support countries tackling these barriers.

BACKGROUND:World Health Organization (WHO) tuberculosis (TB) screening guidelines recommend computer-aided detection (CAD) software for chest radiograph (CXR) interpretation. However, studies evaluating their diagnostic and prognostic accuracy are limited. METHODS:We conducted a prospective cohort study of household contacts of rifampicin-resistant TB in South Africa. Participants underwent baseline CXR and sputum investigation (routine [single spontaneous] and enhanced [additionally 2-3 induced]) for prevalent TB and follow-up for incident TB. Three CXR-CAD software products (CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT v3.1.4.111) were compared. We evaluated their performance to detect routine and enhanced prevalent and incident TB, comparing performance with blood tests (Xpert MTB host-response, erythrocyte sedimentation rate, C-reactive protein, QuantiFERON) in a subgroup. RESULTS:483 participants were followed up for 4.6 years (median). There were 23 prevalent (7 routinely diagnosed) and 38 incident TB cases. The AUC ROCs (95% CIs) to identify prevalent TB for CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT v3.1.4.111 were .87 (.77-.96), .88 (.79-.97), and .91 (.83-.99), respectively. More than 30% with scores above recommended CAD thresholds who were bacteriologically negative on routine baseline sputum were subsequently diagnosed by enhanced sputum investigation or during follow-up. The AUC performance of baseline CAD to identify incident cases ranged between .60 and .65. Diagnostic performance of CAD for prevalent TB was superior to blood testing. CONCLUSIONS:Our findings suggest that the potential of CAD-CXR screening for TB is not maximized as a high proportion of those above current thresholds, but with a negative routine confirmatory sputum, have true TB disease that may benefit intervention.

Background To meet incidence reduction goals, the Global Plan to End TB 2023-30 emphasises for the first time that detection of subclinical TB is a priority. WHO Systematic Screening guidelines (2021) have stressed the importance of CXR as a screening tool to achieve this including recommending the use of Computer Aided Detection (CAD) technology. Methods We conducted a cross-sectional survey of National TB Programmes who reported >1000 TB cases annually. The questions aligned with 2021 WHO screening guidelines and aimed to understand country's practices, policies, and challenges when screening for TB disease. Results Sixty of 123 invited countries responded representing 82% of the global TB burden. Only 66% carried out all 6 WHO-recommended steps to implement screening and 39% collected all 7 of the WHO-recommended datapoints for monitoring activity. Although most countries had a policy for using CXR and increasing CXR-based screening (77% and 68% respectively), 90% reported at least one significant barrier to implementing this and 92% reported at least one barrier to implementing CAD technology. Conclusion Many countries do not carry out all recommended steps for implementation and monitoring of TB screening and although CXR and CAD use are expanding and hold promise as tools to find people with TB, many programmes do not have adequate access to them. While global policy is in place that recommends the use of these tools more efforts should be made to support countries in tackling the barriers that prohibit implementation to make sure that we can close the TB case finding gap. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by a Medical Research Council award (grant number: MR/V00476X/1) to HE. HE is partially supported by and Medical Research Council unit grant (grant number: MC UU 00004/04). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study had ethical approval from University College London Ethics Committee (19219/001). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Diagnosing and treating people with bacteriologically-negative but radiologically-apparent tuberculosis (TB) may contribute to more effective TB care and reduce transmission. However, optimal treatment approaches for this group are unknown. It is important to understand peoples’ preferences of treatment options for effective programmatic implementation of people-centred treatment approaches. We designed and implemented a discrete choice experiment (DCE) to solicit treatment preferences among adults (≥18 years) with TB symptoms attending a primary health clinic in Blantyre, Malawi. Treatment attributes included in the DCE were as follows: duration of treatment; number of tablets per dose; reduction in the risk of being unwell with TB disease; likelihood of infecting others; adverse effects from the treatment; frequency of follow up; and the annual travel cost to access care. Quantitative choice modelling with multinomial logit models estimated through frequentist and Bayesian approaches investigated preferences for the management of bacteriologically-negative, but radiographically-apparent TB. 128 participants were recruited (57% male, 43.8% HIV-positive, 8.6% previously treated for TB). Participants preferred to take any treatment compared to not taking treatment (odds ratio [OR] 5.78; 95% confidence interval [CI]: 2.40, 13.90). Treatments that reduced the relative risk of developing TB disease by 80% were preferred (OR: 2.97; 95% CI: 2.09, 4.21) compared to treatments that lead to a lower reduction in risk of 50%. However, there was no evidence for treatments that are 95% effective being preferred over those that are 80% effective. Participants strongly favoured the treatments that could completely stop transmission (OR: 7.87, 95% CI: 5.71, 10.84), and prioritised avoiding side effects (OR: 0.19, 95% CI: 0.12, 0.29). There was no evidence of an interaction between perceived TB disease risk and treatment preferences. In summary, participants were primarily concerned with the effectiveness of TB treatments and strongly preferred treatments that removed the risk of onward transmission. Person-centred approaches of preferences for treatment should be considered when designing new treatment strategies. Understanding treatment preferences will ensure that any recommended treatment for probable early TB disease is well accepted and utilized by the public.

