Tuberculosis and Nontuberculous Mycobacterial Infections, Seventh Edition

Tuberculosis is an ancient infection that has plagued humans throughout recorded and archeological history. It is always a surprise to those of us who live in Western countries that even today the infection remains the cause of higher rates of morbidity and mortality than any other infection in the world. This is because of its great prevalence in the densely populated developing countries; however, the incidence of tuberculosis is grossly underreported in these countries. According to estimates of the World Health Organization (WHO), in 2014 there were approximately 9.6 million active cases, of which 3 to 4 million cases were infectious, with positive sputum smears ( 1 ). Deaths due to tuberculosis occur in 1.5 million people worldwide each year ( 1 , 2 ). The estimates are that a death from tuberculosis occurs every minute. Thus, tuberculosis is still a major cause of disease and death, and its elimination will be extremely difficult as long as poverty, overpopulation, and multidrug-resistant (MDR) disease characterize large portions of the earth. Human immunodeficiency virus (HIV) is already deemed the number one preventable cause of death in developing countries ( 3 ).

The perspectives described in this chapter address both preclinical tuberculosis (TB) in animal hosts and clinical TB in human populations. They are a guide to how new TB vaccines can be more effectively evaluated in each group. This chapter is not a review of new TB vaccines or the mechanisms in which they may reduce the prevalence or morbidity of TB in the world.

The modern clinical microbiology laboratories have a number of methods available that provide an accurate and rapid laboratory diagnosis of tuberculosis. Molecular methods are now part of the diagnostic algorithm in many laboratories and have dramatically shortened the time to diagnosis. An FDA-approved rapid-cycle PCR assay, for the first time, is being recommended not only for the direct detection of Mycobacterium tuberculosis but also for the rapid detection of multidrug-resistant M. tuberculosis (i.e., MDR-TB) and, when one or two negative results are obtained, for removing patients from respiratory isolation ( 1 , 2 ).

In 2015, there were a total of 9,563 tuberculosis (TB) cases reported in the United States, corresponding to an overall TB incidence of 3.0 cases per 100,000, unchanged compared to the rates for 2013 and 2014. With this trend, the progress toward TB elimination in the United States appears to have stalled after 2 decades of decline. Foreign-born persons and racial/ethnic minorities continued to have TB disease disproportionate to their respective populations ( 1 ). This is a trend observed in the United States and other industrialized nations with a low incidence of TB. In these countries, most new, active cases have occurred among persons who were once infected, contained the infection, and then later developed active disease ( 2 ). Resuming declines in TB incidence in the United States will require that more emphasis be placed on strengthening systems for detecting and treating latent TB infection (LTBI) as well as accelerating TB care globally. This chapter reviews the tuberculin skin test (TST) and blood assays to detect LTBI.

The World Health Organization (WHO) has recently reported that the global tuberculosis (TB) epidemic is larger than previously projected, with an estimated 10.4 million new (incident) cases occurring in 2015 ( 1 ). It has thus become clear that the WHO End TB Strategy targets of a 90% reduction in TB incidence and a 95% reduction in TB deaths by 2035 can be achieved only by combining the effective detection and treatment of active TB with measures to prevent new infection with Mycobacterium tuberculosis and to eradicate existing latent TB infections (LTBI) ( 1 – 6 ). Recent estimates indicate that approximately 1.7 billion people, nearly one-quarter of the world’s population, are latently infected with Mycobacterium tuberculosis and are at risk of progression to active TB without treatment ( 7 ). Moreover, an estimated 11% of those are likely infected with an isoniazid-resistant strain. With ongoing transmission of M. tuberculosis and a high rate of reactivation from LTBI to active TB, a heightened global commitment to the identification and treatment of infected persons is thus critical for achievement of TB elimination ( 1 – 6 , 8 – 10 ).

Here we review the underlying principles of tuberculosis (TB) chemotherapy, medical management, and current treatment recommendations for drug-susceptible TB.

The treatment of active tuberculosis (TB) disease began in the 1940s ( 1 ). With the introduction of each new drug, different combinations were tried until investigators settled on the current regimen in the 1970s (while this author was still in high school) ( 2 ). The regimen of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) became the standard regimen for TB in countries with developed economies, while countries with smaller economies continued to use rifampin-sparing regimens in order to save money. Eventually, nearly all countries adopted the RIPE regimen, once it was clearly shown that treatment outcomes were significantly better with rifampin, despite the initial greater cost of the drug ( 3 ). This focus on cost remains a major driving force in the treatment of TB.

