Tuberculosis and Nontuberculous Mycobacterial Infections, Sixth Edition

Tuberculosis is one of the oldest of humankind’s plagues. Mycobacterium tuberculosis probably emerged as a pathogen of our early ancestors 20,000 to 15,000 years ago in east Africa. A unified concept of tuberculosis first emerged with the work of Laennec in the early 19th century, and from that time forward one can recognize the impact that this disease has had on the way we live. This impact can be illustrated by the life stories of many individuals, some often told, others less commonly recounted. For scores of years the treatment of tuberculosis pervaded the practice of nearly every physician. The studies of tuberculosis treatment protocols conducted by the British Medical Research Council are often cited as pioneering in this arena. Creative works of art, music, dance, and literature all express the lives of their creators, and thus tuberculosis in these lives affected their works. Some were greatly afflicted by the disease, others less so or were treated and fared well. Literature is replete with descriptions of tuberculosis, often reflecting the author's lives. As the course of history moved into the 20th and 21st centuries, tuberculosis incidence declined. Fewer dramatic instances of disease occurred. The practice of medicine has reflected the prevalence of tuberculosis over the course of time. Tuberculosis has intruded upon the political arena, but its impact has been minor. In the world of creative arts, the impact of tuberculosis is most readily seen and was often dramatic.

The history of tuberculosis in Europe and North America is better known for the past 150 years; however, there is a paucity of historic information on the epidemiology of tuberculosis in other parts of the world. The waveform of the tuberculosis epidemic occurs by natural selection of susceptible persons and runs its course in about 300 years. Industrialization and overcrowding of the cities can produce an epidemic of tuberculosis by bringing together large numbers of susceptible people and promoting transmission of Mycobacterium tuberculosis to new hosts. Although tuberculosis can affect any organ of the body, the lungs are virtually always the portal of entry. Infection with tubercle bacilli evokes cell mediated immunity (CMI) 2 to 8 weeks after infection. Activated T lymphocytes and macrophages form granulomas. Granulomas inhibit replication and spread of organisms. The chapter discusses various factors that may influence the risk of developing tuberculosis in an individual or a population. Utilizing a new molecular epidemiology technique of restriction fragment length polymorphism (RFLP) showed that 40% of cases were due to recent transmission rather than reactivation of previously acquired infection. With advancement in immunology and genomics, T- cell-based in vitro assays of interferon released by T cells after stimulation with M. tuberculosis antigens have been developed to identify tuberculosis infection. Tuberculin testing is most effective in detecting infection among the close contacts of newly diagnosed patients. Further, the chapter talks about special-high risk factors.

This chapter talks about pathophysiology and immunology of tuberculosis. The pathogenesis of human pulmonary tuberculosis can be considered as a series of battles between the host and the tubercle bacillus. The chapter discusses the measures for reducing the incidence of new cases of clinical tuberculosis, and gives an overview of five stages of pulmonary tuberculosis. It reviews the innate and acquired (adaptive) immune factors that play a role in tuberculosis. The term tissue-damaging delayed-type hypersensitivity (DTH) is used for the immunological reaction that causes necrosis. The chapter explores the major types of lymphocytes. Additional insight has recently been gained into the adjuvanticity of tuberculosis vaccines. In dermal BCG lesions, the percentage of mononuclear cells containing cytokine mRNA and protein was highest during the first 3 days. This finding suggests that the most effective tuberculosis vaccines would contain not only the most appropriate mycobacterial antigens but also mycobacterial adjuvants that recruit the largest number of macrophages, lymphocytes, and dendritic cells (DCs) into local sites of antigen deposition. Combination vaccines which consist of BCG and one or more booster immunizations with important mycobacterial antigens (including those produced by DNA vaccines) will probably provide the most effective protection against active disease. The major research advances in immunology that have direct bearing on the pathogenesis of tuberculosis are also described in the chapter. They include interactions between innate immunity and acquired immunity, interactions among the cytokines, and upregulating and downregulating mechanisms of both inflammatory and immune response.

This chapter talks about laboratory diagnosis and susceptibility testing of Mycobacterium tuberculosis complex. Clinical microbiology laboratories currently have a number of methods available that provide an accurate and rapid laboratory diagnosis of tuberculosis. Mycobacterial culture of stool specimens may be of value in intestinal tuberculosis cases, but these are rare. This type of culture has been requested to detect M. avium-M. intracellulare infections in patients with AIDS; however, given that intestinal involvement with M. avium-M. intracellulare is thought to be a component of disseminated disease, a blood culture for mycobacteria is the specimen of choice in this setting. When colonies resembling mycobacteria are observed, an acid-fast smear and subculture for identification and susceptibility testing should be made. Nucleic acid probe testing or another comparable molecular method of identification can be performed on colonies as soon as they appear, and the definitive identification can be made if results are consistent with M. tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG, M. africanum, M. microti, and “M. canetti”). Cultures are essential to exclude the possibility of mixed infections, which exist although are rare; in some instances, for further characterization or identification (most amplification tests give results only at the M. tuberculosis complex level); and, most importantly, for complete antimicrobial susceptibility testing. Susceptibility tests should be performed on all isolates of M. tuberculosis complex recovered from previously untreated patients and also on isolates from patients on therapy who have positive acid- fast smears or cultures after 2 months of treatment.

This chapter reviews the tuberculin skin test (TST) and the newer blood tests to detect latent tuberculosis infection (LTBI). TST is still the most widely used and available test for the diagnosis of tuberculous infection. Tuberculous infection with Mycobacterium tuberculosis, a cascade of immune responses ensues triggered by activated macrophages and carried out by T cells. Two types of tuberculin preparations have been in use, old tuberculin (OT) and purified protein derivative (PPD). PPD antigen is administered by multiple-puncture tests and the intradermal Mantoux test. The Mantoux test is performed by intradermally injecting 0.1 ml of PPD tuberculin (5 TU) into the skin of the volar aspect of the forearm. A negative reaction to the tuberculin test does not rule out tuberculous infection. A poor technique of administration can result in a falsely negative reaction. Though skin sensitivity usually persists and is lifelong, waning can occur, often with age, resulting in an apparent negative reaction. In such instances reactivity can be accentuated with repeated testing (the booster effect). Two gamma interferon release assays (IGRA) systems using RD1-encoded antigens are currently commercially available for TB detection. An IGRA or a TST may be used without preference for testing recent contacts of persons with infectious pulmonary TB with considerations for follow-up testing. An IGRA or a TST may also be used without preference for periodic screening of persons who might have occupational exposure to M. tuberculosis with considerations for conversions and reversions.

