Target condition being diagnosed
Tuberculosis (TB) is an important infectious cause of morbidity and mortality among adults worldwide. In 2011, there were 8.7 million new and 12 million prevalent cases of TB, almost one million TB deaths of HIV-uninfected people and an additional 0.43 million deaths among HIV-infected people (WHO 2012). An estimated one-third of the world's population is infected with Mycobacterium tuberculosis, the microorganism that causes TB. In humans, M. tuberculosis (MTB) infection usually affects the lungs and spreads by airborne transmission (Lawn 2011). Patients with infectious TB spread bacilli, most commonly through coughing. After initial infection, approximately 5% of infected people develop active tuberculosis, referred to as TB. Between 90 to 95% of infected people develop a latent TB infection (LTBI), which may reactivate at a later stage especially in the presence of conditions that affect immunity (including HIV infection, undernutrition, and old age) (Rieder 1999). It can take months to years for people to develop symptomatic and bacteriologically detectable TB. LTBI and TB are increasingly seen as two ends of a continuous spectrum. In between are early disease states that may be described as incipient TB and subclinical TB (Achkar 2011). In the absence of diagnosis and treatment, people with active TB may be infectious for prolonged time periods. In HIV-negative people with active TB, the average duration until self-cure or death is three years, and case fatality with no treatment is approximately 70% for smear-positive (that is, detectable with sputum smear microscopy) and 20% for smear-negative TB (Tiemersma 2011).
The decline in estimated global TB incidence, about 2% per year, is far below the average decline of 20% per year required to reach the elimination target of < one case per million population in 2050 (Raviglione 2012; WHO 2012). In 2011, only an estimated 66% of incident TB cases were detected globally (WHO 2012). Recent prevalence surveys have revealed a considerable burden of undiagnosed culture positive (that is, detectable with mycobacterial sputum culture) smear-negative TB, and a minority of those cases report classical symptoms (Ayles 2009; Corbett 2009; van't Hoog 2011a; MoH Myanmar 2012). Improving TB case detection to reduce the pool of infectious TB that contributes to transmission (Corbett 2010) is important to further reduce TB incidence, prevalence and mortality, and reach the goals of TB control (WHO 2006; Raviglione 2012). Most TB cases are detected passively, among symptomatic people seeking care (Golub 2005). Passive case detection results in considerable delay in TB detection. (Sreeramareddy 2009) and at the time of diagnosis TB patients identified through passive case detection have more symptoms and signs of illness compared to patients found through active case detection (den Boon 2008; van't Hoog 2013). Thus, a large proportion of patients with infectious TB will go undiagnosed if only passive case detection is used. More active approaches are needed to increase case detection, and systematic screening for active TB is a possible means of achieving this (Raviglione 2012; Lonnroth 2013).
The Strategic and Technical Advisory Group TB (STAG-TB) recommends that the World Health Organization (WHO), working with partners, develops guidelines on TB screening (Stop TB 2011). The WHO has defined screening as "the presumptive identification of unrecognized disease or defect by the application of tests, examinations, or other procedures which can be applied rapidly. Screening tests sort out apparently well people who probably have a disease from people who probably do not. Screening tests are not intended to be diagnostic. People with positive or suspicious findings must be referred to their physicians for diagnosis and necessary treatment" (Wilson 1968). For the purpose of guideline development, TB screening is defined as "systematic identification, in a predetermined target group, of people with suspected active TB, by the application of tests, examinations, or other procedures which can be applied rapidly" and these people should be tested with a confirmative diagnostic test. Screening could be offered to both those who seek health care (with or without symptoms or signs compatible with TB) and those who do not. Screening is offered systematically to predetermined groups, and not only in response to a specific request or complaint by an individual seeking care (Lonnroth 2013; WHO 2013). The two main goals of systematic screening for active TB are (1) better health outcomes for people with TB, through earlier detection and treatment; and (2) more effective reduction of TB transmission and incidence through shortening the average duration of TB infectiousness (Lonnroth 2013; WHO 2013).
