5 курс / Пульмонология и фтизиатрия / Clinical_Tuberculosis_Friedman_Lloyd_N_,_Dedicoat

\6.\ Dharmadhikari AS et al. Rapid impact of effective treatment on transmission of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2014;18:1019–25.

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\8.\ Barrera E, Livchits V, and Nardell E. F-A-S-T: A refocused, intensified, administrative tuberculosis transmission control strategy. Int J Tuberc Lung Dis. 2015;19:381–4.

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\13.\ Queval CJ, Brosch R, and Simeone R. The macrophage: A disputed fortress in the battle against Mycobacterium tuberculosis. Front Microbiol. 2017;8:2284.

\14.\ Brennan PJ. Structure, function, and biogenesis of the cell wall of

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\15.\ Garton NJ et al. Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum. PLoS Med. 2008;5:e75.

\16.\ Warner DF, and Mizrahi V. Tuberculosis chemotherapy: The influence of bacillary stress and damage response pathways on drug efficacy. Clin Microbiol Rev. 2006;19:558–70.

\17.\ Wells W. (ed.) Airborne Contagion and Air Hygiene. Cambridge: Harvard University Press, 1955.

\18.\ Wells W, Ratcliff H, and Crumb C. On the mechanism of droplet nuclei infection II: Quantitative experimental airborne infection in rabbits. Am J Hyg. 1948;47:11.

\19.\ Edwards DA et al. Inhaling to mitigate exhaled bioaerosols. Proc Natl Acad Sci USA. 2004;101:17383–8.

\20.\ Nardell EA. Air sampling for tuberculosis—Homage to the lowly guinea pig. Chest. 1999;116:1143–5.

\21.\ Nardell E. Wells revisited: Infectious particles vs quanta of Mycobacterial tuberculosis infection—Don’t get them confused.

Mycobact Dis. 2016;6.

\22.\ Dharmadhikari AS et al. Natural infection of guinea pigs exposed to patients with highly drug-resistant tuberculosis. Tuberculosis (Edinb). 2011;91(4):329–38.

\23.\ Lerner TR, Borel S, and Gutierrez MG. The innate immune response in human tuberculosis. Cell Microbiol. 2015;17:1277–85.

\24.\ Sultan L, Nyka C, Mills C, O’Grady F, and Riley R. Tuberculosis disseminators—A study of variability of aerial infectivity of tuberculosis patients. Am Rev Respir Dis. 1960;82:358–69.

\25.\ Catanzaro A. Nosocomial tuberculosis. Am Rev Respir Dis. 1982;125:559–62.

\26.\ Riley RL MC et al. Aerial dissemination of pulmonary tuberculosis: A two-year study of contagion in a tuberculosis ward: 1959. Am J Epidemiol. 1995;142:3–14.

\27.\ Riley RL. The contagiosity of tuberculosis. Schweiz Med Wochenschr. 1983;113:75–9.

\28.\ Riley R, and Permutt S. Room air disinfection by ultraviolet irradiation of upper air—Air mixing and germicidal effectiveness. Arch Environ Health. 1971;22:208–19.

\ 29.\ Riley R. Aerial dissemination of pulmonary tuberculosis— The Burns Amberson Lecture. Am Rev Tuberc Pulmon Dis. 1957;76:931–41.

\30.\ Fennelly KP, Martyny JW, Fulton KE, Orme IM, Cave DM, and Heifets LB. Cough-generated aerosols of Mycobacterium tuberculosis: A new method to study infectiousness. Am J Respir Crit Care Med. 2004;169:604–9.

\31.\ Escombe AR et al. Upper-room ultraviolet light and negative air ionization to prevent tuberculosis transmission. PLoS Med. 2009;6:e43.

\32.\ Andrews JR, Morrow C, Walensky RP, and Wood R. Integrating social contact and environmental data in evaluating tuberculosis transmission in a South African township. J Infect Dis. 2014;210:597–603.

\33.\ Dharmadhikari AS et al. Surgical face masks worn by patients with multidrug-resistant tuberculosis: Impact on infectivity of air on a hospital ward. Am J Respir Crit Care Med. 2012;185:1104–9.