This chapter focuses on the treatment of persons with latent tuberculosis infection (LTBI) to prevent future development of TB disease. The identification and treatment of persons with LTBI constitute an essential component of TB elimination through two fundamental mechanisms. The first is the individual clinical benefit conferred through the prevention of morbidity and mortality associated with active TB disease. The second benefit is gained at the population level through the prevention of spread of Mycobacterium tuberculosis infection within the community and the associated reduction in health care spending. Prior to the initiation of treatment, all persons with evidence of LTBI should be evaluated for the presence of pulmonary and extrapulmonary TB disease, including a thorough review for TB symptoms, a clinical examination, and a chest radiograph. Specific LTBI treatment regimens are summarized in this chapter according to their effectiveness and level of tolerability. Adverse effects of LTBI treatment drugs such as isoniazid, rifampin and pyrazinamide are also listed in this chapter. To ensure that the maximal benefit of LTBI therapy is achieved, adherence to treatment should be monitored closely for all patients at the recommended monthly clinical visits. Cost-effectiveness is an important consideration for public health programs when determining the most appropriate LTBI treatment regimen to use for targeted testing and LTBI treatment outreach activities. Choosing the most appropriate LTBI regimen, clinical monitoring for potential adverse events, and utilization of adherence-promoting strategies to ensure completion are critical elements for the success of LTBI treatment to prevent additional TB disease.

This chapter reviews the underlying principles of tuberculosis (TB) chemotherapy, medical management, and current treatment recommendations. TB is caused by members of the Mycobacterium tuberculosis complex, with M. tuberculosis being responsible for the vast majority of disease. Early in the history of anti-TB chemotherapy, the highly effective agent streptomycin (SM) was applied as monotherapy. Current first-line regimens consist of three or four agents that, in concert, can eradicate organisms within all compartments and prevent the development of drug resistance. Isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), ethambutol (EMB), and SM are the five standard first-line agents. Elevated transaminases, clinical hepatitis, and peripheral neuropathy are among the most common adverse events seen with INH. M. tuberculosis strains resistant to SM may be susceptible to other aminoglycosides, but the susceptibility to each agent must be confirmed by resistance testing. The drugs used in the standard treatment of pulmonary TB are recommended for all extrapulmonary TB. In patients with renal dysfunction, PZA and EMB dosing should be adjusted. Serum levels of drugs should be obtained to ensure adequate treatment if any question of adequacy exists. Patients may require intramuscular and intravenous treatment regimens until oral absorption can be ensured. Diagnosis of TB is often based on smear microscopy without culture. Fixed- dose combinations of anti-TB agents are recommended to prevent the use of inadequate regimens and monotherapy.

This chapter deals with multidrug-resistant tuberculosis (MDR-TB), caused by strains resistant to at least isoniazid and rifampin. MDR-TB is difficult to treat and requires medications that are expensive, toxic, and less effective. MDR-and extensively drug-resistant tuberculosis (XDR-TB) strains are resistant to the most important antituberculous medications required for successful outcomes. Despite the absence of prospective clinical trials using fluoroquinolones for MDR-TB, because of considerable experience with levofloxacin and moxifl oxacin, they are regarded as critical to good treatment outcomes. Fluoroquinolone drugs should always be protected by being given in combination with several other active agents, particularly in cases of suspected or possible Mycobacterium tuberculosis disease. Clofazimine is now available for MDR-TB treatment in the United States only from the manufacturer under an individual patient investigational new drug. Treatment should preferably begin with six but not fewer than four new drugs with proven susceptibility, two of which should be bactericidal. Treatment of XDR-TB is based on the same principles as is the treatment of MDR-TB. An aggressive empirical regimen is recommended prior to knowledge of drug sensitivities. Patients with MDR-TB should remain in respiratory isolation at least until they have three separate final negative sputum cultures while adherent with and responding to an optimized regimen. The current global interest offers hope that the discovery and development of new anti-TB drugs will accelerate.

This chapter provides an overview of the role that modern thoracic surgery can play in diagnosing and managing patients with TB and its sequelae. When operating on patients with tuberculosis (TB), the same fundamental principles and considerations of any thoracic surgical operation still apply. It is worth considering some of the common concepts before proceeding with the detailed discussion of surgery for specific aspects of TB management. The first consideration when called upon to diagnose TB through surgery is to identify a potential target site for biopsy. Secondary considerations include the patient’s suitability for surgery. For patients for whom surgery is potentially hazardous, alternative investigation modalities or even empirical anti-TB treatment may need to be considered. The primary management of TB today is undoubtedly medical, and anti-TB drugs are highly effective in the vast majority of cases. The aim of surgical treatment is to remove the predominant pulmonary lesion(s), thereby circumventing difficulty in drug penetration and reducing the mycobacterial burden. Whenever surgery is considered for a patient with bronchiectasis, it is crucial to fully counsel him or her on the implications of surgery. In patients without the need for urgent resections or who may not tolerate resections, autopneumonectomy or lobectomy may be allowed to occur. The advantage of minimally invasive thoracic surgery is not only its capacity to reduce morbidity for individual patients but also its potential to allow a wider range of TB patients to be considered for effective surgical management.