Multidrug-resistant tuberculosis (MDR-TB), caused by Mycobacterium tuberculosis strains resistant to at least isoniazid (INH) and rifampin ( 1 ), is difficult to treat effectively and requires medications that are expensive, toxic, and less effective than first-line anti-TB therapy. In March 2006 the original definition of extensively drug-resistant TB (XDR-TB) was reported in the CDC’s Morbidity and Mortality Weekly Report ( 2 ). In October of the same year a revised definition was reported: XDR-TB is defined as TB resistant to INH, rifampin, a second-line injectable drug (SLID; kanamycin, amikacin, or capreomycin), and any fluoroquinolone ( 3 ). This new definition was better able to identify a group with worse outcomes, including higher mortality rates, than with MDR-TB ( 4 ). MDR- and XDR-TB strains are resistant to the most potent anti-TB medications that are reliably associated with successful outcomes. The outbreak of MDR-TB in New York City in the 1990s caught the world’s attention, as has the rapid spread of XDR-TB globally ( 5 – 7 ).

The history of thoracic surgery as a specialty is inseparable from that of the development of tuberculosis (TB) management. Many surgeons would suggest that the very first surgical procedure in the chest was probably performed in the time of the Ancient Greeks. Hippocrates himself described a technique of open pleural drainage for empyema thoracis resulting from TB ( 1 ). Modern thoracic surgery as clinicians would recognize it today was born soon after the identification of Mycobacterium tuberculosis by Koch in the 1880s. When it was realized that the microbe responsible for “consumption” was an obligate aerobe, a variety of collapse therapies were developed in the late 19th and early 20th centuries to kill the organism through oxygen deprivation. These included thoracoplasty, induced pneumothorax, ball plombage, pneumoperitoneum, and phrenic nerve crushing ( 2 ). Crucially, most of the basic skills and approaches still used in modern thoracic surgery today were also honed at this time, including the ubiquitous thoracotomy incision. Even minimally invasive thoracic surgery traces its roots to this period, when Jacobeus introduced the technique of thoracoscopy for pleural biopsy and adhesiolysis in TB patients ( 3 ).

A critical component of global tuberculosis control is the development of more effective immunization strategies. Several tuberculosis vaccines have been shown to reduce the risk of disease and death due to tuberculosis in humans, but only one is used in global immunization programs: Mycobacterium bovis bacillus Calmette-Guérin (BCG). BCG is an attenuated live vaccine administered at birth to children in most countries where tuberculosis is endemic. BCG has been the most widely administered vaccine in the world, with an estimated three billion doses administered to date ( 1 ). BCG has likely reduced the burden of tuberculosis in many areas, but it has numerous limitations. These limitations, together with the continuation of the global tuberculosis epidemic, have made the development of a more effective vaccine against tuberculosis a major international public health priority ( 2 , 3 ).

Tuberculosis (TB) remains one of the major causes of human suffering and deaths, causing a pandemic of relevant proportions. However, great progress has been made in the fight against TB in the last two decades following the implementation and scale-up of World Health Organization (WHO) public health strategies. The TB elimination goal can be achieved by 2050, but joint efforts from the international community are required ( 1 ). However, several challenges must be faced; in particular, the occurrence and spread of multidrug-resistant TB (MDR-TB), TB and human immunodeficiency virus (HIV) coinfection, the old-fashioned diagnostic, therapeutic, and preventive armamentarium, and the increasing prevalence of chronic conditions fueled by socioeconomic determinants could significantly hamper the elimination. A new comprehensive approach to fight TB, the End TB strategy, was introduced by the WHO in 2014. It is the third WHO public health strategy focused on TB, following the DOTS (“directly observed treatment, short course”) ( 2 – 4 ) in 1993 and the Stop TB strategy in 2006 ( 5 , 6 ). The great success of the first two successful WHO strategies was not sufficient to significantly reduce the annual TB incidence rate to achieve TB elimination by 2050 (i.e., incidence rate of less than one TB case per million population) globally. The principles behind the first WHO strategy were oriented to patient care and interruption of Mycobacterium tuberculosis in the community, through early bacteriological case index detection and the cure of contagious pulmonary forms through a standardized therapy. At the beginning of the century, the widespread occurrence of cases involving TB/HIV coinfection and MDR-TB patients required a more tailored and comprehensive public health strategy (the Stop TB strategy) encompassing the DOTS elements and new tactics adapted to the new epidemiological scenario (e.g., universal access to care for all TB patients, engagement between the private and public sectors, and involvement of the civil society and patients’ organizations) in TB control efforts.