\ 34.\ Dharmadhikari AS, and Nardell EA. What animal models teach humans about tuberculosis. Am J Respir Cell Mol Biol. 2008;39:503–8.

\35.\ Khan N, Vidyarthi A, Javed S, and Agrewala JN. Innate immunity holding the flanks until reinforced by adaptive immunity against

Mycobacterium tuberculosis infection. Front Microbiol. 2016;7:328.

\36.\ Nardell EA, and Wallis RS. Here today—Gone tomorrow: The case for transient acute tuberculosis infection. Am J Respir Crit Care Med. 2006;174:734–5.

\37.\ Orme IM, and Ordway DJ. Mouse and guinea pig models of tuberculosis. Microbiol Spectr. 2016;4.

\38.\ Escombe AR et al. The detection of airborne transmission of tuberculosis from HIV-infected patients, using an in vivo air sampling model. Clin Infect Dis. 2007;44:1349–57.

\39.\ Riley RL, Mills CC, O’grady F, Sultan LU, Wittstadt F, and Shivpuri DN. Infectiousness of air from a tuberculosis ward. Ultraviolet irradiation of infected air: Comparative infectiousness of different patients. Am Rev Respir Dis. 1962;85:511–25.

\40.\ Mphahlele MDA et al. Highly effective upper room ultraviolet germicidal air disinfection (UVGI) on an MDR-TB ward in SubSaharan Africa. 2009.

\41.\ Smith D, and Wiengeshaus E. What animal models can teach us about the pathogenesis of tuberculosis in humans. Rev Infect Dis. 1989;11:S385–S93.

\42.\ Grzybowski S, Barnett G, and Styblo K. Contacts of cases of active pulmonary tuberculosis. Select Papers Roy Netherlands Tuber Assoc. 1975;16:90–9.

\43.\ Riley E, Murphy G, and Riley R. Airborne spread of measles in a suburban elementary school. Am J Epidemiol. 1978;107:421–32.

\44.\ Gammaitoni L, and Nucci MC. Using a mathematical model to evaluate the efficacy of TB control measures. Emerg Infect Dis. 1997;3:335–42.

\45.\ Forrellad MA et al. Virulence factors of the Mycobacterium tuberculosis complex. Virulence. 2013;4:3–66.

\46.\ Manca C et al. Mycobacterium tuberculosis CDC1551 induces a more vigorous host response in vivo and in vitro, but is not more virulent than other clinical isolates. J Immunol. 1999;162:6740–6.

\47.\ Rudnick SN, and Milton DK. Risk of indoor airborne infection transmission estimated from carbon dioxide concentration. Indoor Air. 2003;13:237–45.

\48.\ Andrews JR, Morrow C, and Wood R. Modeling the role of public transportation in sustaining tuberculosis transmission in South Africa. Am J Epidemiol. 2013;177:556–61.

\49.\ Joosten SA et al. Mycobacterial growth inhibition is associated with trained innate immunity. J Clin Invest. 2018;128:1837–51.

\50.\ Kaufmann E et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. 2018;172:176–90 e19.

\51.\ Brighenti S, and Joosten SA. Friends and foes of tuberculosis: Modulation of protective immunity. J Intern Med. 2018. doi: 10.1111/ joim.12778.

52.Arts RJW et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 2016;17:2562–71.

53.Stead WW, Senner JW, Reddick WT, and Lofgren JP. Racial differences in susceptibility to infection by Mycobacterium tuberculosis [see comments]. N Engl J Med. 1990;322:422–7.

54.Andrews RH, Devadatta S, Fox W, Radhakrishna S, Ramakrishnan CV, and Velu S. Prevalence of tuberculosis among close family contacts of tuberculous patients in South India, and influence of segregation of the patient on early attack rate. Bull World Health Organ. 1960;23:463–510.

55.Le H et al. Process measure of FAST tuberculosis infection control demonstrates delay in likely effective treatment. Int J Tuberc Lung Dis. 2019;23:140–6.

56.Nathavitharana RR et al. FAST implementation in Bangladesh: High frequency of unsuspected tuberculosis justifies challenges of scale-up. Int J Tuberc Lung Dis. 2017;21:1020–5.

57.Miller AC et al. Turning off the tap: Using the FAST approach to stop the spread of drug-resistant tuberculosis in Russian Federation. J Infect Dis. 2018;218(4):654–58.

