Nosocomial Tuberculosis
Dick Menzies
Faiz Ahmad Khan
INTRODUCTION
The infectious disease tuberculosis (TB) has plagued humankind for millennia (1). Over the past 130 years, several milestone events shaped our understanding of and approach to TB: Koch’s discovery of the etiologic agent in 1892, the confirmation of its airborne transmission by Wells and Riley in the mid-20th century, the advent—nearly 60 years ago—of antimicrobial agents capable of curing TB, and, more recently, the sequencing of the organism’s entire genome (2,3,4). Largely due to improvements in general living conditions, public health interventions, and the availability of effective antimicrobials, TB incidence was declining in many nations through most of the 20th century. In the past 25 years, however, TB has experienced a resurgence in many parts of the world, a change attributable to multiple factors, including the HIV pandemic, increasing prevalence of drug-resistant Mycobacterium tuberculosis, and weakened public health infrastructure (the latter related, in some areas, to structural adjustment programs) (5,6,7). Today, TB control remains elusive and challenging. In 2010, there were 8.8 million incident cases and 1.5 million deaths attributable to TB (8).
Several characteristics of M. tuberculosis make it an ideal organism to be transmitted in medical facilities. When such transmission occurs, the infection is referred to as “nosocomial” or “healthcare-associated” TB. Under the right circumstances, nosocomial TB transmission can lead to nosocomial outbreaks, in which large numbers of people are exposed and infected in facilities providing medical care to patients with TB. Infection control measures are critical to prevent nosocomial M. tuberculosis transmission. In the United States, inadequate infection control measures contributed to a series of nosocomial TB outbreaks in the late 1980s and early 1990s (9,10,11). The widespread implementation of infection control measures was critical in controlling these outbreaks, and has effectively prevented their recurrence. In contrast to the United States and other high-income nations, nosocomial M. tuberculosis transmission and outbreaks continue to pose a significant threat to public health in low- and middle-income countries. There is an urgent need to strengthen TB infection control measures in resource-constrained areas, particularly those burdened with a high prevalence of both HIV and TB (12).
Our chapter begins by reviewing the basic microbiologic, pathogenic, and clinical aspects of TB infection. We then provide the reader with an overview of the epidemiology of nosocomial TB transmission. The last portion of the chapter provides a detailed discussion of infection control measures and current recommendations regarding their implementation.
TUBERCULOSIS INFECTION AND DISEASE
MICROBIOLOGY
Virtually all episodes of human TB are due to infection by M. tuberculosis (MTB), a subspecies of the Mycobacterium tuberculosis complex (13). Most of the other subspecies rarely cause human disease; the exception is M. africanum, which accounts for a significant proportion of human TB in parts of Africa (13). The genus Mycobacterium possesses certain unique, micro-biologic characteristics. Their lipid-rich cell wall, described by some as “the most complex in all of nature,” “resists acid decolorization of carbol fuchsin stain,” which is why mycobacteria are termed “acid-fast bacilli” (14). In addition to being an obligate aerobe, M. tuberculosis is slow-growing, and requires 2 to 6 weeks in culture before colonies are visible (14).
TRANSMISSION
Transmission of M. tuberculosis occurs person to person via the airborne route. When an infected person speaks, coughs, sneezes, or sings, they release “droplet nuclei” into the air. Droplet nuclei are small, liquid particles, some of which contain M. tuberculosis organisms (15). Infectious droplets are also generated during certain medical procedures, including sputum induction, bronchoscopy, endotracheal intubation, autopsy, and drainage of tuberculous abscesses (16). Not all droplets transmit M. tuberculosis infection. Most large droplets (>10 µm in diameter) settle to the ground before susceptible hosts can inhale them. Those that are inhaled get trapped in the upper airways where they are expunged into the oropharynx by beating cilia, and subsequently swallowed and sterilized by gastric acid (15). Droplets <1 µm in diameter also are ineffectual at transmitting infection; the majority evaporate before they can be inhaled by susceptible hosts, and those that manage to enter the respiratory tract are typically exhaled during subsequent breaths. Droplet nuclei between 1 and 5 µm in diameter carry the greatest risk of transmitting infection. In this size range, droplets can remain suspended in the air for prolonged periods of time and be transported long distances via air currents and ventilation systems. Furthermore, these droplets are more likely to reach and settle in the alveolar airspaces once inhaled (16). The droplets need carry only one viable M. tuberculosis organism to transmit infection (17). Several factors determine the probability that an individual who is exposed to a patient with TB will inhale infectious droplets and develop TB infection (Table 33.1) (18).
