Earlier and improved tuberculosis (TB) case detection including smear negative disease, often associated with HIV co-infection as well as expanded capacity to diagnose multidrug resistant tuberculosis (MDRTB), are global priorities for TB control. Conventional laboratory methods are slow and cumbersome and novel technologies for rapid detection are therefore the focus of TB research and development.
With support from NIH, the Foundation for Innovative New Diagnostics (FIND) has partnered with Cepheid, Inc. (Sunnyvale, CA) and the University of Medicine and Dentistry of New Jersey (UMDNJ) to develop a TB specific automated, cartridge based nucleic amplification assay (Xpert MTB/RIF) based on the GeneXpert multi-disease platform, currently unique in its simplification of molecular testing with fully integrated and automated sample preparation, amplification and detection required for real time polymerase chain reaction. Xpert MTB/RIF detects M. tuberculosis as well as rifampicin resistance conferring mutations directly from sputum, in an assay providing results within two hours.
In August 2013, the FDA permitted marketing of the Xpert MTB/RIF assay to detect DNA of the Mycobacterium tuberculosis complex (MTBC) and genetic mutations associated with resistance to rifampin (RMP) in unprocessed sputum and concentrated sputum sediments. Along with clinical, radiographic, and other laboratory findings, results of the assay aid in the diagnosis of pulmonary tuberculosis (TB).
The assay is a nucleic acid amplification-based (NAA) test using a disposable cartridge in conjunction with the GeneXpert Instrument System. Sensitivity and specificity of the Xpert MTB/RIF assay for detection of MTBC appear to be comparable with other FDA-approved NAA assays for this use, although direct comparison studies have not been performed. Sensitivity of detection of RMP resistance was 95% and specificity 99% in a multicenter study. The CDC continues to recommend following published U.S. guidelines for TB diagnosis and infection control practice, including the use and interpretation of NAA test results. Providers and laboratories need to ensure that specimens are available for other recommended mycobacteriological testing.
The Xpert MTB/RIF assay aids in the prompt diagnosis of RMP-resistant disease. RMP resistance most often coexists with isoniazid (INH) resistance; TB that is resistant to both drugs is multidrug-resistant (MDR) TB. Rapid drug-susceptibility tests are a pressing public health and diagnostic need because of the rise in multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR TB) globally. Published studies suggest that, compared to conventional culture-based methods, the rapid detection of rifampin-resistance using molecular methods can enable earlier initiation of effective therapy and thereby reduce periods of infectiousness of MDR TB cases by as much as six weeks and improve patient outcomes; both of which may have a large impact on efforts to control MDR TB. It is estimated that preventing a single case of MDR TB would save the U.S. health care system more than $250,000.
In 2008, the Association of Public Health Laboratories and CDC convened a panel that recommended NAA testing as standard practice in the United States to aid in the initial diagnosis of patients with suspected TB. On the basis of the panel report and consultation with the Advisory Council for the Elimination of TB, the CDC published revised NAA guidelines, including a detailed testing and interpretation algorithm for initial diagnosis. Recent studies further support NAA test use in the United States to avoid delays in diagnosis and treatment, especially for patients with suspected TB and sputum smears negative for acid-fast bacilli on microscopy. Because of rapid results, NAA testing can help avoid unnecessary respiratory isolation, treatment, and contact investigation of patients without TB and can contribute to system cost savings in patients with HIV infection, homelessness, or substance abuse, compared with smear microscopy alone.
For any test, even with high sensitivity and specificity (including NAA testing, DNA sequencing, and growth-based DST), the positive predictive value is low for a rare condition; accordingly, health-care providers should consult with their public health laboratory for confirmation by rapid molecular detection of mutations associated with drug resistance. Consultation with a TB expert is recommended if the clinician is not experienced in the interpretation of NAA and other molecular test results or the diagnosis and treatment of TB. This is especially important in cases of suspected drug resistance.
The CDC recommends airborne infection isolation (AII) precautions for patients with suspected TB disease of the lungs, airway, or larynx in health-care settings. AII precautions may be discontinued when contagious TB disease is considered unlikely and either 1) another diagnosis is made that explains the clinical syndrome or 2) the patient has three consecutive sputum smears negative for acid-fast bacilli on microscopy. Because of the intermittent presence of TB bacilli in the sputum of patients with TB, three specimens separated in time have been recommended to have a sufficiently high predictive value for excluding contagious disease.
Three sputum specimens, each collected 8–24 hours apart, with one being an early morning specimen, should be collected to inform decisions regarding the discontinuation of AII precautions for patients with suspected TB in health-care settings. For patients with a diagnosis of TB, decisions regarding discontinuation of AII precautions should be based on microscopy (i.e., three consecutive negative smears) and other clinical criteria. Cultures take 2-6 weeks and smear microscopy takes 24 hours but is limited by poor sensitivity and poor positive predictive value in settings where non-TB mycobacteria are common.
Because NAA testing, including that with the Xpert MTB/RIF assay, is significantly more sensitive and specific for the detection of MTBC than microscopy alone, substitution of Xpert MTB/RIF assay results that are negative for MTBC for microscopy results increases the negative predictive value for MTBC. Therefore, in ruling out contagious TB, specimens can be tested by microscopy, NAA, or a combination of the two.
See the CDC Report
See also Medical Law Perspectives, January 2012 Report: Hospital-Acquired Infections: Who Is Liable and Why?