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-Guerin (BCG). The development of new tuberculosis vaccines has been informed by evolving data on the natural history of tuberculosis, by new data on the immunology of infection with and immunization against Mycobacterium tuberculosis, by reanalysis of the role of nontuberculous mycobacteria (NTM) in protection against tuberculosis, by a clearer understanding of the benefits and risks of BCG, and by molecular techniques that have permitted identification of immunodominant antigens of M. tuberculosis and new methods of antigen delivery. This chapter talks about tuberculosis in children, older children, adults, elderly, and immunocompromised hosts, health care providers and other International travelers. At least partial immune protection from tuberculosis disease results from prior mycobacterial infection, whether naturally acquired or vaccine induced. The chapter discusses mechanisms of immune control of tuberculosis, and talks about BCG vaccine. Immunization with BCG induces a mild systemic infection in healthy hosts. It has been shown that immune responses to BCG are impaired in infants with human immunodeficiency virus (HIV) infection. The efficacy of BCG against tuberculosis is described. The favorable and unfavorable characteristics of BCG are summarized. There is wide consensus that additional tuberculosis vaccine development should focus on identifying a booster vaccine to follow BCG immunization, or on developing a completely novel two-vaccine booster regimen.

One of the main goals of the DOTS- based programs was the interruption of transmission of Mycobacterium tuberculosis through early detection using sputum smear microscopy and the cure of infectious tuberculosis (TB) cases through short-course chemotherapy (SCC). This chapter describes progress and challenges in implementing the Stop TB strategy, built around DOTS, through the Global Plan to Stop TB 2006-2015. The global burden of TB is also presented in terms of incidence, prevalence, mortality, human immunodeficiency virus (HIV)-related TB, and drug- resistant TB, specially MDR- TB and extensively drug-resistant TB (XDR- TB). The chapter reviews progress towards the achievement of the 2015 TB related Millennium Development Goals (MDG) and the Stop TB Partnership targets of halving prevalence and mortality compared to 1990 levels. Full scale-up of collaborative activities between the HIV and TB national programs aiming to reduce the burden of HIV among people infected with M. tuberculosis and vice versa will be critical to accelerate TB control in the region. The sequencing of the M. tuberculosis genome in 1998 was probably the turning point for the realization that the development of new tools against TB could be within reach, as new frontiers were to open in the field of basic TB research. The global progress in implementation of the Stop TB strategy via the Global Plan to Stop TB and progress in the development of new and improved TB control tools indicate some cause for optimism regarding future prospects for controlling the global TB epidemic.

This chapter reviews the factors involved in the transmission of tuberculosis (TB) in various congregate settings and the methods employed for curtailment and prevention. The probability of transmission of Mycobacterium tuberculosis depends on the concentration of infectious droplet nuclei in the air, the duration of exposure to these particles, and the closeness of contact with infectious persons. At least three factors contribute to the high rate of TB in correctional and detention facilities. First, disparate numbers of incarcerated persons are at high risk for M. tuberculosis infection (e.g., users of illicit substances, persons of low socioeconomic status, and persons with HIV infection). Second, the physical structure of the facilities contributes to disease transmission, as facilities often provide close living quarters, might have inadequate ventilation, and can be overcrowded. Third, movement of inmates into and out of overcrowded and inadequately ventilated facilities, coupled with existing TB related risk factors of the inmates, makes correctional and detention facilities a high-risk environment for the transmission of TB and makes implementation of TB control measures particularly difficult. UV germicidal irradiation (UVGI) is the least well understood of the three approaches to air disinfection despite its use for over 70 years. Although there are good laboratory data supporting the germicidal activity against a number of virulent bacteria, viruses, and mycobacteria (including M. tuberculosis), there are few recent field trials showing that it can prevent TB transmission in populations.

This chapter describes the role of the health department in the context of the core components of public health tuberculosis control programs that were identified by the Advisory Council for the Elimination of Tuberculosis (ACET). This discussion is primarily applicable to tuberculosis prevention and control programs in the United States. State and local public health departments must work with their legal counsel to ensure that their actions comport with constitutional provisions and their jurisdiction’s legal authorities to prevent and control tuberculosis. The first priority of tuberculosis control in the United States is detection and treatment of patients with active tuberculosis. After a patient with tuberculosis has been reported to the health department, it is the responsibility of the health department, in conjunction with the patient’s medical provider, to ensure that the patient completes an adequate treatment regimen. In addition to core services, public health laboratories should provide or ensure availability of nucleic acid amplification to detect Mycobacterium tuberculosis complex directly in clinical specimens, when clinically indicated for patients for whom a diagnosis of tuberculosis is being considered but has not yet been established, and for whom the test result would alter case management or tuberculosis control activities. Tuberculosis control programs should analyze the data collected to monitor morbidity trends, determine the demographic characteristics of their patient population, monitor drug resistance rates, and determine the outcomes of treatment. Finally, the chapter provides tuberculosis training and education.

Pulmonary tuberculosis frequently develops without any striking clinical evidence of disease. The chest radiography is the single most useful study for suggesting the diagnosis of TB. In the past, primary TB was seen mostly in children and reactivation TB in adults. Computed tomography (CT) scans allow practitioners to examine both the pulmonary parenchyma and the lymph nodes in greater detail than can be done with plain chest X ray alone. For patients with HIV infection but without the manifestations of AIDS, the tuberculin skin test is positive in 50 to 80% of patients with TB. One meta-analysis of 12 studies of TB found that the elderly were less likely to have symptoms such as fever, sweating, hemoptysis, and cavitary lung disease. They were more likely to have dyspnea and significant comorbidities. In this study, the only difference seen in radiographic patterns between young adults and the elderly was an increased incidence of miliary disease in the older population. In a prospective cohort study of patients diagnosed with TB, it was found that the older group had more toxicity from the TB therapy (22% versus 9%) and a greater 30-day mortality rate (18% versus 2%). Inhibition of Tumor necrosis factor alpha (TNF-α); is now used for the treatment of several diseases, including rheumatoid arthritis, Crohn’s disease, juvenile rheumatoid arthritis, ankylosing spondylitis, and psoriatric arthritis. Tuberculous pleural effusions are usually due to rupture of a subpleural focus of TB. This release is then followed by a T-cell-mediated hypersensitivity response with marked inflammation.

