Non-invasive TB Triage and Patient Mapping Platform Using Breath Via Low-Cost Titanium Dioxide Nanotube Sensor
Non-invasive TB Triage and Patient Mapping Platform Using Breath Via Low-Cost Titanium Dioxide Nanotube Sensor
The purpose of this pilot study is to evaluate the sensitivity and specificity of a
 nanotube-based point-of-care breath-based tuberculosis screening test as compared to the
 current standards of care including sputum microscopy, sputum culture, chest X-ray, and
 GeneXpert (MTB/RIF).

 The primary objective is to determine an initial estimate of the sensitivity and specificity
 of a nano-tube based point-of-care test for the diagnosis and screening of active pulmonary
 tuberculosis.

 Secondary objectives include the collection of user data to test and further develop the
 screening platform based on end-user feedback.
TB is an infectious disease caused by various strains of mycobacteria. It typically infects
 the lungs and is spread through the air when an infected patient sneezes, coughs, or spits.
 When this occurs, the TB bacilli are propelled into the air in droplets that can remain
 suspended for long periods of time. An individual simply needs to inhale a small amount of
 bacilli to become infected.

 Conventional methods for TB detection and diagnosis are traditionally performed in
 laboratories or hospitals. For example, the most common method for diagnosis of TB is the
 acid fast staining of a sputum sample which is then followed by a sputum smear microscopy
 test. However a disadvantage with the sputum smear test is its poor sensitivity, which is
 estimated to be at 70%. Additionally, the sensitivity of sputum smear spectroscopy in field
 settings has been shown to be much lower (35%), especially in populations that have high
 rates of TB and HIV coinfection. Culturing of mycobacterium from sputum samples is a more
 sensitive technique. Sputum samples are collected and cultured in either solid media or
 liquid media looking for the presence of the mycobacterium. However this methodology takes
 time to conduct (3-4 weeks for solid cultures, and 10-14 days for liquid cultures), which
 makes it difficult to employ in low resource settings that are typically far from testing
 facilities.

 Recently, other technologies have been developed including fluorescence microscopy for smear
 tests (10% more sensitive than light microscopy), LED fluorescent microscopy for inexpensive
 imaging equipment that can be used in the field without the need for a darkroom, and rapid
 culturing techniques to reduce incubation time. Despite all the improvements that have been
 made in TB diagnosis, no simple inexpensive POC test is currently available. The techniques
 mentioned above either focus on variations of microscopy or culture technique. In either
 case, these methods require lab facilities and highly trained personnel that typically are
 not available in many rural or low resource areas.

 Recent research has shown that various strains of the mycobacteria produce distinct gaseous
 volatile biomarkers that can be used as a methodology for detecting and identifying the
 mycobacterium. Specifically, Syhre and Chambers found that Mycobacterium tuberculosis and
 Mycobacterium bovis cultures give off four specific volatile organic biomarkers (VOBs):
 methyl phenylacetate, methyl p-anisate, methyl nicotinate, and o-phenylanisole. These
 compounds were detectable before the visual appearance of colonies, which could have
 implications in detection of latent TB infection. Syhre et al. were able to detect
 statistically significant differences of methyl nicotinate in the breath of smear positive TB
 patients when compared to healthy (smear negative) subjects. Analyses in these studies were
 done using gas chromatography/mass spectroscopy analysis tools. While they are effective in
 identifying and quantifying complex gas samples, they are expensive, bulky, and not
 appropriate for point of care (POC) diagnostics.

 These challenges associated with the diagnosis of TB are significant as TB is the second
 leading cause of death due to a single infectious organism and is responsible for 1.3 million
 deaths annually (over 3,500 every day), according to the WHO. Overall, an estimated 2 billion
 people are currently infected worldwide with 8.6 million new active infections occurring each
 year.[8] Each of these individuals can transmit the disease to 10 to 15 people per year and
 face a mortality rate of 50% if untreated. The economic burden of TB is staggering as the
 World Bank estimates that high burden countries can lose up to 7% of GDP due to productivity
 losses from TB patients and their caretakers. It is so critical that the World Bank committed
 $100 million to testing for and treating TB in India in 2014 alone.

 Of the 8.6 million new active TB cases that occur annually, the WHO estimates that roughly 3
 million of these patients are 'missed' and do not receive the diagnosis or care they need.
 One of the primary reasons for this gap is delays in accessing TB-related care or long lead
 times for diagnostic tests. As a result, developing new large scale screening tests (also
 known as triage or 'rule out' tests) are particularly needed due to the fact that up to 80%
 of people tested for TB do not have active disease, stretching the limited and valuable
 resources that are devoted for diagnostic testing. As a result, FIND, a world leader in
 guiding and coordinating research and development for diseases such as TB, ranked the
 development of new screening tests as one of the top 3 priorities in the fight against TB.

 This pilot study will be conducted to determine if a newly developed sensing methodology for
 screening TB at the POC based on volatile biomarkers is feasible through the use of a low
 cost solid-state sensor using functionalized 3D TiO2 nanotube arrays that bind the volatile
 biomarkers. If the clinical sensitivity is sufficient, this technology could provide a means
 for identifying many of the 'missed' TB patients and allow testing resources and efforts to
 be focused on those at the highest risk of having the disease.

 Previously, we have tested the breath profile of a small number patients from local TB
 clinics and have confirmed the presence of these biomarkers in their breath (IRB_0065207).
 Larger patients studies are now required to gain an estimate of the sensitivity and
 specificity to determine the potential of using the sensor as a screening test. This study
 will be conducted in Mumbai, India with the University's Research Electronic Data Capture
 (REDCap) system used to securely collect and store the data from this study.

 This study has been reviewed and approved by the Mahatma Gandhi Mission Institute of Health
 Sciences Ethical Committee for Research on Human Subjects and Scientific Advisory Committee.
Inclusion Criteria:

 -  No TB Symtoms No history of TB Negative Mantoux test Normal Chest X-ray HIV Negative

 Exclusion Criteria:

 Prior history of TB