58.Kendall EA, Fofana MO, and Dowdy DW. Burden of transmitted multidrug resistance in epidemics of tuberculosis: A transmission modelling analysis. Lancet Respir Med. 2015;3:963–72.

59.WHO. Global Tuberculosis Report. In: Department ST, (ed.) Geneva: WHO, 2016.

60.Gelmanova IY et al. Non-adherence, default, and the acquisition of multidrug resistance in a tuberculosis treatment program in Tomsk, Siberia. (submitted for publication - to be resolved or listed as personal communication before publication).

61.Andrews JR et al. Exogenous reinfection as a cause of multidrugresistant and extensively drug-resistant tuberculosis in rural South Africa. J Infect Dis. 2008;198:1582–9.

62.Andrews JR, Noubary F, Walensky RP, Cerda R, Losina E, and Horsburgh CR. Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis. Clin Infect Dis. 2012;54:784–91.

63.Moodley P et al. Spread of extensively drug-resistant tuberculosis in KwaZulu-Natal province, South Africa. PLOS ONE. 2011;6:e17513.

64.Lim JR et al. Incidence and geographic distribution of extensively drug-resistant tuberculosis in KwaZulu-Natal Province, South Africa. PLOS ONE. 2015;10:e0132076.

65.Gandhi NR et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006;368:1575–80.

66.Davis LW, and Gertler PJ. Contribution of air conditioning adoption to future energy use under global warming. Proc Natl Acad Sci USA. 2015;112:5962–7.

67.Nardell E, Vincent R, and Sliney DH. Upper-room ultraviolet germicidal irradiation (UVGI) for air disinfection: A symposium in print. Photochem Photobiol. 2013;89:764–9.

68.Nardell EA. Environmental infection control of tuberculosis.

Semin Respir Infect. 2003;18:307–19.

69.Brickner PW, Vincent RL, First M, Nardell E, Murray M, and Kaufman W. The application of ultraviolet germicidal irradiation to control transmission of airborne disease: Bioterrorism countermeasure. Public Health Rep. 2003;118:99–114.

70.First M, Nardell E, Chaission W, and Riley R. Guidelines for the application of upper-room ultraviolet germicidal irradiation for preventing transmission of airborne contagion—Part II: Design and operations guidance. ASHRAE Trans. 1999;105:877–87.

71.First M, Nardell E, Chaission W, and Riley R. Guidelines for the application of upper-room ultraviolet germicidal irradiation for preventing transmission of airborne contagion—Part I: Basic principles. ASHRAE Trans. 1999;105:869–76.

72.Nardell EA et al. Safety of upper-room ultraviolet germicidal air disinfection for room occupants: Results from the Tuberculosis Ultraviolet Shelter Study. Public Health Rep. 2008;123:52–60.

73.Zhang Jetal. Aradiometryprotocol for UVGIfixturesusinga movingmirror type gonioradiometer. J Occup Environ Hyg. 2012;9:140–8.

74.Miller-Leiden S, Lobascio C, Nazaroff WW, and Macher JM. Effectiveness of in-room air filtration and dilution ventilation for tuberculosis infection control. J Air Waste Manag Assoc. 1996;46:869–82.

75.Campbell DL, Coffey CC, Jensen PA, and Zhuang Z. Reducing respirator fit test errors: A multi-donning approach. J Occup Environ Hyg. 2005;2:391–99.

76.WHO Guidelines on Tuberculosis Infection Prevention and control: 2019 Update. Geneva: 2019.

77.Pollock NR et al. Interferon gamma-release assays for diagnosis of latent tuberculosis in healthcare workers in low-incidence settings: Pros and cons. Clin Chem. 2014;60:714–8.