The upper respiratory tract is the portal of entry of all inhaled matter in the lungs. Tubercular involvement of the upper respiratory tract is not surprising, as inhalation is the most common and important route of mycobacterial infection. Symptoms and signs of upper respiratory tract tuberculosis (TB) depend upon the site of organ involvement. Patients with nasal TB are commonly present with nasal obstruction and purulent rhinorrhea. Lupus vulgaris, a slowly growing, indolent ulcerative lesion caused by Mycobacterium tuberculosis, may affect the nasal vestibule, the septum, and the alae. Infection of the oral cavity is associated with poor dental hygiene and other causes which result in mucosal injury. The larynx is the most vital part of the upper respiratory tract. It can be involved in different infective, neoplastic, granulomatous, and other conditions. There has been a shift in the age and sex distributions of laryngeal TB in the last three or four decades. Involvement of the posterior larynx was thought to result from pooling of infected saliva in the recumbent position, although not all reports have shown this predilection for posterior laryngeal involvement, and some experience has emphasized anterior vocal cord involvement; hypertrophic lesions are seen more commonly than ulcerative lesions. TB should be kept in the differential diagnosis of upper airway diseases and/or cervical lymphadenopathy whenever a patient presents with insidious onset of symptoms, ulcerative or granulomatous lesions, and failure of response to therapy for more common lesions.

Tuberculous otitis media and tuberculous mastoiditis occur together as a single disease process and are referred to as tuberculous otomastoiditis. Most of the medical literature on tuberculous otomastoiditis is from Europe and Asia, where the disease is more prevalent. The chapter discusses pathogenesis and pathology of tuberculous otomastoiditis. Tuberculous otomastoiditis may be masked by suprainfection with other bacteria as well as by systemic antituberculous therapy. The diagnosis of tuberculous otomastoiditis is considered confirmed by culture of Mycobacterium tuberculosis from the local discharge or biopsy sample. Once the diagnosis of tuberculous otomastoiditis is made, the combined talents of the primary care physician, an ear, nose, and throat surgeon, and an infectious disease specialist are required for optimum therapy. Isoniazid plus rifampin is the preferred antituberculous therapy, with pyrazinamide added for the first 2 months. Ethambutol is also usually given until resistant M. tuberculosis is ruled out. In addition to obtaining tissue for diagnosis, the surgeon may have a role in therapy by removing a nidus of infected debris. Complications mandating surgical approach include facial nerve paralysis, subperiosteal abscess, labyrinthitis, persistent postauricular fistula, and extension of infection into the central nervous system. After therapy is completed, reconstructive procedures may improve hearing in certain patients.

This chapter describes several different mechanisms through which eye can become infected with tuberculosis. Tuberculosis can involve the lid, conjunctiva, cornea, and sclera. In parts of the world where the prevalence of tuberculosis infection is higher in the general population, uveitis is still more likely to be attributed to tuberculosis. Uveitis can also manifest as simple iritis, the clinical signs of which are limited to cells and flare in the anterior chamber, or as iridocyclitis with involvement of the ciliary body. Iridocyclitis occurs clinically with inflammatory cells in the ciliary body and anterior vitreous and is associated with ciliary body pain and ciliary vasodilation. Alternatively, the inflammation may involve primarily the posterior part of the uvea (choroids), leading to choroiditis, the most common manifestation of ocular tuberculosis. Choroidal tubercles should always be looked for on funduscopic examination when a patient is suspected to have tuberculosis or has a fever of unknown origin. The chapter also talks about choroidal tuberculomas, ciliary body tuberculoma, tuberculous retinitis, tuberculous panophthalmitis, and orbital tuberculosis. Before the introduction of PCR technology, a definitive diagnosis of ocular tuberculosis was often elusive because it required the demonstration of the Mycobacterium tuberculosis bacilli in ocular tissues or secretions by microscopy or culture. Once the diagnosis of ocular tuberculosis is made, systemic antituberculous therapy should be initiated at once. Any patient with a clinical picture highly suspicious for ocular tuberculosis should be treated with a multidrug regimen of proven efficacy.

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. The sequence of events that leads to clinical neurologic illness begins with the hematogenous dissemination of Mycobacterium tuberculosis that follows primary pulmonary infection or late reactivation TB elsewhere in the body. The continued proliferation and coalescence of tubercles result in larger caseous foci. Such lesions, if located adjacent to the ependyma or pia, may subsequently rupture into the subarachnoid space, producing meningitis. This conceptual understanding of the pathogenesis of tuberculous meningitis (TBM) is derived from the observations of Rich and McCordock, who performed meticulous autopsy examinations of TBM patients dying at the Johns Hopkins Hospital during the early part of the last century. The key to the diagnosis in most instances rests with the proper interpretation of the spinal fluid cellular characteristics and chemistries combined with the demonstration of mycobacteria in the cerebrospinal fluid (CSF) by stained smear or culture. The nucleic acid-based amplification technique, based on PCR, is a new and effective method for the rapid detection of specific bacterial DNA in clinical specimens. Late sequelae include cranial nerves (CN) palsies, gait disturbance, hemiplegia, blindness, deafness, learning disabilities, dementia, and various syndromes of hypothalamic and pituitary dysfunction.

The incidence of tuberculosis has increased worldwide, resulting in an increased incidence of tuberculous lymphadenitis. Tuberculous infection in the parotid gland usually develops following infection of intraparotid lymph nodes. As the capsule of the infected lymph tissue breaks down, parotitis may ensue. Historically, lymph node and parotid tuberculosis was caused mainly by Mycobacterium bovis, but nearly all tuberculous lymphadenitis is now due to M. tuberculosis. Symptoms associated with tuberculous lymphadenitis depend largely on the location of involved nodes. Differential diagnosis of tuberculous lymphadenitis or parotitis is extensive. Tuberculin skin testing is the most definitive noninvasive diagnostic procedure, yielding positive results in more than 90% of persons with tuberculous lymphadenitis. When diagnosis of tuberculous lymphadenitis remains in doubt, biopsy material must be submitted for histology, culture, and potentially PCR. Cytologic findings identify granulomatous changes in 50 to 80% of patients with tuberculous lymphadenitis, but acid-fast bacilli are identified in only 30 to 60% and cultures are positive for only 20 to 80%. A recent systematic review found that nucleic acid amplification tests for tuberculous lymphadenitis produce highly variable and inconsistent results, precluding the determination of clinically meaningful results. Management of tuberculous lymphadenitis and parotitis involves appropriate use of antituberculous chemotherapy with the judicious use of surgical excision in a minority of patients. There are no published trials of therapy for parotitis, so guidelines for lymphadenitis should be followed. Treatment involves the use of combination antituberculous chemotherapy, with occasional need for surgical excision.