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PATHOGENESIS
Once droplet nuclei settle in the distal pulmonary airspaces (or “alveoli”), the bacilli within them are phagocytosed by macrophages. However, the macrophage’s antibacterial mechanisms are only partially effective at killing M. tuberculosis. Persistent intracellular replication leads to macrophage death and fuels the local immune response, which carries organisms to hilar and mediastinal lymph nodes (17,19). Caseating granulomas are the hallmark histologic lesion arising from host immune responses to M. tuberculosis infection (20). The intraparenchymal granuloma at the initial nidus of infection is called the “Ghon focus,” and the combination of this lesion and locally enlarged hilar or mediastinal lymph nodes is referred to as the “Ranke complex” (20). The host eventually develops cell-mediated immunity and delayed-type hypersensitivity, resulting in a positive tuberculin skin test (TST) within 2 to 8 weeks of primary infection (19,21). It is during this minimally symptomatic period of primary TB infection that a critical event occurs: bacilli enter the bloodstream and seed other parts of the body (including the lung apices) through hematogenous spread (22).
What happens next depends on the effectiveness of the host’s immune response to M. tuberculosis. If the immune system is unable to control the primary infection, bacterial replication continues, with increasing inflammation and tissue destruction (either at the site of the initial pulmonary infection or at the metastatic loci) (23). This condition, termed “primary progressive TB,” manifests within 2 years of the initial exposure. Only 5% of immunocompetent individuals develop primary progressive TB. Among the other 95%, the immune system halts bacterial replication, effectively controlling M. tuberculosis infection. This process leaves multiple granulomatous lesions in the organs and lymph nodes where the bacilli spread. While the infection is controlled, it is not entirely eliminated—bacilli survive in a near-dormant state for several years within the granulomatous lesions (24). Individuals who harbor these dormant bacilli are said to have “latent TB infection” (LTBI). Because the bacilli are near-dormant and confined to the granuloma, LTBI is an asymptomatic state in which individuals cannot transmit M. tuberculosis to others. Of the immunocompetent individuals with LTBI, 95% remain asymptomatic and noninfectious throughout their lives and 5% develop “postprimary TB” (also known as “reactivation” TB).
LATENT VS. ACTIVE TB INFECTION
It is important to have a clear understanding of the distinction between the two forms of TB—LTBI and active TB (the latter is often called “tuberculosis disease,” or even simply, “tuberculosis”)—as the two differ in their epidemiology, implications for public health, clinical manifestations, and treatment.
As described above, LTBI is a nontransmittable, asymptomatic infection by dormant, essentially nonreplicating M. tuberculosis. One-third of the world’s population has LTBI. In 5% of people with LTBI, the bacilli will exit the dormant state and multiply, causing inflammation and local tissue destruction, and rendering the carrier capable of transmitting infection to others. This is known as “postprimary” or “reactivation” TB. The risk factors for reactivation TB are discussed in the next subsection. Both reactivation and primary progressive TB are forms of “active TB.” Bacterial replication, inflammation, and tissue destruction characterize active TB, which is the contagious form of TB infection. Active TB develops in sites that were seeded during the hematogenous phase of primary TB infection, and hence active TB can be pulmonary, extrapulmonary, or both, and can present with a myriad of symptoms. As nearly all M. tuberculosis transmission is airborne, the probability that a TB patient will transmit infection to others is, in part, dependent on the organ systems involved (Table 33.1). The risk of transmission is highest in patients with pulmonary (parenchymal or endobronchial) or upper airway TB, with laryngeal disease being the most contagious form. In low-burden settings, most episodes of active TB are likely due to reactivation of LTBI. In contrast, primary progressive disease accounts for a greater proportion of episodes of active TB in high-burden settings (15).