Diagnosis of pulmonary TB in a public health context Guiding principles of TB diagnostic evaluation History and physical examination

Chest radiography

Specimen collection methods Current sputum tests Non-sputum tests Conclusion

References

DIAGNOSIS OF PULMONARY TB

IN A PUBLIC HEALTH CONTEXT

Globally, an estimated 10 million people developed incident tuberculosis (TB) in 2018, but nearly 30% of these individuals were never reported to public health authorities.1 Sometimes referred to as the “missing 3 million,” these individuals either never sought care because they did not have symptoms or access to diagnostic evaluation services, sought care but were not diagnosed with TB, or were diagnosed with TB but never notified to national TB authorities.2 Undiagnosed TB is associated with substantial morbidity and mortality and with ongoing TB transmission in the community, a fact that makes improving performance and delivery of diagnostic testing services a leading priority for control and elimination of TB worldwide.3 Nevertheless, to be effective, novel tests must facilitate early treatment initiation to minimize individual complications and prevent further TB transmission in the community. It is also important to note that TB testing itself is often time-consuming and expensive, irrespective of the diagnostic result. Thus, the major objectives of TB diagnostic evaluation should be to maximize the proportion of individuals who obtain timely and accurate diagnosis and treatment; to minimize the proportion who are harmed by missed diagnoses, delayed diagnoses, over-testing, and over-treatment; and to prevent individuals and their households from experiencing catastrophic financial costs.

The World Health Organization’s annual report on the global and local epidemiology of TB provides critical context for understanding TB diagnostic practices around the world. The key indicator for evaluating diagnostic performance is known as “TB

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treatment coverage,” and represents the ratio of annual TB case notifications to estimated annual TB incidence. The accuracy of this indicator may be limited by under-reporting of TB diagnoses, especially from the private and non-governmental sectors, and by uncertainty in TB disease estimates that are derived from country-specific mathematical models. Nonetheless, the indicator is valuable for following national trends and comparing the relative quality and effectiveness of national TB programs in detecting and initiating treatment for TB patients. The wide range in TB treatment coverage rates between countries illustrates substantial variation in the quality of TB diagnostic services between countries. In high-incidence, low-income communities that account for the majority of the world’s undiagnosed TB patients, limitations in patient access to healthcare facilities and in the availability of high-quality TB diagnostic services at these facilities contributes to low TB case detection rates and high mortality from undiagnosed TB. In contrast, in low-incidence, high-income countries where clinicians encounter TB patients less frequently, missed diagnoses with resulting higher morbidity and mortality may still be common, in spite of the greater availability of high-level diagnostic capacity. Worldwide, persons living with HIV (PLWH) account for approximately 10% of all TB patients, but over a quarter of all fatalities.4 While TB prevalence and incidence are declining among PLWH, PLWH experience unique diagnostic challenges. For example, PLWH have higher levels of poverty and stigma, which make accessing care more difficult, and also tend to have more rapidly progressive but more paucibacillary forms of TB. This combination of factors helps explain the reduced sensitivity and clinical impact of TB diagnostics among PLWH.5 Finally, treatment coverage ratios are particularly low for individuals with drug-resistant TB: although

multidrug-resistant TB affects at least a half-million new individuals each year, only about one-third receive treatment.1 Because multiple barriers to TB diagnosis exist and vary widely between settings, the TB diagnostic process must be grounded in knowledge of local epidemics.4

In recent years, multiple advances in TB testing have made it more likely that widely deployable, low-cost technologies will someday close the gaps that prevent early, accurate TB case identification. This process began with new WHO diagnostic policies that reduced the number of samples required for sputum smear microscopy, simplified interpretation of microscopy results, and approved several low-cost culture methods.6–8 In addition, the WHO issued its first-ever negative diagnostic recommendation, against the use of inaccurate commercial serodiagnostic tests for TB, a recommendation that highlighted the harms of using unvalidated commercial diagnostics.9 Over the last decade, new WHO policies have inaugurated a new era of molecular diagnostics in lowand middle-income countries, beginning with the approval of line-probe assays for diagnosis of drug-resistant TB and semi-automated nucleic acid amplification assays for both drug-susceptible and drug-resistant TB. Whole-genome sequencing, now standard in public health laboratories in several high-income countries, promises to further revolutionize the diagnosis and management of drug-resistant TB. In 2015, the WHO approved the first non-sputum-based, point-of-care diagnostic test for TB, the urinary lipoarabinomannan (LAM) assay. This and later generation assays represent an important development as the first truly point-of-care technologies for TB diagnosis.10