Urogenital tuberculosis is responsible for 30 to 40% of extrapulmonary tuberculosis cases, being second only to lymph node involvement. Urogenital tuberculosis most frequently affects the kidneys, renal infection being slowly progressive, asymptomatic, and highly destructive, with instances of unilateral renal loss of function and renal failure on diagnosis. Tuberculosis affects the entire male genital tract, with lesions in the prostate, seminal vesicles, vas deferens, epididymis, Cooper glands, penis, and testicles, the last through contiguity with the epididymis, since the blood- testicle barrier plays a protective role. Female genital tuberculosis is secondary to hematogenous spread from a primary focus, generally in the lungs or, less commonly, through lymphatic spread from tuberculosis of abdominal. Urogenital tuberculosis seems to be very important in AIDS patients. Identification of the tuberculosis bacillus in the urine is achieved through Ziehl-Neelsen`s acidfast staining technique or through urine culture in Lowenstein-Jensen medium. Over half (54.9%) the patients with urogenital tuberculosis undergo surgery. Most authors recommend nephrectomy without ureterectomy in cases of unilateral renal dysfunction to avoid relapse, eliminate irritative voiding symptoms, treat hypertension, and avoid abscess formation. The author proposes that any patient presenting with gross hematuria, persistent microscopic hematuria or pyuria, recurrent urinary tract infection, and persistent irritative micturition symptoms be investigated for urogenital tuberculosis, with six urine samples being collected for culture or PCR. The author proposes a periodic urine examination for hematuria or pyuria in patients with previous pulmonary tuberculosis or immunosuppressed subjects. Bactericidal and bacteriostatic drugs are used as the pharmacological treating urogenital tuberculosis.

Musculoskeletal tuberculosis (TB) accounts for approximately 10% of all extrapulmonary TB cases in the United States and is the third most common site of extrapulmonary TB after pleural and lymphatic disease. The majority of TB cases in the United States occur among foreign-born persons, reflecting the global TB epidemic. Tuberculous spondylitis begins with infection of the subchondral bone that then spreads to the cortex. This chapter also talks about pathophysiology and diagnosis of tuberculous osteomyelitis and arthritis, Poncet’s disease, tuberculous myositis, and tuberculous tenosynovitis. Early diagnosis and initiation of appropriate antituberculous therapy are important, as early treatment can prevent loss of function and mobility. The basic principles that underlie the treatment of pulmonary TB also apply to extrapulmonary forms of the disease. Based on experience from treating tuberculous spondylitis and the experience with treating other forms of extrapulmonary disease, it is recommended that treatment of drug-susceptible tuberculous arthritis and osteomyelitis be carried out using rifampin-based short-course regimens similar to those that are used for the treatment of pulmonary disease. Early diagnosis of bone and joint disease is important in order to minimize the risk of deformity and enhance outcome. The introduction of new imaging modalities, including CT and MRI, has enhanced the diagnostic evaluation of patients with musculoskeletal TB and for directed biopsies of affected areas of the musculoskeletal system.

Cardiovascular tuberculosis is an uncommon extrapulmonary manifestation of mycobacterial disease. With the advent of AIDS, which has increased the incidence of mycobacterial disease, particularly of the extrapulmonary type, one can expect an increase in cardiovascular tuberculosis. Pericardial tuberculosis is the disease present in the greatest percentage of patients with cardiovascular tuberculosis. Tuberculosis of the aorta and myocardium are reported but extremely unusual forms of cardiovascular tuberculosis. Pericardial tuberculosis is rare, occurring in less than 1% of cases of tuberculosis, and may be life threatening. In a study in sub-Saharan Africa, researchers found that the major independent predictors of death were an additional proven nontuberculosis final diagnosis, presence of clinical signs of human immunodeficiency virus (HIV) infection, coexistent pulmonary tuberculosis, and older age. Pericardial biopsy has also been advocated in the diagnosis of pericarditis. Between 1950 and 1970, many investigators thought that examination of the entire pericardium at pericardiectomy or autopsy was required to definitively diagnose tuberculosis. The prednisolone group had a significantly more rapid resolution of hepatomegaly and elevated jugular venous pressure and more rapid improvement in physical activity. The authors conclude that antituberculosis medication with prednisolone resulted in a significant decrease in constrictive pericarditis, particularly in patients with a shaggy tuberculous pericardial effusion compared with those who did not receive prednisolone.

This chapter on gastrointestinal tuberculosis (TB) highlights that the colon and small bowel alone are the next most frequent sites of infection following the ileocecal region. The esophagus and stomach are rarely involved. Symptoms of gastrointestinal TB such as abdominal pain weight loss, fever nausea, vomiting, diarrhea and constipation are discussed in the chapter. The first primary case of esophageal TB was described in 1837 on an autopsy by Denonvilliers. The middle one-third of the esophagus is the most common location for tuberculous involvement. The diagnosis and various medical therapies for esophageal TB are discussed in the chapter. Surgery is usually required for gastric outlet obstruction, and the most common procedures described are gastrojejunostomy or antrectomy with Billroth II reconstruction. The importance in distinguishing ileal TB from Crohn’s disease is further highlighted because the treatment is vastly different. Colonic TB can involve any portion of the large bowel; however, the ileocecal region is the most common site of intestinal involvement, followed by the ascending colon. The diagnosis of intestinal TB should be considered in anyone with abdominal symptoms from an area where TB is endemic. PCR analyses of mucosal biopsy specimens from endoscopy have been shown to be a valuable tool in improving diagnostic yield with a high specificity of 95%. Radiographic imaging studies usually provide corollary information to prompt further investigation but rarely establish the diagnosis because of the nonspecific signs of intestinal TB.