RISK FACTORS FOR REACTIVATION
While the average risk of developing active TB among individuals with LTBI is ~5% over a lifetime, many factors increase the risk of progression (Table 33.2). The important risk factors for reactivation include HIV infection, other causes of severe immunosuppression, and recently acquired LTBI (25).
Treatment of LTBI significantly lowers the risk of progression from LTBI to active TB, but also carries risks of adverse effects; thus, it is important to offer treatment to individuals whose risk of progressing from LTBI to active TB is greater than the risks associated with LTBI treatment (26).
DIAGNOSIS AND TREATMENT
Different diagnostic approaches apply to LTBI and to active TB. Diagnosis of the former is based on eliciting immune reactions to M. tuberculosis antigens, and necessitates accounting for the probabilities of false-positive and negative test results, as well as the probability of progression to active disease. In contrast, active disease is confirmed through the visualization of acid-fast bacilli (AFB) on smear microscopy, the growth of M. tuberculosis
in culture, the identification of M. tuberculosis DNA through nucleic acid amplification, or seeing typical histopathological changes consistent with TB (caseating granulomas) in tissue specimens. When the presence of active TB cannot be confirmed through these methods, a presumptive diagnosis can be made on the basis of radiologic and clinical features (such as response to antituberculosis treatment).
in culture, the identification of M. tuberculosis DNA through nucleic acid amplification, or seeing typical histopathological changes consistent with TB (caseating granulomas) in tissue specimens. When the presence of active TB cannot be confirmed through these methods, a presumptive diagnosis can be made on the basis of radiologic and clinical features (such as response to antituberculosis treatment).
TABLE 33.2 Risk Factors for the Development of Active TB Among Persons with Latent TB Infection (25) | |||||||||||||||||||||||||||||||||||||||
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Diagnosis and Treatment of LTBI
Two tests can be used to diagnose LTBI: the TST and the interferon gamma-release assays (IGRAs). The TST is an inexpensive, reliable, and widely available test that has been used to diagnose LTBI since the early 20th century. Some practitioners prefer using IGRAs to diagnose LTBI because they are easier to interpret, have a lower false-positive rate, and require only one patient visit (TST requires at least two visits). Different guidelines identify different tests as the preferred method for diagnosing LTBI (27).
The Mantoux test is the most reliable and widely used technique for performing the TST (28,29,30). The test is performed by injecting 0.1 mL of 5-tuberculin units of purified protein derivative (PPD) in the dermis of the volar aspect of the forearm (29). The test is read 48 to 72 hours following implantation, by measuring the diameter of induration transverse to the long axis of the forearm. The “ballpoint” method is recommended to reduce interobserver variability. Interpretation outside the recommended postimplantation period may underestimate the extent of induration. The dose, lot number, manufacturer date, and expiry date of the PPD vial should be recorded in addition to the dates of implantation and interpretation, the size of the induration, any adverse reactions, and the name of the interpreter. The only absolute contraindication to TST is a history of serious adverse reaction to a previous TST. The test does not provide clinically useful information in individuals with a documented history of active TB, previously documented positive TST reaction (with the size recorded), and those with a documented history of adequate TB treatment.