The rapid progress in introducing new diagnostics with improved sensitivity and turn-around time has been welcome, but their impact on patient-important outcomes remains unclear. Unfortunately, regulatory bodies do not require such information for their approval processes and few studies report measures of patient impact.11,12 Without further advances that demonstrate integrated strategies for driving down TB incidence, TB mortality, and catastrophic costs of TB, it will be difficult to advance the larger END TB Strategy goals of eliminating TB as a public health threat by 2035.13 There is a greater need than ever for translational research in real-world settings to produce the next generation of diagnostics that can leapfrog current resource limitations and engage patients and providers.14

In this chapter, we focus on the principles, tools, and practices that support a high-quality evaluation for pulmonary TB. We first outline key principles of diagnostic evaluation for TB, then provide an overview of the role of the clinical history and physical examination in screening patients for active pulmonary TB. We then discuss sample collection for diagnostic testing, and conclude with a review of current and emerging diagnostic tests for TB, focusing on the principles underlying these new technologies and drawing examples from the tests most commonly implemented in routine clinical and public health practice. Table 7.1 summarizes the sensitivity and specificity of routinely available diagnostic tests for active pulmonary TB, including clinical symptoms, chest radiography, and other commonly used tests.

GUIDING PRINCIPLES OF TB

DIAGNOSTIC EVALUATION

A thorough and accurate diagnostic evaluation for TB requires that clinicians integrate information from the clinical assessment with knowledge of the performance of different testing strategies using a formal or informal likelihood-based approach.15 A fundamental aspect of diagnostic testing for TB and other diseases is that sensitivity varies widely between settings, and statistical heterogeneity is almost universally reported in systematic reviews of diagnostic test accuracy.16 Common reasons for this variability in performance are worth noting here. First, the predictive value of diagnostic testing depends on the prior probability of disease, which is informed by knowledge of the local prevalence of the disease within the general population or within specific communities or populations to which the patient belongs. Second, the accuracy of diagnostic tests depends on the severity or spectrum of disease in the population being evaluated, as determined by the burden and distribution of Mtb bacilli, and/or the host response. For example, more severe illness usually increases the sensitivity of the clinical history, physical findings, and inflammatory markers for TB, often at the cost of lower specificity. In contrast, immunosuppressed patients may become ill with a lower burden of bacilli, and more commonly with extrapulmonary manifestations, reducing the sensitivity of sputum microbiologic assays for TB. Finally, performance depends on the quality with which tests are performed, so that automation, inclusion of internal controls, and external quality assurance programs are important strategies for improving accuracy and reproducibility.

The second important principle of TB diagnostics is that given the expected heterogeneity of presentation and performance, no single diagnostic test has been identified as well-suited to all settings. Moving testing closer to the point-of-care is desirable if accuracy and quality can be assured, as this is likely to make TB diagnostic evaluation more patient-centered. To do so, the ideal test would be simple, affordable, reliable, reproducible, rapid, sensitive, and specific, as well as deliverable without need for electricity, maintenance, or additional supplies or equipment.14 It would detect both drug-susceptible and drug-resistant TB, and provide information on disease severity and prognosis. Because no single test is likely to have all desirable features, it is valuable to define different test phenotypes according to where they may fit into standard diagnostic pathways.17 Thus, WHO has identified four high priority test types for diagnostic development and created target product profiles (TPPs) for each.18 The first of these, a community-based triage or referral test, would improve TB screening by reducing the number of individuals who require confirmatory testing using a costly reference standard assay (i.e., nucleic acid amplification testing [NAAT] or mycobacterial culture). According to WHO, a useful triage test should provide high sensitivity (≥90%) and moderate specificity (≥70%) for active TB disease at low cost (<US$2) and with a short turn-around time (<30 minutes). The second test type, a rapid (<1 hour), sputumbased test for detecting TB in primary-care settings should have higher sensitivity and similar or higher specificity than smear

microscopy at modest cost (<US$6). The third, a rapid (<1 hour), biomarker-based, non-sputum test should be as accurate as smear microscopy for pulmonary TB but should also be able to detect extrapulmonary TB and pediatric TB. A non-sputum test should also be inexpensive (<US$6) and simple enough to be offered in clinic and community settings without need for biosafety protocols that sputum tests require. Finally, in areas with a high prevalence of drug-resistance, there is a need for a rapid (<2 hours), next-generation, drug-susceptibility assay deployable in primary care settings and above. This assay would serve as an add-on test for individuals in whom a diagnosis of active TB has been confirmed via other methods.

