Our findings relating to technical details of safe collection and processing of sputum for testing outside a laboratory have previously been published.83 Parts of this section have been reproduced or adapted from Gliddon et al.83 Copyright © ERS 2019. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. See: http://creativecommons.org/licenses/by/4.0/. The text includes minor additions and formatting changes to the original text.
Introduction
Experience of tuberculosis screening among socially complex groups and other tuberculosis patients by the pan-London Find&Treat tuberculosis outreach service has shown that current service provision in the UK rarely achieves same-day diagnosis in smear-positive pulmonary cases. In the UK, patients often have to wait for a follow-up appointment to be given the results of smear microscopy. Patients who are smear negative and clinically well often have to wait several weeks for the results of the culture prior to commencing treatment and there is further delay in the availability of drug sensitivity tests to inform clinical management. This carries an important risk of loss to follow-up care, especially among socially complex groups, and inappropriate arrangements for isolation and infection control in hospital and prison settings. The use of PCR-based molecular technologies allows a high proportion of smear-negative cases (later confirmed by culture) to be diagnosed within 48 hours.84 In addition, these technologies enable the identification of mutations specific to rifampicin drug resistance (a key marker of multidrug resistance). The reagents used in the test are effective in sterilising samples, making them suitable for testing outside category 3 laboratories and suggesting a potential role as a point-of-care test.85 Although these tests are available on request in several London laboratories, there is a paucity of evidence to support their use as a near-patient test in field conditions.
Methods
Setting
The setting was a rapid diagnostic service within the mobile radiographic screening unit run by the Find&Treat service, an NHS pan-London specialist community outreach team.
Development of the point-of-care diagnostic service
The use of the Cepheid Xpert MTB/RIF test as a point-of-care test in this setting was approved by the Royal Free London NHS Foundation Trust point-of-care testing committee. Training and competence assessment to ensure the safe handling of specimens was performed on the mobile radiographic unit by the Royal Free Microbiology Department staff.
Considerable work went into establishing the Cepheid technology as a point-of-care test. Major hurdles that needed to be addressed were the installation of the Cepheid Unit on the mobile radiographic unit, acquisition and installation of an uninterruptable power supply to enable the tests to continue while the mobile radiographic unit was in transit, development of specialist sputum pots to enable safe handling and aliquoting of sputum samples into Cepheid-reagent tubes, laboratory accreditation of the mobile radiographic unit as a diagnostic facility and training of mobile radiographic unit staff in conducting the assay. Further details are provided in Report Supplementary Material 2.
Participants and eligibility
The eligibility criteria were any socially complex patient, male or female, aged ≥ 16 years with an abnormal chest radiograph that was suggestive of pulmonary tuberculosis identified through mobile radiographic unit screening for active pulmonary tuberculosis. The patient needed to be willing and able to provide informed consent.
Study description
Staff on the mobile radiographic unit aimed to provide eligible participants with written information, explain the differences in the diagnostic approach and care pathway for those in the intervention arm and the control arm, answer any questions that participants may have and obtain written consent. Those who consented were then randomised using a text messaging randomisation service provided by Sealed Envelope. Baseline data and follow-up information were collected on all participants.
Intervention arm
Those randomised to the intervention arm were asked to produce a sputum sample for immediate analysis using the Cepheid Xpert MTB/RIF test by staff working on the mobile radiographic unit. An additional sample was also submitted for routine sputum microscopy and culture in the hospital laboratory. Patients with a positive point-of-care Cepheid Xpert MTB/RIF test result were referred immediately to a local hospital for clinical assessment, isolation and to commence tuberculosis treatment. Patients with a negative test result but with clinical symptoms of haemoptysis, night sweats or weight loss were also referred as above. Intervention arm participants who were negative according to Cepheid Xpert MTB/RIF and who did not have symptoms (e.g. haemoptysis, night sweats or weight loss) were followed up in the community with two further sputum samples (including one early-morning specimen for microscopy and culture) and clinic referral if these subsequent tests were positive. Patients with three negative microscopy and culture results were offered a repeat chest radiograph on the mobile radiographic unit 3 months from the initial radiograph.