This chapter reviews the epidemiology, pathogenesis, clinical features, available diagnostic techniques, and therapy of tuberculous peritonitis. Of all sites affected by extrapulmonary tuberculosis (TB), the abdomen is the sixth most common after lymphatic, genitourinary, bone and joint, miliary, and meningeal involvement. Tuberculous peritonitis is predominantly a disease affecting young adults in the third and fourth decades of life but can occur at any age. In a retrospective study, 80% of mycobacterial isolates were identified as Mycobacterium bovis and the rest were M. tuberculosis. Tuberculous peritonitis as the initial manifestation of HIV infection was reported first in 1992. Peritoneal TB is thought to be the result of reactivation of latent foci established in the peritoneum via hematogenous spread to the mesenteric lymph nodes from previous pulmonary infection. The average duration of symptoms prior to diagnosis extends from weeks to months. Peritoneal TB has been classified as the more common ''wet type,'' which is characterized by ascites, and the less common ''plastic or fibroadhesive type,'' which manifests as abdominal masses comprised of adherent bowel loops. Laparoscopic examination and biopsy confirm tuberculous peritonitis in 85 to 90% of cases. The differential diagnosis of tuberculous peritonitis includes the differential diagnosis of ascites as well as the differential diagnosis of granulomatous peritonitis. Granulomatous peritonitis on histopathology may not always be secondary to M. tuberculosis. The treatment of peritoneal TB is primarily medical. Ascitic fluid cultures have low yield, but peritoneoscopy with biopsy or cultures frequently confirms the diagnosis.

This chapter reviews the clinical, biochemical, and histopathologic spectrum of tuberculosis (TB) and atypical mycobacteria involving the liver and pancreaticobiliary tract, as well as the hepatotoxicity caused by antituberculosis therapy. Classic Mycobacterium tuberculosis infection in persons not infected with human immunodeficiency virus (HIV) precedes the discussion of the disease in patients with HIV and AIDS and other immunocompromised persons, such as liver transplant recipients. The liver can be involved in all forms of TB (i.e., pulmonary, extrapulmonary, and miliary). In addition, infection confined predominantly to the liver or biliary tract has been recognized with some regularity, especially in areas where TB remains endemic. Pulmonary TB involves the liver less frequently than does miliary TB, with an average of approximately 20% for pulmonary TB and 68% for extrapulmonary or miliary disease. A subset of patients with extrapulmonary TB has the infection confined solely or predominantly to the liver or biliary tract. TB of the pancreas or of the peripancreatic lymph nodes is infrequent compared to the liver. Of greater concern than active TB developing posttransplant is the risk of hepatotoxicity associated with isoniazid (INH) prophylaxis. Antituberculosis agents are among the most common causes of non-acetaminophen-related acute liver failure leading to emergency liver transplantation. Fluoroquinolones are frequently used to replace agents in first-line anti-TB regimens in patients with TB who have drug-induced hepatic dysfunction. With proper clinical and biochemical monitoring, it is thought that the risk of INH and combination chemotherapy- induced hepatic injury can be significantly reduced.

Cutaneous tuberculosis (TB) is not a well-defined entity but comprises a wide spectrum of clinical manifestations. Primary inoculation TB results from the entry of mycobacteria into the skin or, less frequently, the mucosa of a person who has not previously been infected or who has no natural or artificial immunity to Mycobacterium tuberculosis. The pathogenesis of cutaneous TB from an exogenous source is similar to that of other primary diseases. Lupus vulgaris is a particular type of chronic cutaneous TB in a previously sensitized person with a high degree of TB sensitivity. The histopathological picture of lupus vulgaris is diverse and not always diagnostic. TB of the breast-tuberculosis mastitis-is difficult to recognize and frequently misdiagnosed as breast cancer. Breast involvement is a result of retrograde lymphatic extensions from underlying mediastinal, parasternal, axillary, or cervical lymph nodes. Tuberculids are a group of cutaneous conditions occurring in the presence of TB but containing no stainable or culturable acid- fast bacilli (AFB); based on histopathology, then, they were previously regarded as an allergic reaction to the infection. Monoclonal antibody assays and the PCR technique have become increasingly useful clinically. Treatment of lupus vulgaris with isoniazid alone has resulted in high cure rates. Combination chemotherapy is recommended for patients with extracutaneous disease and multiple skin lesions and for those with profound immunosuppression.

Miliary tuberculosis (TB) is a lethal form of disseminated TB that results from a massive lymphohematogenous dissemination from a Mycobacterium tuberculosis-laden focus. Diagnosis of miliary TB requires the presence of a diffuse miliary infiltrate on a chest radiograph or high-resolution CT (HRCT) or histopathological evidence of miliary tubercles in tissue specimens obtained from multiple organs. The majority of the patients in a study had chest radiographs consistent with miliary TB; in some, these classical radiographic changes evolved over the course of the disease. The diagnosis of miliary TB is easier when the patient presents with classical miliary shadowing on chest radiograph in an appropriate setting. Magnetic resonance imaging (MRI) of the brain and spine is very useful in the initial evaluation and follow-up of miliary TB patients with TB meningitis (TBM) or spinal TB and also protects from radiation exposure. Adenosine deaminase and gamma interferon level estimation in ascitic fluid and pleural fluid can be helpful in the diagnosis of miliary TB. Changes in the WHO revised recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system regarding the timing of starting of antiretroviral drugs, the choice of drugs, and the timing of initiation in relation to institution of anti-TB treatment, have been provided in this chapter. Assisted mechanical ventilation and other interventions may be required for the management of patients with miliary TB who develop acute respiratory distress syndrome (ARDS). BCG vaccination is effective in reducing the incidence of miliary TB, especially in children.