This review focuses on symptom and chest radiography (CXR) screening. In symptom screening, individuals are questioned about the presence of one or more symptoms considered suggestive of pulmonary TB, which are respiratory symptoms such as persistent cough and haemoptysis, and systemic symptoms including weight loss, fever, night sweats and fatigue (Maher 2009). Chest radiography as a screening tool involves having participants undergo one posterior-anterior CXR recording. Different technologies exist: conventional CXR (producing a 36 cm x 43 cm film), digital radiography and mass miniature radiography (MMR) (Kerley 1942). CXR classification systems may distinguish between any abnormality versus normal, or among abnormal CXRs only abnormalities suggestive of TB may qualify as a positive screen (den Boon 2006). The latter requires interpretation by specialist readers (usually radiologists or pulmonologists), while presence for any abnormality can more easily be interpreted by health workers with a general medical background (for example, medical officers, clinical officers, radiographers) (WHO 2010; van't Hoog 2011).
Screening may be done with either symptom or CXR screening, or with symptom and CXR screening combined in parallel or sequentially (Figure 1) (Hayen 2010). Sequential (or serial) screening means that in the first step people are screened for symptoms, and as a second step, CXR screening is offered only to symptom positives. Parallel screening implies that both symptom and CXR screening are offered, and people found to have symptoms, or abnormalities, or both on CXR are eligible for further bacteriological examination. This is for example practiced in TB prevalence surveys in order to have as high sensitivity as possible, while at the same time avoiding the need for laboratory investigation on all study subjects (WHO 2010).
In a TB screening program, the screening test(s) are offered as part of a diagnostic algorithm that also includes one or more confirmatory tests. Individuals with a positive screen are offered further confirmatory testing to establish a TB diagnosis. True screen positives are people rightfully referred for confirmatory testing, and false screen positives are people who are referred for confirmatory testing while they do not have TB. They may or may not be ruled out by the confirmatory test. Individuals with a positive screen, but negative confirmatory test would not necessarily be declared disease-free, but may be advised on further examination or follow-up if warranted by the actual finding on screening (for example, severity of symptoms or the CXR finding (Okada 2012). People with a negative screen would not be further evaluated. This group includes both the true screen negatives who do not have TB, and false screen negatives, who will not be evaluated further although they do have TB. The confirmatory test may be sputum smear microscopy, the Xpert® MTB/RIF test (Cepheid, Sunnyvale, CA), and, in more resourceful settings, mycobacterial culture. These are also reference tests for the purpose of this review. People that have a negative result of the confirmatory test(s) available in their setting may be started on empirical TB treatment after further clinical evaluation and a trial of broad spectrum antibiotics, or chest radiography, or both. New reference tests may become available in the future.
The main goal of systematic TB screening is early detection of people who are infectious and can spread M. tuberculosis. For this condition, confirmation of mycobacterial growth in cultured sputum followed by mycobacterial speciation to demonstrate M. tuberculosis presence is considered the reference test. Culture on liquid medium is believed to be the most sensitive, although prior to the availability of automated reading of mycobacterial growth inhibitor tubes (MGIT culture), culture on solid medium (Löwenstein-Jensen (LJ)) has been the mainstay, and may still be the only available method in resource-constrained settings. MGIT culture increases the recovery of mycobacteria by 11 to 18% compared to LJ culture, but MGIT culture alone may have slightly lower specificity due to higher contamination rates (Hanna 1999; Chien 2000; Somoskövi 2000; Whitelaw 2009). The yield of mycobacterial culture also increases if two or three specimens per patient are tested (Monkongdee 2009).
Sputum smear microscopy
Sputum smear microscopy is the most commonly available TB diagnostic test. Sputum smear microscopy detects acid fast bacilli (AFB) presence, which is considered indicative of M. tuberculosis in high TB-incidence settings. Compared to culture, sensitivity of the Ziehl-Neelsen method (ZN) shows wide variation, and is between 50 to 70% in a majority of studies (Steingart 2006a; Steingart 2006b). Direct ZN microscopy specificity is 98% (95% CI 97 to 99%) (Steingart 2006a; Steingart 2006b; Cattamanchi 2010). Smears may also be positive due to AFBs that are not M. tuberculosis or to artefacts. Auramine-stained fluorescence microscopy (FM) sensitivity is on average 10% higher than of ZN, but with slightly reduced specificity (Steingart 2006a). Processing sputum by centrifugation and various chemicals, including bleach and NaOH, show varying levels of increase in the sensitivity of microscopy compared with the direct smear method, and similar or slightly lower specificity (Steingart 2006b; Cattamanchi 2010).