Throughout history, tuberculosis (TB) as well as humanitarian crises have occurred, mostly episodically and sometimes together ( 1 ). Higher TB incidence and adverse TB outcomes have often been associated with socioeconomic deprivation and other social risk factors, and during the 20th century, large TB incidence and mortality increases were observed during the two world wars in several European countries. This review aims to summarize the evidence of health effects in crises-affected populations, with a particular focus on TB epidemiology, care, and outcomes.

Tuberculosis (TB) transmission in enclosed environments was responsible for large outbreaks during the 1990s. These occurred primarily among human immunodeficiency virus (HIV)-infected persons, homeless shelter residents, jail and prison inmates, acute-care facility in-patients, long-term care facility (LTCF) residents, and health care workers (HCWs). Risk factors which contributed include decay in public health infrastructure, rise of HIV infection (with limited highly active antiretroviral treatments), increase in the number of homeless persons, immigration from countries with high TB incidence, HCWs’ decreased vigilance, and few existing adequate airborne isolation facilities. The resulting major public health efforts to upgrade facilities in hospitals and jails, provide directly observed treatment (DOT), and educate HCWs and the public all led to a dramatic decrease in new TB cases, especially multidrug-resistant TB (MDR-TB), from 10.5 cases per 100,000 in 1992 to 3.0 cases per 100,000 in 2015 ( 1 ).

Because tuberculosis is caused by an infectious organism that is spread from person to person through the air, public health measures are essential to control the disease. There are three priority strategies for tuberculosis prevention and control in the United States: (i) identifying and treating persons who have tuberculosis disease; (ii) finding persons exposed to infectious tuberculosis patients, evaluating them for Mycobacterium tuberculosis infection and disease, and providing subsequent treatment, if appropriate; and (iii) testing populations at high risk for latent tuberculosis infection (LTBI) and treating those persons who are infected to prevent progression to disease ( 1 ).

The lung is the most commonly affected organ in tuberculosis infection in the immunocompetent host, with estimates of lung involvement in subjects with active tuberculosis of 79 to 87% ( 1 – 3 ). Estimates of lung involvement are similar in immunocompromised hosts, such as those with human immunodeficiency virus (HIV) infection, with studies from the 1980 to 1990s suggesting that the rates of pulmonary involvement were on the order of 70 to 92% ( 4 – 6 ). However, these individuals are also more likely to have extrapulmonary disease as well ( 7 ).

The upper respiratory tract is the portal of entry of all inhaled matter in the lungs. It also constitutes the first line of defense against the inhalational insults. Tubercular involvement of the upper respiratory tract is not surprising, as inhalation is the most common and important route of mycobacterial infection. On the other hand, upper respiratory tract TB (URT-TB) is one of the rare forms of extrapulmonary TB (EPTB). It is the relative rarity of URT-TB which is somewhat puzzling. Possibly, the continuous airflow and the smooth mucosal lining do not allow the mycobacteria to settle down in the respiratory tract, except for the entrapment areas, such as the larynx. In the prechemotherapeutic era, patients with active pulmonary TB often developed laryngeal, otological, nasal, paranasal, and pharyngeal involvement and deteriorated progressively. The incidence came down significantly with the advent of effective anti-TB drugs.

Tuberculous otitis media and tuberculous mastoiditis occur together as a single disease process and are referred to herein as tuberculous otomastoiditis. One year after the isolation of the tubercle bacillus by Koch in 1882, the organism was cultured from a middle-ear lesion. Otologic tuberculosis was relegated to the status of “other” in the list of localizations of tuberculosis by the American Thoracic Society in their 1981 Diagnostic Standards and Classification of Tuberculosis and Other Mycobacterial Diseases ( 1 ) and receives no mention in more recent guidelines ( 2 ). Presumably, it was given this status because tuberculosis of the ear is extremely uncommon in the United States (11 cases reported from 1990 through 2003) ( 3 ). However, there are still occasional patients who have chronically draining ears due to Mycobacterium tuberculosis infection ( 4 ). Additionally, tuberculosis remains a problem in the United States, as overall incidence has plateaued and reported cases have recently increased ( 5 ). These increasing numbers of tuberculosis cases in both U.S.- and foreign-born populations coupled with growing rates of immunosuppressed patients, such as transplant recipients, those receiving tumor necrosis factor alpha inhibitors, and those with human immunodeficiency virus infection, will likely spawn other cases of tuberculous otomastoiditis; therefore, a brief summary of the problem is justified.

