Xpert Active Case-finding Trial 3 (XACT-3)

In the proposed study (XACT III) the investigators will use the same approach (as for XACT II), but it remains to be shown that such a strategy is scalable and feasible in different settings where the challenges and conditions vary. More importantly, the investigators need to methodologically optimize the ACF model. Thus, the investigators aim to determine where Xpert (the diagnostic test) should be optimally placed from a physical location point-of-view, i.e. does it really need to be installed in the mobile mini clinic, or, can it be located in centralized laboratories (as it is now) with samples being sent to these laboratories? This is a very important question: it is known that sending collected sputum samples to centralized laboratories will be much easier as it uses existing infrastructure, however, the downside is between 20 and 40% of patients fail to come back to collect their results (pre-treatment loss to follow-up; PTLF). Using the diagnostic in the mobile mini van (at point-of-care; POC) dramatically reduces this PTLF enabling quick diagnosis and interrupting transmission. To definitively settle the question, a study is needed using the two different strategies to find out which strategy is most cost-effective yet can rapidly pick up the most cases and minimize transmission.

There are two other important sub-questions that the study will answer. Chest X-rays, which can identify people at high risk of having TB, can now be automatically read by a computer algorithm (called computer-assisted diagnosis of TB; CAD-TB). It will be very important to know whether mass screening using CAD-TB can triage individuals i.e. narrow the net so that the investigators target the ACF only to those at high risk of having TB. This could save even more money yet be just as effective.

Secondly, a fundamental unanswered question is why individuals with minimal or no symptoms can be highly infectious (transmit disease)? The investigators need to study this phenomenon in greater detail using cough aerosol readouts, chest X-rays, and looking at the TB strains. In addition the investigators would like to screen contacts of individuals with confirmed tuberculosis This might provide medical science with the information it needs to design diagnostic or therapeutic interventions to address this important problem.

However, the key priority now is to show that the XACT approach is feasible in different settings and to clarify how the molecular diagnostics should be optimally located. Answering these questions will allow the initiation of ACF programmes in many countries and will contribute critical data to policy makers so that guidelines on ACF can be disseminated and implemented.

Inclusion criteria

• Community participant willing to complete community-based symptom screening, finger-prick blood testing, and/or undergo TB diagnostic testing.
• Provision of informed consent.
• Has documentation of, or willingness to be tested for HIV infection. HIV testing does not need to be repeated if there is written documentation of a confirmed positive test at any time in the past.
• HIV-negative adults (older than 18 years) with 1 or more of the following:• cough ≥ 2 weeks• loss of weight• Fever• night sweats• generalized fatigue• haemoptysis• chest pain.
• Any HIV+ve adult (older than 18 years).
• Agrees to the collection and storage of blood, urine, sputum specimens for use for future research. (The participant may decline collection of specimens for human genetic research and still be eligible for the study).

Exclusion criteria

• Inability to provide informed consent (e.g. mentally impaired).
• Patients who have completed TB treatment in the last 2 months, or who have self-presented to their local TB clinic and are currently being worked up for suspected TB.
• Patients already diagnosed with active TB.
• Patients unable to commit to a two month follow up or who do not wish to be followed up.

Inclusion criteria

for Household contacts (HHC)

• Adult (> 18 years old) with significant recent exposure (within the past 6 months) to an adult with untreated or inadequately treated pulmonary TB.
• No clinical signs or symptoms of active TB that include, but are not limited to: persistent cough, haemoptysis, fever, unintended weight loss or failure to thrive (children), fatigue or lethargy, night sweats, pleuritic chest pain, draining lymph node, or other evidence of extra-pulmonaryTB. If clinical signs or symptoms of TB are present, Chest X-Ray and/or sputum culture results must be included in the overall evaluation to rule out active TB.
• Has signed a written consent or witnessed oral consent in the case of illiteracy, prior to his/her first sample or other study-specific data being collected.
• Agrees to the collection and storage of blood, urine, saliva and sputum specimens for use for future research. (The participant may decline collection of specimens for human genetic research and still be eligible for the study.)

Exclusion criteria

for Household contacts

• Plans to move from his/her current residence, which would interfere with the participant's ability to complete all study visits (through the Month 24Visit).
• Has an active psychiatric condition, or alcohol or drug dependence that, in the opinion of the site investigator or designee, might interfere with the ability to give true informed consent and to adhere to the study requirements.