HISTORY AND PHYSICAL

EXAMINATION

The history and physical examination provide an important starting point in the diagnostic evaluation of active TB disease. A careful assessment by a competent clinician is among the most rapid and lowest cost screening tests available, and recognizing the many clinical presentations of TB is essential to obtaining additional directed diagnostic testing to confirm the diagnosis.

Furthermore, a well-done history and physical helps ground subsequent testing and interpretation of results in the patient’s clinical and epidemiological circumstances.19

The classic symptoms of pulmonary TB can be identified by taking a careful clinical history, in which patients should be asked about the presence of cough and its duration; the presence of sputum and its physical appearance; and the presence and duration of fever, chills, night sweats, and weight loss. Among children, the failure to grow taller and gain weight appropriately should be explored as this may precede weight loss. A comprehensive history and physical should also investigate any other physical complaints or abnormalities. These may suggest extrapulmonary manifestations of TB, and may provide additional opportunities for diagnostic confirmation of TB (e.g., fine-needle aspiration of palpable lymph nodes). Thus, a comprehensive history should explore any other physical complaints or abnormalities noted by the patient. For example, the presence of headache, confusion, neck stiffness, or motor weakness could indicate TB of the central nervous system; eye pain, blurry vision, or photophobia should raise concern for uveitis; back pain could implicate spinal TB; and shortness of breath might indicate pulmonary, pericardial, or pleural TB.

Symptom screening is the most commonly used triage test for TB. The International Standards of TB Care recommend that a

criterion of cough of two to three weeks’ duration be used as a screening question to identify individuals who should be further evaluated for TB.20 This range in the duration of cough that should prompt evaluation acknowledges that cough has different performance characteristics in different clinical settings and in different parts of the world. In a systematic review carried out by the WHO to inform global policy recommendations on screening for active TB, the diagnostic performance of prolonged cough was found to have 25% sensitivity and 96% specificity in low HIV-prevalence settings in Asia and 49% sensitivity and 92% specificity in high HIV-prevalence areas of sub-Saharan Africa, although wide confidence intervals surrounded these estimates.21 In a large, com- munity-level cluster-randomized trial in communities in Zambia and South Africa with a high prevalence of HIV, cough had a sensitivity of only 25%, while the combination of cough of any duration, fever, chills, night sweats, or weight loss was sensitive enough to detect TB in only 40% of all TB patients.22 In the WHOcommissioned systematic review, the presence of any of these symptoms of TB was 77% sensitive and 68% specific for active TB, again with wide precision estimates. A limitation is that almost all of the contributing studies are community-based prevalence studies, and therefore likely underestimate the sensitivity and overestimate the specificity of symptoms among patients undergoing evaluation in health facilities.

One population for whom symptoms have particularly high sensitivity are PLWH. The so-called “four-symptom rule”—the reported presence of cough of any duration, fever, night sweats, or weight loss of at least three kilograms—has an extremely high sensitivity of 99% for active TB among PLWH, although the specificity of these criteria is only 30%. This combination of symptoms was identified through a systematic review of the performance and yield of many different combinations of symptoms, and in 2011 WHO recommended that these be used as the standard criteria for screening of all PLWH.23 WHO undertook a similar evidence review process in 2011 to provide recommendations for TB screening among individuals without HIV.24 A 2018 update of this systematic review highlights the important finding that comparing studies enrolling populations taking antiretroviral therapy to those not taking antiretroviral therapy, the four-symptom rule has a substantially lower sensitivity (51% vs. 89%) and higher specificity (71% vs. 28%).25 The authors conclude that additional screening tests beyond symptoms should be incorporated into diagnostic testing algorithms for PLWH on antiretroviral therapy (ART).