Maitre-Jan ( 1 ) is often credited with publishing the earliest description of ocular tuberculosis (1707). Major contributions to the understanding of the disease mechanism were not made until the latter part of the 19th century. In 1855, Eduard von Jaeger first described the ophthalmoscopic appearance of choroidal tubercles ( 2 ). Cohnheim, in 1867 ( 3 ), showed that choroidal tubercles were similar microscopically to tubercles found elsewhere in the body and postulated that ocular involvement was a metastatic manifestation of systemic infection. In addition, Cohnheim was able to produce similar lesions in guinea pigs by injecting them with tuberculous material. In 1882, Koch identified the tubercle bacillus as the causative agent ( 4 ), and 1 year later, Julius von Michel identified the organism in the eye ( 5 ).

Central nervous system (CNS) tuberculosis (TB) is among the least common yet most devastating forms of human mycobacterial infection. Conceptually, clinical CNS infection is seen to comprise three categories of illness: subacute or chronic meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. All three forms are seen with about equal frequencies in high-prevalence regions of the world where postprimary, extrapulmonary clinical infection is encountered commonly among children and young adults ( 1 ). Meningitis syndrome predominates in low-prevalence countries such as the United States and in Europe, where extrapulmonary TB is encountered primarily in older adults with reactivation disease. The natural history of tuberculous meningitis (TBM) is that of insidious onset and subacute progression, prone to rapid acceleration once neurologic deficits supervene, leading to stupor, coma, and, finally, death within 5 to 8 weeks of the onset of illness. Consequently, in order to achieve a favorable therapeutic outcome, it is important to begin treatment promptly, empirically during the early stages of illness, relying on clinical suspicion and a presumptive diagnosis rather than awaiting laboratory confirmation. Of necessity, this requires some knowledge of the causes and clinical features of granulomatous meningitis, the pathology that subserves the neurologic manifestations of disease, and the expected radiographic and laboratory (chiefly cerebrospinal fluid [CSF]) findings.

Tuberculosis (TB) of the lymphatic glands has afflicted humans for thousands of years. Scrofula is usually a term used to describe the swelling of the lymph nodes in the neck caused by TB; the name scrofula was given because pigs were considered susceptible to the disease, and it comes from the Latin scrofulae, meaning brood sow. Hippocrates (460–377 BC) mentioned scrofulous tumors in his writing, and Herodotus (484–425 BC) described the exclusion of those afflicted with leprous or scrofulous lesions from the general population. In the Middle Ages, it was believed in England and France that a touch from royalty could heal skin disease known as scrofula or the “king’s evil.” The practice began in the 11th century in France with Robert the Pious (970–1031), King of France, and in England with King Edward the Confessor (1003–1066). Subsequent English and French kings were thought to have inherited this royal touch, which was supposed to show that their right to rule was God given. In grand ceremonies, kings touched hundreds of people afflicted by scrofula ( 1 ).

Tuberculosis has a worldwide distribution, without cyclical or seasonal variations and with greater prevalence in regions of high population densities and poor socioeconomic and sanitary status. It is estimated that 30% of the world’s population (1.7 billion people) are carriers of Mycobacterium tuberculosis ( 1 ). In spite of the availability of pharmacological treatment and of technological breakthroughs, the last 3 decades have witnessed a recrudescence of the infection due to the emergence of resistant bacilli, human migration, and the AIDS epidemic. In fact, tuberculosis is still a serious challenge to the world public health, chiefly in developing countries ( 2 ).

Musculoskeletal tuberculosis (TB) accounts for approximately 10% of all extrapulmonary TB cases in the United States and is the third most common type of extrapulmonary TB after pleural and lymphatic disease. Vertebral involvement (tuberculous spondylitis, or Pott’s disease) is the most common type of skeletal TB, accounting for about half of all cases of musculoskeletal TB. The presentation of musculoskeletal TB may be insidious over a long period and the diagnosis may be elusive and delayed, as TB may not be the initial consideration in the differential diagnosis. The diagnosis is often confused with malignancy. Concomitant pulmonary involvement may not be present, thus confusing the diagnosis even further.

