Non-sputum diagnostics and their role in the detection of Mycobacterium Tuberculosis (Mtb).

Mtb can be challenging to diagnose at multiple stages including lack of access to testing services, difficulty obtaining samples from patients and limited laboratory capabilities for analysis. Currently the most common sample used for diagnosis is sputum however many patients, especially children and the elderly, cannot produce a sample to be analysed. Recent studies have highlighted that often people with Tuberculosis (TB) do not present with traditionally recognised symptoms and can therefore be missed by current diagnostic approaches. For this reason diagnostic tests are urgently needed that are based on alternative sample types, patient centred and can be collected at the time of consultation.

Although current testing focuses on samples from the lower respiratory tract, historically, many different sample types have been used. In Europe in the early 20th century Mtb was routinely looked for in the tonsils of patients undergoing tonsillectomy, as a marker of infection and to monitor the prevalence of TB. The incidence found varied between 0.44% (Magee, 1937) to 9% (Mitchel, 1916) however, as the incidence of TB dropped the practice fell out of use. There is no data on whether this is a method that could be optimised by using modern diagnostic methods (e.g. GeneXpert Ultra, liquid culture), which may complement surveillance efforts to monitor the prevalence of infection. Research was also carried out on laryngeal swabs in the 20th century in Europe and India which were found to be a potential alternative to gastric lavage.

Recently the World Health Organisation (WHO) has developed a target product profile (TPP) of the type of tests desired to improve the diagnosis of TB. Desirable samples are non-sputum and non-invasive samples, such as urine or stools, or minimally invasive methods (such as finger prick or saliva).

Studies in South Africa, Moldova and Nigeria have detected Mtb on oral mucosa specimens obtained by swabbing in a significant proportion of both children with negative sputum specimens and adults with Mtb disease. Detecting the bacilli in the oral cavity would be considerably easier than obtaining sputum and thus efforts to improve the performance of the tests by optimising sampling techniques and sample processing are desirable. Furthermore, recent developments on the detection of Mtb fractions, such as LAM, have resulted in rapid and point of care tests based on fresh urine (Fujilam), which have higher sensitivity and specificity (70-80% in Nigeria) than previous LAM prototypes (<40% in HIV infected).

Recent studies have reported that an acute phase protein (C-Reactive Protein (CRP)) has a sensitivity ranging from 90% to 95% to identify people with TB, but that the specificity is much lower, at about 50-60% and modified by the presence of HIV coinfection. Although CRP does not meet the WHO TPP requirements, its use in combination with other tests, in a diagnostic algorithm is being explored by several research groups, with significant efficiency gains. Using combinations of tests based on non-sputum specimens has major potential to improve current diagnostic algorithms.