TST interpretation often is challenging, and a systematic approach can help clinicians avoid misdiagnosis. Three dimensions must be considered when interpreting TST results: size, positive predictive value (PPV), and risk of progression to active TB. The minimum size of induration required to classify a TST as positive depends on the risk of progression to active TB. The U.S. Centers for Disease Control and Prevention (CDC) recommends cutoffs of 5, 10, and 15 mm for patients at high, intermediate, and low risk, respectively (Table 33.3) (28,29). In areas where prevalence of nontuberculous mycobacteria is low, it is reasonable to use a cutoff of 10 mm even for individuals at low risk of reactivation to increase sensitivity without compromising specificity. When the induration diameter is sufficiently large to be declared positive, one must consider the next dimension of TST interpretation, the PPV. The PPV is the probability that a positive TST result is truly due to the presence of LTBI. This can be the most challenging step in TST interpretation as several factors affect the PPV, including the TST reaction size, country of origin (and the state, if U.S.-born), current age, age at immigration, BCG vaccination status, and history of contact with TB (31,32). Nontuberculous mycobacterial (NTM) infection and childhood BCG vaccination are common causes of false-positive TST (31,32). The latter can be ignored as a cause of false-positive TST in the following circumstances: (a) if the vaccination was received in the first year of life and the individual being tested is at least 10 years old, (b) when the probability of true infection is high (e.g., in contacts of active TB cases, or individuals from high-incidence settings), or (c) when the risk of progression to TB is high. The last dimension of TST interpretation—the probability of progression to active disease if the patient truly has LTBI—is determined by the presence of risk factors for developing active TB (Table 33.2). An online tool is available to assist practitioners with TST interpretation (www.tstin3d.com).
TST “conversion” is said to have occurred when an individual who previously tested negative becomes TST-positive. Caution should be applied when interpreting repeated TSTs, as induration measurement is subject to substantial inter- and intrareader variability (21). Different approaches can be taken to address this issue (21). The CDC recommends that increases in induration diameter of 10 mm or more, within a 2-year period, be considered as conversion.
For individuals who will have multiple TSTs (such as healthcare workers), it is recommended that the first TST be a “two-step TST.” In the first step, the test is performed as described
above. The second step is performed only if the first reaction was negative. The second step involves repeating the TST 1 to 3 weeks after the first TST was performed. If the second TST is positive, this is termed a “booster response” (or “booster phenomenon”). Infection by NTM, BCG vaccination, and the presence of true LTBI are all causes of the booster reaction (21). The PPV of a booster response can be estimated with the help of the same factors that help us interpret positive TSTs. The purpose of the two-step TST is to identify those individuals in whom a positive TST on repeat tests may be due to boosting rather than conversion from a negative to positive TST. It is important to note that the risk of progression to active TB among individuals with a booster response is roughly half the risk among individuals with the same size induration on the first TST (21). Two-step testing should only be performed once, and only when there has been no contact with persons with active TB in the preceding 1 to 5 weeks (21). Increases in TST size should not be interpreted as booster phenomena if there has been recent contact with a person with active TB.
above. The second step is performed only if the first reaction was negative. The second step involves repeating the TST 1 to 3 weeks after the first TST was performed. If the second TST is positive, this is termed a “booster response” (or “booster phenomenon”). Infection by NTM, BCG vaccination, and the presence of true LTBI are all causes of the booster reaction (21). The PPV of a booster response can be estimated with the help of the same factors that help us interpret positive TSTs. The purpose of the two-step TST is to identify those individuals in whom a positive TST on repeat tests may be due to boosting rather than conversion from a negative to positive TST. It is important to note that the risk of progression to active TB among individuals with a booster response is roughly half the risk among individuals with the same size induration on the first TST (21). Two-step testing should only be performed once, and only when there has been no contact with persons with active TB in the preceding 1 to 5 weeks (21). Increases in TST size should not be interpreted as booster phenomena if there has been recent contact with a person with active TB.