Endocrine and metabolic derangements are infrequent in patients with tuberculosis, but they are important when they occur. When infection is not isolated to the adrenals, the most common extra-adrenal manifestations are pulmonary and genitourinary tuberculosis. The potential causes of tuberculosis-associated hyponatremia include adrenal insufficiency, the syndrome of inappropriate antidiuretic hormone (SIADH), and cerebral salt wasting. The degree of hyponatremia is variable in patients with tuberculosis, and most patients are asymptomatic. In the vast majority of patients, hyponatremia resolves concurrently with response to antituberculosis therapy. In one large series of patients from Hong Kong, 6% of patients with confirmed hypercalcemia had tuberculosis. The actual prevalence of hypercalcemia in patients with tuberculosis is difficult to estimate, as concurrent serum albumin levels are not always reported. The majority of the reports of hypercalcemia are for patients with pulmonary tuberculosis, perhaps reflecting the preponderance of pulmonary infection over infection at other sites. The physiological role for macrophage production of 1,25-dihydroxyvitamin D is uncertain. According to one proposed mechanism, 1,25-dihydroxyvitamin D enhances the antimycobacterial activity of the monocyte, either as a direct effect or by enhancing cellular responses to gamma interferon. Diabetes may lead to increased susceptibility to tuberculosis through several mechanisms. Diabetic patients demonstrate impaired granulocyte chemotaxis, phagocytosis, bactericidal activity, and superoxide production. The endocrine and metabolic manifestations of tuberculosis are protean. Direct involvement of endocrine glands is only one way in which tuberculosis can affect hormonal and metabolic function.

Tuberculosis (TB) affects the production and life span of all hematologic cellular components. This chapter reviews and updates known hematologic effects of TB and its therapy. Myelophthisic anemias are characterized by the presence of teardrop erythrocytes, nucleated erythrocytes, and early granulocytes, which can be seen on the peripheral blood smear. In miliary TB, the bone marrow may become directly infiltrated with tuberculosis. Neutrophils, basophils, eosinophils, and the monocyte/macrophage line are all subtypes of granulocytes and all are commonly affected during the course of TB and its treatment. Lymphocytopenia and lymphocytosis have both been reported for active TB. While lymphocytopenia may be associated with marrow dysfunction, haptoglobin has recently been reported to suppress T-cell proliferation. Haptoglobin is an acute-phase protein which primarily scavenges hemoglobin and exhibits strong inhibition of T-cytokine release. Lymphocytopenia and lymphocytosis have both been reported for active TB. Lymphocyte proliferation occurs in the blood, secondary lymphoid tissues, and organs affected by TB. Diverse coagulation abnormalities have been reported in the setting of TB. Acquired factor V dysfunction due to the presence of an immunoglobulin inhibitor has been reported to cause hemorrhage. Despite the fact that nearly all of the antituberculous antimicrobials may produce hematologic side effects, routine hematologic monitoring is recommended by the manufacturer for only three commonly used anti-TB antibiotics—cycloserine, ethambutol, and rifabutin—and the strength of the recommendation varies from drug to drug.

This chapter focuses on the fundamental nature of exposure and infection of pediatric tuberculosis, emphasizing how and why children should be approached differently from adults. The effects of these differences on the public health approach to tuberculosis control in children are also explained in the chapter. Disease occurs when signs or symptoms or radiographic manifestations caused by Mycobacterium tuberculosis become apparent. Infants are more likely to experience signs and symptoms, probably because of their small airway diameters relative to the parenchymal and lymph node changes in primary tuberculosis. The hallmark of primary pulmonary tuberculosis is the relatively large size and importance of the lymphadenitis compared with the less significant size of the initial parenchymal focus. The most common manifestations are at the anatomic site of the existing tuberculosis, but new onset of tuberculomas, lymphadenopathy, and abdominal manifestations can occur. As with tuberculin skin test (TSTs), gamma interferon release assays (IGRAs) cannot distinguish between latent infection and disease, and a negative result from these tests cannot exclude the possibility of tuberculosis infection or disease in a patient with findings that raise suspicion for these conditions. The chapter gives current recommendations for use of gamma IGRAs in children. The main form of nucleic acid amplification studied in children with tuberculosis is the PCR, which uses specific DNA sequences as markers for microorganisms. An expert in tuberculosis always should be involved in the management of children with drug-resistant tuberculosis infection or disease.

The issue of tuberculosis during pregnancy is not simply an historical inquiry but rather an increasingly familiar clinical problem facing industrial nations as well as the developing countries of the world. This chapter focuses on the maternal aspects of tuberculous infection, as well as transmission to the fetus, and newborn. The epidemiology of tuberculosis in pregnancy reflects that of tuberculosis at large. A number of reports from the 1950s, showed that pregnancy did not predispose women to progressive disease. In a report of 250 women with active tuberculosis in the pretreatment era, 83.9% remained stable during pregnancy and 9.1% improved. Although only 7% had evidence of progressive disease during pregnancy, an additional 8.2% experienced progression in the year following pregnancy. Pregnancy itself, however, may mimic and thus mask the symptoms of early tuberculosis, such as tachypnea and fatigue; this in turn may delay diagnosis and treatment. Infection of the reproductive organs may result in infertility as well as abdominal or tubal pregnancy. With early recognition and effective chemotherapy, however, there is no evidence of an adverse effect on pregnancy. The tuberculin skin test (Mantoux) is the test of choice for diagnosing tuberculosis infection in pregnant women. These tests have potential advantages in terms of logistics and accuracy (not subjectively interpreted and not affected by previous Mycobacterium bovis BCG vaccination). The major side effect of isoniazid (INH) is hepatitis, which occurs most frequently in persons over 35 years of age.

Tuberculosis and human immunodeficiency virus (HIV) infection are two major global public health threats that undermine the development of societies because of their high morbidity and mortality. This chapter reviews the pathogenesis of the coinfection of HIV and Mycobacterium tuberculosis (MTB), the epidemiology, and the clinical aspects of tuberculosis associated with HIV infection. Antiretroviral therapy (ART) greatly reduces the risk of tuberculosis in HIV infection, but it appears that in most populations, even after effective treatment with ART, the risk of tuberculosis is still on average 5- to 10- fold higher than in the HIV- uninfected population. Due to the high frequency of coinfection of MTB and HIV, all patients infected with HIV should be screened for latent tuberculosis infection (LTBI) and tuberculosis. Also, all patients with tuberculosis should be advised to undergo voluntary counseling and testing for HIV infection. Rifabutin is the least powerful inducer and recommended for the treatment of tuberculosis in patients with HIV infection, especially if protease inhibitors are required to treat HIV. The interaction of rifampin and rifabutin with approved antiretroviral drugs is summarized in the chapter. It is remarkable how difficult it has been to control the epidemic of tuberculosis, a curable disease. HIV is the most important factor contributing to the increase of cases of tuberculosis, but tuberculosis is both preventable and treatable even in persons with HIV infection. We need to accelerate the development of new diagnostic tools, new antituberculosis drugs, and a new effective vaccine.