Background WHO Tuberculosis (TB) screening guidelines recommend computer-aided detection (CAD) software for chest radiograph (CXR) interpretation. However, studies evaluating their diagnostic and prognostic accuracy are limited. Methods We conducted a prospective cohort study of household TB contacts in South Africa. Participants all underwent baseline CXR and sputum investigation (routine [single spontaneous] and enhanced [additionally 2-3 induced] sputum investigation and passive and active follow-up for incident TB. CXR were processed comparing 3 CAD softwares (CAD4TBv7.0, qXRv3.0.0 , and Lunit INSIGHT CXR 3.1.4.111). We evaluated their performance to detect routine and enhanced prevalent, and incident TB, comparing the performance to blood-based biomarkers (Xpert MTB host-response, Erythrocyte Sedimentation Rate, C-Reactive Protein, QuantiFERON) in a subgroup. Findings 483 participants were followed-up for 4.6 years (median). There were 23 prevalent (7 routinely diagnosed) and 38 incident TB cases. The AUC ROC to identify prevalent TB for CAD4TB, qXR and Lunit INSIGHT CXR were 0.87 (95% CI 0.77-0.96), 0.88 (95% CI 0.79-0.97) and 0.91 (95% CI 0.83-0.99) respectively. >30% with scores above recommended CAD thresholds who were bacteriologically negative on routine baseline sputum were subsequently diagnosed by enhanced baseline sputum investigation or during follow-up. The AUC performance of baseline CAD to identify incident cases ranged between 0.60-0.65. The diagnostic performance of CAD for prevalent TB was superior to blood-based biomarkers. Interpretation Our findings suggest that the potential of CAD-CXR screening for TB is not maximised as a high proportion of those above current thresholds but with a negative routine confirmatory sputum have true TB disease that may benefit intervention. Funding UKRI-MRC ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by an MRC award (Grant Ref: MR/V00476X/1) to HE. HE is partially supported by and MRC unit grant (MC UU 00004/04). AKC is partially supported by the NHMRC (GNT2020750) and WEHI. RJW is supported by the Francis Crick Institute which receives funding from Cancer Research Uk (FC2112), UK Research and Innovation-MRC (CC2112) and Wellcome (CC2112). He also receives funding from Wellcome (203135), South African MRC via its Strategic health Partnerships and the Bill and Melinda Gates Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committees of University of Cape Town (449/2014), Boston University (H-35831), Rutgers University (Pro2018001966), NIH (DMID 16-0112) and University College London (19219/001) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Background The evolution of tuberculosis (TB) disease during the clinical latency period remains incompletely understood. Methods 250 HIV-uninfected, adult household contacts of rifampicin-resistant TB with a negative symptom screen underwent baseline 18 F-Fluorodeoxyglucose positron emission and computed tomography (PET/CT), repeated in 112 after 5-15 months. Following South African and WHO guidelines, participants did not receive preventive therapy. All participants had intensive baseline screening with spontaneous, followed by induced, sputum sampling and were then observed for an average of 4.7 years for culture-positive disease. Baseline PET/CT abnormalities were evaluated in relation to culture-positive disease. Results At baseline, 59 (23.6%) participants had lung PET/CT findings consistent with TB of which 29 (11.6%) were defined as Subclinical TB, and 30 (12%) Subclinical TB-inactive. A further 83 (33.2%) had other lung parenchymal abnormalities and 108 (43.2%) had normal lungs. Over 1107-person years of follow-up 14 cases of culture-positive TB were diagnosed. Six cases were detected by intensive baseline screening, all would have been missed by the South African symptom-based screening strategy and only one detected by a WHO-recommended chest X-Ray screening strategy. Those with baseline Subclinical TB lesions on PET/CT were significantly more likely to be diagnosed with culture-positive TB over the study period, compared to those with normal lung parenchyma (10/29 [34.5%] vs 2/108 [1.9%], Hazard Ratio 22.37 [4.89-102.47, p<0.001]). Conclusions These findings challenge the latent/active TB paradigm demonstrating that subclinical disease exists up to 4 years prior to microbiological detection and/or symptom onset. There are important implications for screening and management of TB.

BACKGROUND:People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease. METHODS:We conducted a systematic review and meta-analysis. We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2·0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. This study was registered with PROSPERO (CRD42021248486). FINDINGS:We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19·1% to 57·9% of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0·27, 95%CI 0·13-0·56), although multi-drug TB treatment (RR 0·11, 95%CI 0·05-0·23) was significantly more effective than isoniazid treatment (RR 0·63, 95%CI 0·35-1·13) (p = 0·0002). INTERPRETATION:Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach.