Cardiovascular tuberculosis is an uncommon extrapulmonary manifestation of mycobacterial disease. With the advent of AIDS, which has increased the incidence of mycobacterial disease ( 1 – 7 ), particularly of the extrapulmonary type ( 8 – 21 ), one can expect an increase in cardiovascular tuberculosis. Nevertheless, cardiovascular tuberculosis is a rare complication of AIDS in the United States ( 8 , 11 , 22 ). Pericardial tuberculosis is the disease presentation in the greatest percentage of patients with cardiovascular tuberculosis ( 23 – 27 ). In the United States and other developed countries, most patients with AIDS and pericarditis with effusion have an idiopathic cause. However, in Africa, 86 to 100% of patients with AIDS and pericarditis with effusion have Mycobacterium tuberculosis as the etiology ( 28 ). Tuberculosis of the aorta ( 29 , 30 ) and tuberculosis of the myocardium ( 31 ) are reported but extremely unusual forms of cardiovascular tuberculosis.

Involvement of the gastrointestinal tract by tuberculosis (TB) remains a prevalent and relevant disease entity in certain areas of the world and in certain at-risk patient populations. Although the more common forms of extrapulmonary TB (EPTB) include lymph node, pleural, disseminated, pericardial, and meningeal TB, gastrointestinal TB is believed to be the next most frequent form ( 1 , 2 ). Although there is significant variability in the prevalence of intestinal TB by geographic location and by the population’s risk profile, the true prevalence of the disease is difficult to ascertain, as many patients with pulmonary TB may be asymptomatic from their intestinal involvement ( 3 , 4 ). This requires a very high index of suspicion, as a delay in diagnosis may result in detrimental outcomes. When patients do become symptomatic, their presentation may be nonspecific. Furthermore, as TB can involve any part of the gastrointestinal tract, the manifestations are protean ( 5 ).

Abdominal tuberculosis (TB), most common in the developing world ( 1 – 3 ), is not entirely uncommon in the United States and Europe. Patients with AIDS, immigrants from areas where TB is endemic, Native Americans on reservations, the urban poor, and the elderly are at particular risk ( 4 , 5 ). TB rates have decreased from 52.6 cases per 100,000 population in 1953 to 4.2 per 100,000 population in 2008 to 3.0 per 100,000 in 2014 ( 6 ). While the United States experienced a temporary resurgence in the late 1980s and early 1990s, this has clearly abated and recent rates appear to be plateauing ( 6 ). The case rate among those born outside the United States is 13 times higher than for those born in the United States, for whom the rate is exceedingly low, at 1.2 cases per 100,000 ( 6 ). Interestingly, the proportion of extrapulmonary TB cases has increased (from 16% in 1993 to 20% in 2008). Peritoneal TB, the principal but not the only form of intra-abdominal TB, accounts for 6.1% of all extrapulmonary TB cases ( 6 ). Symptoms and signs of peritoneal TB are nonspecific, and a high index of suspicion needs to be maintained to make the diagnosis in a timely manner. Here, we review the epidemiology, pathogenesis, clinical features, available diagnostic techniques, and therapy of tuberculous peritonitis.

Involvement of the liver in patients with Mycobacterium tuberculosis has been described for nearly two centuries. One of the earliest descriptions was published in Guy’s Hospital Reports by Thomas Addison in 1836 ( 1 ). The first recorded case of hepatic tuberculosis was reported in 1858 by John Bristowe in England ( 2 ), and hepatic tuberculosis was classified into miliary and local forms by Rolleston and McNee in 1905 ( 3 ). Autopsy studies during the latter half of the 19th century and early 20th century demonstrated granulomas and a variety of other lesions in the livers of patients dying with tuberculosis ( 1 , 4 – 6 ). The reports by Gillman and Gillman ( 7 ) and subsequently by many others ( 8 , 9 ) on the use of needle biopsy of the liver to demonstrate tuberculous lesions have made the procedure a valuable tool for diagnosis of the disease, especially in cases of cryptic miliary tuberculosis without recognized pulmonary involvement ( 10 ). Although isolated hepatobiliary tuberculosis was described infrequently in years past ( 11 , 12 ), a number of detailed reviews attest to its continued importance in the clinical spectrum of the disease ( 13 – 17 ).

Cutaneous tuberculosis (TB) is not a well-defined entity but comprises a wide spectrum of clinical manifestations. In the past, much of the confusion regarding cutaneous TB has resulted from misleading, redundant nomenclature and cumbersome, non-clinically oriented classifications of cutaneous disease. These classifications have been based on various criteria, including chronic versus labile disease, localizing versus hematogenous disease, histologic forms of disease, immunologic status of the patient, primary disease versus reinfection, and listing of the various types of cutaneous mycobacteriosis ( 1 – 3 ). A more clinically relevant classification has been developed that uses three criteria: pathogenesis, clinical presentation, and histologic evaluation ( Table 1 ).