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The IGRAs are an alternative to TST for the diagnosis of LTBI. These assays measure the release of interferon gamma in blood samples exposed to M. tuberculosis antigens. While they are as sensitive as the TST, their specificity is greater for M. tuberculosis, as IGRA results are not affected by BCG vaccination status or exposure to NTM (33). Persons with a history of BCG vaccination and those unlikely to return for the TST-interpretation visit are groups in whom IGRAs are the preferred test for the diagnosis of LTBI (34).
TST is the preferred test for groups in whom serial testing for LTBI is likely (such as healthcare workers). A recent systematic review and meta-analysis on the use of IGRAs in serial testing of healthcare workers found no data to suggest that these tests perform better than serial TST (35). Furthermore, several studies have documented high rates of spontaneous reversion when using IGRAs for serial testing (20% to 30% of those with initially positive tests have reverted) (35,36). These studies also reported very high rates of IGRA conversion—much higher than with tuberculin testing (35). This makes it difficult to interpret and manage an individual with an apparent IGRA conversion. In view of this, and until this phenomenon is better understood, it is difficult to recommend serial testing of healthcare workers with IGRAs as part of an institutional TB infection control program.
Under certain circumstances, performing both a TST and an IGRA can be useful. In situations where it might be preferable to maximize the sensitivity for LTBI diagnosis (e.g., in persons with a high risk of progressing to or dying from active TB), if the initial test for LTBI is negative, one can increase the sensitivity by performing the alternative test and interpreting a positive result as sufficient evidence of LTBI. Another circumstance where one can consider using both TST and IGRA is when there is a strong suspicion of a false-positive TST. In this situation, an IGRA can be done to either confirm or refute the TST result. It is important to note, however, that there is no evidence to guide the correct interpretation of discordant TST and IGRA tests.
Multiple regimens can be used to treat LTBI, the most common being isoniazid monotherapy for 9 months. If there is any suspicion of active TB (based on symptoms, exposure history, clinical findings, or radiographic abnormalities), treatment for LTBI should not be initiated until active disease has been ruled out. This is because the administration of only one anti-TB medication to someone with active disease rapidly leads to the development of drug-resistant organisms.
Diagnosis and Treatment of Active TB
In general, TST and IGRA do not provide useful information when investigating someone for active TB (the exception is in young children, where these tests are still used to diagnose active disease). Visualization of AFB on microscopic examination of specimens, growth of M. tuberculosis in culture, and identification of M. tuberculosis DNA are the preferred methods to diagnose active TB. The ease of obtaining specimens for microscopy and culture, and the sensitivity of tests for the detection of active TB depend, in part, on the site of infection. When pulmonary TB is suspected, microscopy and culture of three sputa, collected through cough induction with nebulized hypertonic saline, provides a sensitive and noninvasive initial investigation. In contrast, the sensitivity of microscopy and culture is low for pleural, peritoneal, pericardial, and spinal fluid. Molecular tests—such as nucleic acid amplification and adenosine deaminase levels—also have a low sensitivity for diagnosis of TB in these locations; however, their high specificity can help in ruling in disease.
A new generation of nucleic acid test, the Xpert MTB/RIF assay, is highly sensitive for the diagnosis of pulmonary TB, and provides results faster than smear microscopy and culture. In an international, multicenter study, the assay identified 98% of sputum smear and culture-positive patients, and 70% of sputum smear-negative but culture-positive patients (37). The test has an additional advantage in that it provides rapid identification of rifampin-resistant M. tuberculosis, a process that would otherwise take at least 4 weeks. The disadvantages include its high cost, and that it does not provide information regarding the infectivity of the patient. This test is likely to start playing a greater role in the diagnosis of active TB (38).
The treatment of active disease lasts at least 6 months. In order to prevent the organism from acquiring resistance to anti-TB medications, active TB treatment requires the use of at least three drugs to which the isolate is sensitive. Effective treatment rapidly reduces the number of bacilli in the smear, and in so doing lowers both the magnitude and duration of infectivity.
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