We currently have a binomial approach to managing tuberculosis. Those with active disease, ideally confirmed microbiologically, are treated with a standard 6-month, multi-drug regimen and those with latent infection and no evidence of disease with shorter, one or two drug regimens. Clinicians frequently encounter patients that fall between these two management pathways with some but not all features of disease and this will occur more often with the increasing emphasis on chest X-ray-based systematic screening. The view of tuberculosis as a spectrum of disease states is being increasingly recognised and is leading to new diagnostic approaches for early disease. However, the 6-month regimen for treating disease was driven by the duration required to treat the most extensive forms of pulmonary TB and shorter durations appear sufficient for less extensive disease. It is time undertake clinical trials to better define the optimal treatment for tuberculosis across the disease spectrum.

IntroductionThere were almost 1 million deaths in children aged between 5 and 14 years in 2017, and pneumonia accounted for 11%. However, there are no validated guidelines for pneumonia management in older children and data to support their development are limited. We sought to understand risk factors for mortality among children aged 5–14 years hospitalised with pneumonia in district-level health facilities in Kenya.MethodsWe did a retrospective cohort study using data collected from an established clinical information network of 13 hospitals. We reviewed records for children aged 5–14 years admitted with pneumonia between 1 March 2014 and 28 February 2018. Individual clinical signs were examined for association with inpatient mortality using logistic regression. We used existing WHO criteria (intended for under 5s) to define levels of severity and examined their performance in identifying those at increased risk of death.Results1832 children were diagnosed with pneumonia and 145 (7.9%) died. Severe pallor was strongly associated with mortality (adjusted OR (aOR) 8.06, 95% CI 4.72 to 13.75) as were reduced consciousness, mild/moderate pallor, central cyanosis and older age (>9 years) (aOR >2). Comorbidities HIV and severe acute malnutrition were also associated with death (aOR 2.31, 95% CI 1.39 to 3.84 and aOR 1.89, 95% CI 1.12 to 3.21, respectively). The presence of clinical characteristics used by WHO to define severe pneumonia was associated with death in univariate analysis (OR 2.69). However, this combination of clinical characteristics was poor in discriminating those at risk of death (sensitivity: 0.56, specificity: 0.68, and area under the curve: 0.62).ConclusionChildren >5 years have high inpatient pneumonia mortality. These findings also suggest that the WHO criteria for classification of severity for children under 5 years do not appear to be a valid tool for risk assessment in this older age group, indicating the urgent need for evidence-based clinical guidelines for this neglected population.

INTRODUCTION:Determining the cause of eosinophilia in patients returning from the tropics continues to present a diagnostic challenge. The history, symptoms and degree of eosinophilia are often poor predictors of eventual diagnosis, but helminths are an important cause. The current British Infection Association recommendations use travel history to guide investigation of eosinophilia. However the global burden of helminth disease and travel patterns have changed over the last 3 decades and guidelines based on previous epidemiology need to be reviewed in the light of current data. METHODS:Consecutive patients presenting with, or referred for, investigation of eosinophilia were identified prospectively. Case notes, laboratory results and electronic records were reviewed for demographic and clinical data. Patients with an eosinophil count ≥0.50 × 109/L were included, and grouped based on lifetime history of travel to: West Africa, elsewhere in Africa, and the rest of the world. Results were compared to published data from 1997 to 2002 collected at the same centre. RESULTS:Of 410 patients who met the inclusion criteria, 407 had a documented travel history. Average yearly referrals for eosinophilia fell from 58 per year between 1997 and 2002, to 33 per year (2002-2015). The proportion of eosinophilia cases diagnosed with a parasitic cause fell from 64% to 50%, and yields for all parasitological investigations fell, the largest reduction in stool microscopy (20% yield to 9%) and day bloods for microfilariae (14% yield to 3%). Strongyloides stercoralis was the commonest diagnosis overall in our cohort, accounting for 50% of the total parasites diagnosed, and was present in 38% of patients from West Africa, 19% from rest of Africa, and 34% from rest of world; a relative increase compared to previous data. Schistosomiasis is slightly less common in those who had travelled to West Africa than the rest of Africa, and overall point prevalence has fallen from 33% (1997-2002) to 17% (2002-2015). Travellers were significantly less likely than patients who had immigrated to the UK to be diagnosed with any parasite (OR 0.54 95% CI 0.378-0.778 p = 0.0009). DISCUSSION:A parasitic cause will still be found in half of people returning from the tropics with an eosinophilia, but we observed a fall in the overall prevalence of parasitic diagnoses when compared with the earlier data. This may, in part, be explained by the impact of control programmes on the prevalence of parasites globally, especially filarial disease. S. stercoralis now represents the majority of parasites diagnosed in our cohort from all continents. We identified significantly higher rates of strongyloidiasis in immigrants than returning travellers. Despite the falling yields of stool microscopy and filarial serology the current guidelines based on travel history remain relevant with adequate yield.