Miliary tuberculosis (TB) is a lethal form of disseminated TB that results from a massive lymphohematogenous dissemination from a Mycobacterium tuberculosis-laden focus ( 1 – 5 ). The term “miliary TB” (derived from the Latin word miliarius, meaning related to millet seed) was coined by John Jacob Manget ( 6 ) in republishing the work of Bonetus ( 7 ) in 1700 to describe the resemblance of gross pathological findings to that of innumerable millet seeds in size and appearance ( Fig. 1 ). Traditionally, the miliary pattern on a chest radiograph has been defined as “a collection of tiny discrete pulmonary opacities that are generally uniform in size and widespread in distribution, each of which measures two mm or less in diameter” ( 8 ). In 10% of the cases, the nodules may be greater than 3 mm in diameter ( 9 ).

Tuberculosis may lead to adrenal insufficiency by direct glandular involvement, by extra-adrenal infection, or as a by-product of antituberculous therapy. When primary adrenal insufficiency is a product of direct glandular involvement, signs and symptoms may not appear until more than 90% of the gland has been destroyed. Bilateral adrenal cortex destruction leads to a deficiency in the production of glucocorticoids, mineralocorticoids, and androgens.

Tuberculosis (TB) affects the production and life span of all hematologic cellular components ( Table 1 ). In addition, plasma coagulation factors may be affected. The pharmacological agents used for TB therapy may also cause hematologic changes ( Table 2 ). This chapter reviews and updates known hematologic effects of TB and its therapy.

The clinical expression of disease caused by Mycobacterium tuberculosis is greatly different in infants, children, and adolescents from what it is in adults ( 1 , 2 ). Much adult pulmonary tuberculosis is caused by a reactivation of organisms which were lodged in the apices of the lungs during hematogenous dissemination at the time of infection. Childhood tuberculosis is usually a complication of the pathophysiologic events surrounding the initial infection. The interval between infection and disease is often long (years to decades) in adults but is often only weeks to months in small children. Children are more prone to developing extrapulmonary tuberculosis but rarely develop contagious pulmonary disease. As a result of the basic differences in pathophysiology of tuberculosis between adults and children, the approach to diagnosis, treatment, and prevention of infection and disease in children is necessarily different ( 3 ).

The epidemiology of tuberculosis in pregnancy reflects that of tuberculosis at large. Worldwide, the number of cases of tuberculosis appears to have peaked in 2004, with declining rates in Western and Central Europe, Latin America, the Eastern Mediterranean, Southeast Asia, and the Western Pacific. High prevalence rates have yet to decline substantially in Africa and Eastern Europe ( 1 ). According to the WHO, in 2013 tuberculosis caused half a million deaths among women worldwide, most of whom were human immunodeficiency virus (HIV) negative ( 2 ). For the United States, the rising incidence of tuberculosis seen during the late 1980s and early 1990s appears to have ended. The U.S. case rate (per 100,000 persons) of 10.4 in 1992 declined to 2.96 in 2014, with 66% of reported TB cases occurring among foreign-born persons. Different ethnic groups have widely different rates, however, with Asians having the highest case rate of 17.8 per 100,000 persons, followed by Native Hawaiians and other Pacific Islanders, with a case rate of 16.9 per 100,000 persons ( 3 ). The 2014 tuberculosis case rates for women of childbearing age from various ethnic groups ( 3 ) are shown in Table 1 . A recent systematic review of latent tuberculosis in pregnancy revealed a prevalence of 14 to 48% in the United States, with skin test positivity varying with ethnicity, representing a significant opportunity to potentially impact upon the development of tuberculosis disease in both the mother and the infant ( 4 ). For women of childbearing age, infection with HIV represents a significant risk factor for tuberculosis infection. Of 16 pregnant women with tuberculosis in New York City reported by Margono and coworkers, 7 of 11 (64%) tested were HIV positive ( 5 ). Another study of a cohort of HIV-infected women in the United States found that 5 out of 46 (11%) of the pregnant women were coinfected with the tuberculosis agent ( 6 ). In sub-Saharan Africa, where the burden of HIV and tuberculosis is among the largest worldwide, HIV infection has been correlated with a 10-fold-higher incidence of tuberculosis infection ( 7 ).

