This cost-effectiveness study shows that sputum smear microscopy is the most cost-effective test for active tuberculosis (TB) in India, and liquid culture plus microscopy is more cost-effective for TB diagnosis than serological tests.
Undiagnosed and misdiagnosed tuberculosis (TB) drives the epidemic in India. Serological (antibody detection) TB tests are not recommended by any agency, but widely used in many countries, including the Indian private sector. The cost and impact of using serology compared with other diagnostic techniques is unknown.
Methods and Findings
Taking a patient cohort conservatively equal to the annual number of serological tests done in India (1.5 million adults suspected of having active TB), we used decision analysis to estimate costs and effectiveness of sputum smear microscopy (US$3.62 for two smears), microscopy plus automated liquid culture (mycobacterium growth indicator tube [MGIT], US$20/test), and serological testing (anda-tb ELISA, US$20/test). Data on test accuracy and costs were obtained from published literature. We adopted the perspective of the Indian TB control sector and an analysis frame of 1 year. Our primary outcome was the incremental cost per disability-adjusted life year (DALY) averted. We performed one-way sensitivity analysis on all model parameters, with multiway sensitivity analysis on variables to which the model was most sensitive.
If used instead of sputum microscopy, serology generated an estimated 14,000 more TB diagnoses, but also 121,000 more false-positive diagnoses, 102,000 fewer DALYs averted, and 32,000 more secondary TB cases than microscopy, at approximately four times the incremental cost (US$47.5 million versus US$11.9 million). When added to high-quality sputum smears, MGIT culture was estimated to avert 130,000 incremental DALYs at an incremental cost of US$213 per DALY averted. Serology was dominated by (i.e., more costly and less effective than) MGIT culture and remained less economically favorable than sputum smear or TB culture in one-way and multiway sensitivity analyses.
In India, sputum smear microscopy remains the most cost-effective diagnostic test available for active TB; efforts to increase access to quality-assured microscopy should take priority. In areas where high-quality microscopy exists and resources are sufficient, MGIT culture is more cost-effective than serology as an additional diagnostic test for TB. These data informed a recently published World Health Organization policy statement against serological tests.
Please see later in the article for the Editors' Summary
Every year, about 2 million people develop tuberculosis in India—a fifth of the global incidence of this highly contagious bacterial infection. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze and usually infects the lungs although it can also infect other organs. The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Diagnostic tests for tuberculosis include sputum smear microscopy (microscopic analysis of mucus brought up from the lungs by coughing), culture (growth) of M. tuberculosis from sputum samples in liquid media (using, for example, a commercial product called the mycobacteria growth indicator tube or MGIT), and nucleic acid amplification tests (which detect the bacterium's genome in patient samples) such as the Xpert MTB/RIF system. Tuberculosis can usually be cured by taking several powerful antibiotics daily for at least 6 months.
Why Was This Study Done?
In India, as elsewhere, undiagnosed and misdiagnosed tuberculosis drives the tuberculosis epidemic by increasing the transmission of M. tuberculosis. Unfortunately, sputum smear microscopy, the current mainstay of tuberculosis diagnosis worldwide, detects only half of tuberculosis cases, mycobacterial culture can take weeks to provide a diagnosis, and rapid techniques such as nucleic acid amplification require infrastructure that is often not available in developing countries. Consequently, in India and other developing countries, serological tests are widely used for the diagnosis of tuberculosis. Serological tests detect antibodies against M. tuberculosis in the blood (antibodies are proteins made by the immune system in response to infections). Serological tests are fast and simple to perform, but they are not recommended for clinical use, and the available evidence suggests that they do not diagnose tuberculosis accurately. Even so, and in the absence of information about the cost and impact (cost-effectiveness) of serological testing, about 1.5 million serological tests for tuberculosis are conducted every year in India at a cost of more than US$15 million. Here, the researchers analyze the cost-effectiveness of serological tests compared to other diagnostic tests from the perspective of tuberculosis control in India.
What Did the Researchers Do and Find?
The researchers used “decision analysis” to estimate the cost-effectiveness of sputum smear microscopy, microscopy plus liquid culture using the MGIT system, and serological testing using the widely used anda-tb ELISA commercial test in a hypothetical group of 1.5 million people suspected of having tuberculosis. Decision analysis formally assesses the decision-making process by using models that evaluate outcomes under different scenarios. By feeding data on the costs and accuracy of different diagnostic tests into their decision-analysis model, the researchers estimate that, over a year, serology would generate 14,000 more tuberculosis diagnoses than sputum microscopy. However, it would also generate 121,000 more false-positive diagnoses and 32,000 more tuberculosis transmissions to other people (secondary transmissions), and avert 102,000 fewer disability-adjusted life years (DALYs; a DALY is a year of healthy life lost because of premature death or disability) at four times the incremental cost of sputum microscopy. MGIT culture added to sputum smear microscopy would avert 130,000 DALYs at an incremental cost of US$213 per DALY averted. Finally, sensitivity analyses (reruns of the decision-analysis model using different values for test costs and accuracy) identified no scenario in which serology was either less costly or more effective than sputum smear microscopy alone or in which serology plus sputum microscopy was more cost-effective than MGIT culture plus sputum microscopy.
What Do These Findings Mean?
These findings identify sputum smear microscopy as the most cost-effective existing diagnostic test for tuberculosis in India. Moreover, they suggest that in areas where high-quality microscopy is available, resources are sufficient, and infrastructure to effectively use culture exists, the addition of MGIT culture to sputum smear microscopy would be more cost-effective than the addition of serology. Importantly, these findings suggest that, if used as an initial test for tuberculosis in India, serology would result in more DALYs, more secondary infections, and more false-positive diagnoses than sputum smear microscopy while increasing per-patient costs to the Indian tuberculosis control sector. Given these findings and the results of a recent updated systematic review on the accuracy of serological tests, the World Health Organization's Strategic and Technical Advisory Group for Tuberculosis recently advised against the use of currently available serological tests for the diagnosis of tuberculosis. The WHO negative policy against serological tests must now be implemented in India.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001074.
Details of the recent systematic review of serological tests for tuberculosis diagnosis are available in a PLoS Medicine Research Article by Steingart et al.
The World Health Organization provides information on all aspects of tuberculosis, including tuberculosis diagnostics and the Stop TB Partnership (some information is in several languages); its Strategic and Technical Advisory Group for Tuberculosis recommendations on tuberculosis diagnosis are available
The Evidence-based TB Diagnosis Web site by the Stop TB Partnership's New Diagnostics Working Group provides evidence syntheses on various TB tests, along with guidelines, resources, and training materials
The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the diagnosis of tuberculosis disease
The US National Institute of Allergy and Infectious Diseases also has information on all aspects of tuberculosis
MedlinePlus has links to further information about tuberculosis (in English and Spanish)