In addition to a detailed review of the clinical history by system, a careful history should also inquire about past medical history of active TB; close contact with individuals with confirmed or possible active pulmonary TB; or prior history of TB infection (as defined by a positive tuberculin skin test or interferon gamma release assay). In the context of prior TB exposure or latent infection, risk factors for progression from latent to active TB, such as immunosuppression due to HIV or pharmacologic therapy, diabetes, and chronic kidney disease, are particularly relevant.26

The physical exam should usually be focused, and follow-up on the findings of the clinical history. However, if there are risk factors for extra-pulmonary TB, such as being a PLWH and/or reporting localizing symptoms outside the respiratory system, a

more comprehensive physical exam is recommended. In patients for whom the history suggests TB, the physical exam should assess specific organ systems that are most commonly or most severely affected by extra-pulmonary TB: a comprehensive neurological examination to screen for meningitis, vertebral TB (Pott’s disease), or TB discitis; examination for cervical, axillary, or inguinal lymphadenopathy without tenderness, cutaneous warmth or erythema; examination for abnormal breath sounds, decreased vocal fremitus and dullness to percussion suggestive of a pleural effusion; distant heart sounds and/or pulsus alternans suggestive of a pericardial effusion; ascites suggestive of peritoneal TB; and/ or large, discrete, firm, red, raised skin nodules in a pretibial distribution consistent with erythema nodosum.

CHEST RADIOGRAPHY

Chest radiography is among the most widely used tests to screen for pulmonary TB. Where accessible, it is performed either as a routine part of TB diagnostic evaluation or, in more resource-con- strained settings, as a follow-on test in individuals who are unable to produce sputum or test negative on rapid microbiologic examination of sputum (e.g., by smear microscopy or NAAT). Other groups in whom chest radiography is strongly recommended are persons living with HIV (PLWH), and individuals in whom chest radiography may influence additional diagnostic evaluation (e.g., physical findings suggestive of pleural effusion) or management (e.g., a patient with significant hemoptysis in whom bronchoscopy or other intervention may be indicated). During active case finding in community settings where individuals predominantly have asymptomatic and pre-clinical disease, chest radiography may dramatically increase the yield of TB diagnoses, as shown by the experience with mass radiographic screening in high-income countries at the beginning of the chemotherapy era and by more recent TB prevalence surveys in many countries.21 This experience has promoted substantial interest in emerging, low-cost, portable digital radiography with computer-aided interpretation.

The radiographic manifestations of pulmonary TB depend on the stages of infection and disease. During primary TB, the formation of a granuloma may lead to a focal scar or persistent nodule of the parenchyma, called a Ghon lesion, and occasionally calcified lymph nodes in the hila and/or mediastinum which if seen all together are termed a Ranke complex.27 In a significant minority of individuals, these radiographic abnormalities will persist as a scar or thickening with or without calcifications, with the clinical significance that they will be detectable on screening chest radiography or computed tomography (CT) for a lifetime. Individuals who fail to control a primary TB infection may develop a tuberculoma, or a focal or lobar infiltrate; up to 25% of individuals may have multifocal disease.27 Among the most common and distinctive radiographic manifestations of TB are cavities, often found in the upper lung fields. Another distinctive but rare radiographic finding of TB is a diffuse and random micronodular pattern, which is highly specific for disseminated, also known as miliary, TB. It was once thought that primary disease presented with midand lowerlung zone infiltrates while only post-primary disease gave upper lobe infiltrates and cavities represent post-primary disease, the use

of molecular epidemiology to differentiate between recently and remotely transmitted infections does not support that dogma.28 Among individuals living with HIV, findings may often present atypically as simple pulmonary infiltrates, with manifestations more atypical among PLWH as CD4 count declines.29,30 A substantial proportion may even have normal-appearing chest radiography, although infiltrates may blossom due to immune reconstitution after initiation of antiretroviral therapy.31,32

Although a subset of individuals with early-stage pulmonary TB may have negative chest radiography, the sensitivity of chest radiography is generally high; the greater limitation is poor specificity, especially among patients with advanced HIV, pre-existing chronic lung disease, and other acute pulmonary infections. In a 2013 WHO-sponsored systematic review, any abnormality on CXR had a sensitivity of 98% and a specificity of 75%. When only abnormalities deemed consistent with TB were considered, sensitivity was 87%, and specificity 89%.21 When added to screening using the four-symptom rule among PLWH, chest radiography substantially increases the sensitivity for TB primarily among those taking ART (from 51% to 85%), albeit with a major loss of specificity (from 71% to 30%). The increment in sensitivity gained by adding chest radiography to symptom screening is much less for those not on ART (from 89% to 94%), but the loss in specificity is also diminished (from 28% to 20%).25