Tuberculosis (TB) and HIV infection continue to be major global health threats. While deaths related to HIV infection have decreased markedly over recent years, reductions in TB-related mortality has not kept pace, and in 2014, for the first time, TB surpassed HIV as the number 1 cause of infectious disease-related death. In the 1990s, HIV fueled the reemergence of the TB epidemic ( 1 ), and even today, TB continues to disproportionately affect persons living with HIV. Among 9.6 million people with incident TB in 2014 ( 2 ), 1.2 million (12%) were HIV positive, and of the 1.5 million people who died from TB that same year, 400,000 (33%) were coinfected with HIV ( 3 ). TB remains the leading cause of death among HIV-infected persons. HIV substantially increases the risk of progression from latent TB infection (LTBI) to active disease. The World Health Organization (WHO) estimates that among individuals with LTBI, people living with HIV have a 26-fold-higher risk of progression to TB disease than those without HIV ( 3 ). HIV and TB thus display lethal synergy, with HIV-associated immunosuppression triggering markedly increased susceptibility to TB and TB accelerating HIV-associated morbidity and mortality. Here, we review the pathogenesis, epidemiology, and clinical aspects of HIV-related TB.

The global increase in type 2 diabetes mellitus (DM) is a recognized reemerging risk and challenge to tuberculosis (TB) control ( 1 ). Individuals with DM have three times the risk of developing TB, and there are now more individuals with TB-DM comorbidity than TB-HIV coinfection ( 2 , 3 ). The association between DM and TB was first described centuries ago by Avincenna, a Persian philosopher, and the comorbidity was a frequent topic in the medical literature in the first half of the 20th century ( 4 – 7 ). But this literature dwindled as the association became less evident with the introduction of insulin for DM patients and antibiotics for TB. In the 1980s, publications on joint TB-DM began to reemerge in parallel with the DM “pandemic”: the global prevalence of DM among adults has increased by 20% in less than 30 years ( 8 ), and the number of individuals with DM is predicted to reach 642 million worldwide by 2040, with most (80%) of the patients living in low- and middle-income countries where TB is also endemic ( 9 ). Consequently, the World Health Organization has identified DM as a neglected, important, and reemerging risk factor for TB ( 1 ). In this chapter, “DM” refers mostly to type 2 DM since it is the most prevalent form, but type 1 DM in children has also been associated with TB ( 9 , 10 ). This chapter describes the epidemiology of TB-DM, the impact of DM on the clinical presentation and outcomes of TB, the underlying biology that favors the co-occurrence of the two diseases, and the public health implications for TB control and DM management.

Mycobacterium tuberculosis is an important opportunistic pathogen in solid-organ transplant (SOT) recipients ( 1 – 4 ), with high morbidity and mortality rates. The frequency of tuberculosis (TB) in SOT recipients ranges from 1.2 to 15% ( 1 – 3 ), which is 20 to 74 times higher than that of the general population. Unfortunately, the exact incidence of tuberculosis in SOT recipients is not well known. Table 1 shows the prevalence and incidence rates of TB in SOT recipients in the most numerous series in the literature ( 1 – 8 ) and compares them with information available from the Spanish Network of Infection in Transplantation (RESITRA) ( 7 ).

In recent years, the market of biopharmaceuticals has been growing at a fast pace due to increased availability of targets for biologic agents, approval of biologic agents for new and expanded indications, and increased use of these medications. Biopharmaceuticals, also known as biologic products or agents, biologics, or biologicals, are drugs that are produced through biological processes rather than chemical synthesis. These include recombinant proteins, monoclonal and polyclonal antibodies, peptides, antisense oligonucleotides, therapeutic genes, and recombinant and DNA vaccines. Biopharmaceuticals usually require infusion or injection rather than oral application.

The immune response to mycobacterial infection is complex, involving several arms of the immune system. Organs are damaged by mycobacteria directly and also by the necrotic granulomatous immune response of the host to this pathogen. Ideally, mycobacterial infection is met with a balanced immune response that is sufficient to kill organisms but not so severe as to cause excessive tissue injury. Immunosuppression may promote growth of mycobacteria while decreasing tissue injury by the host response to the infection. Conversely, enhancement of the host’s immune response may kill more organisms but may also result in more organ damage.

The term nontuberculous mycobacteria (NTM) generally refers to mycobacteria other than the Mycobacterium tuberculosis complex and M. leprae ( 1 ). NTM are ubiquitous in the environment, including household water, natural water sources, and soil ( 2 ). Human disease due to NTM is classified into four distinct clinical syndromes: chronic pulmonary disease, lymphadenitis, cutaneous disease, and disseminated disease. Of these, chronic pulmonary disease is the syndrome most commonly encountered clinically ( 1 ).