Control arm
Those randomised to the control arm were managed according to standard practice (i.e. patients were accompanied directly to a hospital and, if possible, a sputum sample was collected for routine analysis in a hospital laboratory). Further investigations at the clinic included collection of additional samples for microscopy and culture.
Primary outcome
The primary outcome was the number of clinic visits needed for the exclusion or confirmation of tuberculosis diagnosis.
Secondary outcome
The secondary outcomes were the proportion of patients completing the investigations required to exclude active tuberculosis (three sputa, including one early-morning sputum, for smear microscopy and culture when possible), time to onset of appropriate treatment, time to isolation for infectious cases, loss to follow-up, and how many patients developed active tuberculosis from the time of the initial radiograph on the mobile radiographic unit.
Analysis
We aimed to recruit 40 participants in each arm based on an ability to detect a decreased number of visits until diagnostic conclusion in the intervention arm compared with the control arm {mean 2.3 visits [standard deviation (SD) 1.1 visits] vs. mean 1.5 visits (SD 1.1 visits), 90% power, 5% significance level}.
Results
During the study period, 95 patients met the inclusion criteria for the study, 37 of whom were recruited (Figure 5). In the 18 patients in whom Cepheid was used, 14 had negative results, two were positive for Mycobacterium tuberculosis and two had indeterminate results. Six of these patients were ultimately diagnosed with active tuberculosis, 10 were classified as not having tuberculosis and two were lost to follow-up. In the control arm, of the 19 patients identified, five were ultimately diagnosed with active tuberculosis, two were lost to follow-up and 12 were classified as not having active tuberculosis. It did not prove possible to obtain more detailed primary and secondary outcome measures from the NHS services. Owing to low recruitment and difficulties collecting primary and secondary outcome data (see Challenges and deviations from the protocol) and following discussion with the funders, the trial was abandoned. The intention was to continue the evaluation as an observational study of the technology on the mobile radiographic unit, but the mobile radiographic unit stopped using the technology soon after trial abandonment.
FIGURE 5 Work package 4: Cepheid recruitment update/outcomes – from August 2013 to July 2015. CXR, chest X-ray; LFU, lost to follow-up; MXU, mobile X-ray unit; PHE, Public Health England; TB, tuberculosis. (Figure not reproduced here; see the original article.)
Challenges and deviations from the protocol
This study, which sought to evaluate the use of molecular diagnostics on a mobile radiographic unit screening highly complex patients, was subject to many challenges. Optimising the Cepheid technology to function in transit was a major challenge. After initial installation, it became apparent that brief interruptions of power supply disrupted its use, requiring the installation of a custom-made back-up battery. We overcame practical issues in implementation, which included the development of sputum pots with one-way valves to allow the safe handling of sputum specimens outside a category 3 laboratory. We also trained non-specialist staff in the use of the equipment and developed procedures and permissions for the local microbiology service to accredit the mobile diagnostic service. Recruitment commenced but became very slow as the mobile radiographic unit was a highly pressured area for the consenting and randomisation of participants alongside routine screening plus other screening tests being offered in the unit that had an important impact on the recruitment rate. Staff reported that it was extremely challenging to explain the randomised nature of the study to patients in a highly pressurised clinical environment. Conducting the test interrupted their other clinical activities. They also reported that the test took too long to produce results (up to 1 hour), which made it hard for patients to wait for results. In addition, in many cases the mobile unit’s schedule meant that it needed to move to another screening location before test results were completed. In light of these challenges, it was decided to terminate the study. Although it was planned to establish this as a service evaluation study rather than a RCT, we found that, following cessation of the trial, the Cepheid system was used only twice (both results were negative). We conclude that routine use of this diagnostic technology has limited utility in the current context. The Find&Treat team now uses the technology in selected cases and during outbreak investigations. More technologically simple and rapid confirmatory tests are required.