Given the wide variety of radiographic manifestations of TB and the variable performance of chest radiography, researchers have sought to develop standardized scoring systems to make interpretation simpler and more reproducible. A recent systematic review found that scoring systems provide high sensitivity (median 96%), but low specificity (median 46%).33 An alternative approach involves the use of computer-aided detection (CAD) not only for standardization but also to reduce the workload for radiologists or technician screeners, a particular need in the use of radiography active case finding. To date, the few high-quality studies examining CAD performance show that it can provide high sensitivity and modest specificity, comparable to the results obtained for scoring systems applied by human readers.34 This technology may help reduce the number of confirmatory tests when used in mass screening.35

SPECIMEN COLLECTION METHODS

Sputum expectoration

Examination of a sample from the lower respiratory tract—expec- torated sputum, most commonly; induced sputum; or specimens obtained during bronchoscopy—is an essential initial step in testing for pulmonary TB using smear microscopy, NAAT, or mycobacterial culture. Obtaining high-quality sputum specimens is likely important but can be challenging. Expert guidance and long-standing practice recommends that the quality of a specimen be judged by an adequate volume of sputum (e.g., ≥ 0.5 mL) and gross appearance (i.e., sputum, not saliva), although there is little published evidence supporting this dogma.36,37

Sputum for examination may be obtained by expectoration or induction. Obtaining good quality sputum requires care in

collection. Expectorated sputum should be procured by a trained and experienced health worker. WHO guidelines on sputum collection for smear microscopy recommend that a health worker follow three steps to instruct a patient how to expectorate good quality sputum, as follows. The health worker should instruct the patient to (1) take three deep breaths immediately prior to collection, (2) cough forcefully, and (3) produce sputum rather than saliva, with the appearance demonstrated to the participant using a visual aid.38 In a study from Pakistan, instruction prior to expectoration was associated with a 63% increase in the yield of positive sputum examinations among women, although not among men.39 A randomized-controlled trial evaluating the impact of a sputum instruction video in Tanzania was associated with a greater than two-fold increase in the proportion of men and women who tested positive, as well as increases in sputum volume and a decrease in the proportion of salivary specimens.40 While an older practice was to reject salivary specimens for microscopic examination, current guidelines recommend that the best available specimen be examined, provided it is properly labeled with the appropriate patient identifiers and correctly packaged in a well-sealed container.38 Specimens with a salivary appearance may still provide a positive microbiologic diagnosis with smear microscopy, and at least one large study suggests that when examined using NAATs, salivary sputum may provide higher sensitivity than other sputum types.41 Thus, it is recommended that all respiratory specimens submitted to the laboratory be examined, especially when no other specimen can be obtained, and any concerns about the effects of the quality of the specimen on the results be explained as an annotation to the result at the time of reporting so that the clinician can adjust the interpretation.

Another important aspect of sputum examination relates to the number, time of collection, and duration of collection of specimens. Since 2007, WHO has recommended that only two sputum specimens per patient be collected for examination by smear microscopy.6 In 2012, WHO approved a novel sputum collection approach called same-day microscopy,42 based on highquality data showing that examination of two samples collected one hour apart provides a similar diagnostic yield as two samples collected on different days, with reduced rates of initial losses to follow-up.43 Early morning sputum collection has long been recommended to maximize yield of sputum smear examination, but requiring patients to return to health facilities has been associated with high rate of drop-out from the diagnostic process. Two recent high-quality studies,44 including a systematic review of 23 studies comprising 8967 individuals undergoing evaluation for active TB,45 found that early-morning sputum collection provided no statistically significant increase in diagnostic yield over randomly timed, “on-the-spot” sputum collection. Even pooled overnight sputum collection did not have a higher yield than spot collection directly observed by a health worker with instructions on how to produce a good quality sputum sample. There are many benefits for patients, providers, and public health in completing sputum evaluation in a single visit, including earlier diagnosis, greater convenience, and reduced costs for patients; fewer episodes of care for providers, and reduced losses to follow-up for public health.47–49