There are over 170 known species and subspecies of mycobacteria that have been identified, and new species continue to be discovered (http://www.bacterio.net/mycobacterium.html). The most widely distributed and common of the mycobacteria are the nontuberculous mycobacteria (NTM), of which organisms in the Mycobacterium avium complex (MAC) are most common. In the early 1980s, the complex was called MAI and represented the two primary pathogens, M. avium and M. intracellulare. However, MAC consists of a growing number of species, including M. arosiense, M. bouchedurhonense, M. chimaera, M. colombiense, M. marseillense, M. timonense, M. vulneris, and M. yongonense ( Table 1 ). The most important human pathogens are M. avium, M. intracellulare, and M. chimaera. Unfortunately, most laboratories are unable to differentiate the many species and subspecies because they lack the molecular methods required. Precise species identification is important, as recent studies have demonstrated different sources of environmental exposure ( 1 ), various degrees of pathogenicity ( 2 ), and even differences in treatment outcome between MAC species ( 3 , 4 ).

The history of the major pathogenic species of rapidly growing mycobacteria (RGM) can be traced back to the early 20th century beginning with Friedmann’s recovery of Mycobacterium chelonae from the lungs of two sea turtles (hence, the name chelonae from the Latin “of a turtle”) ( 1 ). Almost 50 years later, the closely related Mycobacterium abscessus was first reported as a cause of human skin and soft tissue infection in a patient with multiple soft tissue abscesses of a lower extremity ( 2 ).

Mycobacterium kansasii was first isolated in 1953 ( 1 ). The species was initially characterized by the formation of yellow colonies when exposed to light, a phenomenon resulting from the deposition of beta carotene and later termed photochromogenicity ( 2 , 3 ). In his classification of atypical mycobacteria, Runyon divided nontuberculous mycobacteria into four groups based on growth rate and pigmentation. M. kansasii was classified into group I, along with other photochromogens such as M. marinum ( 3 ).

The first report of a mycobacterium isolated in fish, supposed to be Mycobacterium marinum, has been attributed to Bataillon et al. (1897), who isolated acid-fast bacilli named Mycobacterium piscium from a tuberculous lesion in a common carp (Cyprinus carpio) ( 1 ). M. marinum was then originally isolated and identified from marine fish at the Philadelphia Aquarium ( 2 ). M. marinum was initially thought to infect marine fishes only and was named accordingly, but it is now known to be a ubiquitous species. The above-mentioned original freshwater isolate of M. piscium could be a M. marinum variant. In the early literature, several other marine Mycobacterium species were described, such as M. platypoecilus, M. anabanti, and M. balnei. Comparative sugar fermentative reactions together with published morphological, cultural, and pathogenic data suggested that they were all synonymous with M. marinum ( 3 ) even if M. piscium has not been recognized as a species since its type culture is no longer available.

Tuberculosis (TB) is a reemerging disease and a significant health problem caused by members of the Mycobacterium tuberculosis complex (MTC). This group of organisms includes well-known pathogens, such as Mycobacterium tuberculosis, Mycobacterium africanum, and Mycobacterium bovis (including Mycobacterium bovis bacillus Calmette-Guérin [BCG], the vaccine strain), together with other, less common species ( Table 1 ). All members of the MTC exhibit a 99.9% sequence similarity, and their 16S rRNAs are also conserved, with the exception of M. canettii ( 1 ).

The list of clinically important slow-growing nontuberculous mycobacteria (NTM) continues to expand as new species are identified and older ones are found to be pathogenic. More detailed information on these organisms (including many not covered in this chapter) can be found in a number of excellent reviews ( 1 – 5 ). As a group, these mycobacteria currently cause fewer infections than those species discussed in previous chapters. Some of these organisms are not newly discovered but have heretofore been considered virtually nonpathogenic. Previously, many were regarded as contaminants when isolated from clinical specimens. Timpe and Runyon established that these organisms could cause disease in humans and classified them based on pigment production, growth rate, and colonial characteristics. Photochromogens (group I) grow slowly on culture media (>7 days). Their colonies change from a buff shade to bright yellow or orange after exposure to light. Scotochromogens (group II) also grow slowly but demonstrate pigmented colonies when incubated in the dark or the light. Group III mycobacteria grow slowly and lack pigment in the dark or light. Rapid growers (group IV) also lack pigment, but they grow in culture within 3 to 5 days. Collectively, these four groups have been called the “atypical mycobacteria,” NTM, mycobacteria other than tubercle bacilli, or “potentially pathogenic environmental mycobacteria.” Molecular techniques such as DNA probes, real-time PCR, and gene amplification and restriction length polymorphism are useful tools for rapid identification of NTM ( 5 – 7 ).