Nucleic acid amplification tests (NAAT)
The Xpert® MTB/RIF test (Xpert) is currently the only NAAT that is endorsed by WHO for large scale deployment (WHO 2011b). Compared to culture, Xpert has 92% sensitivity and 99% specificity in smear-positive and smear-negative patients combined in pilot studies (Boehme 2011), and a pooled sensitivity of 88% (95% CI 83 to 92%) and pooled specificity of 98% (95% CI 97 to 99%) in a systematic review (Steingart 2013) and is an acceptable reference test.
Other types of active TB are extra-pulmonary TB (EPTB), a condition that may affect almost every other organ and constitutes 13% of new TB cases in all ages globally (WHO 2012), and culture-negative active pulmonary TB, characterized by clinical disease and highly suggestive CXR abnormalities not explained by other causes (Maher 2009). Clinical diagnosis and start of empirical TB treatment, is commonly practiced in settings where mycobacterial culture is not part of routine diagnosis for people with suspected pulmonary TB who have negative sputum smears. Clinical algorithms that include trial of antibiotics and a CXR if the trial was not successful have generally very low sensitivity, while diagnosis based on CXR has low specificity (van Cleeff 2003; Soto 2011; Swai 2011). In this review, we do not consider clinically diagnosed TB as an acceptable reference test because of the lack of a uniform definition, poor and variable accuracy of clinical algorithms, and the varying ability to establish differential diagnostic causes across settings. EPTB and culture-negative active pulmonary TB may be detected earlier through active screening especially in high income countries, but are not a primary focus of active screening in other settings due to diagnostic challenges and low probability of transmission. Also, we do not consider serological tests, which are not recommended for TB diagnosis (Steingart 2007), and other tests that are not endorsed by WHO for TB diagnosis as reference tests for this review.
This review aims to contribute to the development of TB screening guidelines which seek to provide guidance about if, when, whom and how to screen (WHO 2013). We will compile evidence about the accuracy of the most available screening tools, and if possible generate summary estimates of the sensitivity and specificity of symptoms, chest radiography (CXR) and combinations of those if used as TB screening tools. The accuracy of the screening tools and the confirmatory tests, as well as the TB prevalence in the screened population, will determine the potential yield of a screening program and the burden on individuals and the health service. The latter includes the required amount of confirmatory tests and possibly diagnostics and care for other conditions. In practice, screening initiatives may face lower yields if not all eligible individuals accept screening or confirmatory testing, or if some of the people diagnosed with TB as a result of the screening program do not initiate treatment. The literature on those challenges is summarized in other reviews (Lonnroth 2013; Kranzer 2013). The TB screening guidelines aim to provide guidance to decision-makers on the choice of diagnostic algorithms (combinations of one or more screening test(s) and confirmatory test(s)) in different populations and settings (Lonnroth 2013; WHO 2013). Therefore the yield, positive and negative predictive value, and requirements in terms of diagnostic tests of different diagnostic algorithms will be calculated for different levels of TB prevalence as part of the guideline development process. This information should help decision-makers choose the best diagnostic algorithm option for their specific setting, taking into account the TB prevalence, resource availability and logistical aspects (for example, availability of X-ray or Xpert equipment). The pooled estimates of sensitivity and specificity of symptom and CXR screening from this review will inform these calculations and recommendations.
This review includes TB screening of HIV-negative people and people with unknown HIV status (a proportion of whom may be HIV-infected). In regions with a generalized HIV-epidemic, the risk of developing active TB is 20 to 37 times greater in the presence of HIV-infection (Getahun 2010), and mortality in HIV-infected TB patients is high (Cox 2010; Kyeyune 2010). The sensitivity of sputum smear microscopy and Xpert is lower in HIV-infected individuals with presumed TB (Getahun 2007; Boehme 2011). Therefore people living with HIV should be systematically screened for active TB at each visit to a health facility, as outlined in the guidelines for intensified TB case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings (WHO 2011a). Individuals with a known HIV-positive status should be referred for HIV-care and treatment if they are not yet enrolled. For those clinic settings, screening algorithms have already been defined based on a recent systematic review to determine a screening rule in HIV-infected people (Getahun 2011).