Mycobacterium tuberculosis is a significant opportunistic pathogen in solid organ transplant (SOT) recipients due to its high morbidity and mortality. The time of onset of symptoms of tuberculosis after transplantation varies. It is quite common for the diagnosis of tuberculosis in SOT recipients to be delayed for weeks, due to absence of clinical suspicion. After transplant, the diagnostic yield of tuberculin skin test is very low but nevertheless remains the first step in post-transplant evaluation of suspected tuberculosis. Patients awaiting an SOT often have cutaneous anergy due to their underlying disease. Cellular immune testing could be performed at the time of the second positive purified protein derivative (PPD) skin test to determine the presence of anergy. Disseminated tuberculosis is an absolute contraindication for the use of any organ for transplantation. Liver transplant recipients present special problems when receiving treatment for latent tuberculosis infection due to the high risk of hepatotoxicity. In liver recipients, the development of liver toxicity is a particular concern during the treatment of tuberculosis. The main problems that can occur after transplantation are the drug interactions and the recurrence of hepatitis C virus infection, which may increase the risk of tuberculosis and favor toxicity. The most common manifestations of tuberculosis-associated immune reconstitution syndrome are fever, lymphadenopathy, and worsening respiratory symptoms. Tuberculosis has important implications in the outcome of transplant patients. The overall mortality rate in solid organ recipients with tuberculosis is as high as 29%.

Paradoxical reactions may occur in up to 25% of patients treated for tuberculous lymphadenitis, characterized by new or enlarging lymphadenopathy, which may be tender or painful. The frequency of paradoxical reactions in this setting is unknown but was 50% (4 of 8) in one series. Corticosteroids are probably indicated for severe pleural and most central nervous system (CNS) paradoxical reactions to manage symptoms and CNS edema. Although the heightened granulomatous response from highly active antiretroviral therapy (HAART) would help clear mycobacterial organisms, the granulomatous inflammation itself may cause significant damage, thus resulting in immune reconstitution inflammatory syndrome (IRIS). Management of IRIS due to Mycobacterium avium complex disease should be directed at treating the infection and managing symptoms. The major difference is that the antigens responsible for granulomatous inflammation in tuberculosis (TB) are peptides resulting from digestion and processing of the microorganism, whereas in sarcoidosis the putative antigens are unknown. New-onset sarcoidosis is rare in HIV-infected patients. This can probably be explained by the HIV-induced alteration in cell-mediated immunity described. However, several cases of sarcoidosis have been reported after initiation of HAART. The pathogenesis of this condition is likely to be very similar to the paradoxical reactions seen in HAART-treated HIV-infected patients with TB.

Nucleic acid probes are available for the most frequently seen mycobacterial species, Mycobacterium tuberculosis complex, M. avium complex, M. kansasii, and M. gordonae. It has seemed as if there is an increase in nontuberculous mycobacteria (NTM) disease in the United States and other developed countries in recent years, but it has not been clear whether this is a true increase or just better detection. Early on, pulmonary NTM infections seemed to occur mainly in persons who had previous structural lung disease, such as chronic obstructive pulmonary disease, tuberculosis, histoplasmosis, or other causes of bronchiectasis. A more recent cause of immune-suppressiontriggered NTM lung diseases (and NTM disease generally) has been the introduction of biologic agents, especially tumor necrosis factor alpha inhibitor. The 2007 ATS/IDSA Statement includes a section in which the authors conclude that "more fundamental information is needed to improve understanding in essentially all areas of NTM disease". A combination of clinical, radiologic, and bacteriologic features has been suggested for diagnosis of true pulmonary NTM disease. Evaluation should include, beside appropriate history and physical, chest imaging using high-resolution computed tomography (HRCT), unless there is obvious cavitation by chest X ray. If possible, NTM should be identified at the species level. Patients suspected of having NTM disease should be monitored closely until the diagnosis is made or excluded.

Soil characteristics in certain regions may favor the growth of Mycobacterium avium complex (MAC), leading to regional differences in epidemiology. Laboratory abnormalities classically have reflected the disseminated nature of the disease with profound anemia out of proportion to neutropenia or thrombocytopenia, and elevated transaminases and alkaline phosphatase. Either because of improved diagnosis or concurrent antiretroviral therapy, these laboratory abnormalities may be less common among patients with disseminated Mycobacterium avium complex (DMAC) diagnosed in the present day than among those diagnosed earlier in the human immunodeficiency virus (HIV)/AIDS epidemic. One study has suggested that interferon (IFN)-ү release assays, which do not cross-react with MAC, may be useful to make the distinction between nontuberculous mycobacterial lymphadenitis. If highly active antiretroviral therapy (HAART) is ineffective, due to HIV multidrug resistance, for example, or CD4 lymphocyte improvement is delayed in a particular individual, MAC prophylaxis is still an important adjunct to care and is cost-effective. Dyspnea on initial presentation and presence of coexisting lung disease have been associated with increased mortality among patients with MAC pulmonary disease. In studies conducted for a course of clarithromycin monotherapy and a course of azithromycin monotherapy, gastrointestinal side effects were common, and changes in hearing were not infrequent. These two studies strongly suggested that clarithromycin and azithromycin have clinical utility for treatment of pulmonary MAC. DMAC is almost exclusively seen in patients with latestage AIDS and can be treated with the combination of either clarithromycin or azithromycin in combination with ethambutol, with or without rifabutin or a fluoroquinolone.

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. Currently, the RGM are grouped into six major taxonomic groups according to pigmentation and genetic relatedness. The major groups are the M. fortuitum group, the M. chelonae/M. abscessus group, the Mycobacterium smegmatis group (M. smegmatis and Mycobacterium goodii), the Mycobacterium mucogenicum group, the Mycobacterium mageritense/Mycobacterium wolinskyi group, and the pigmented RGM. The RGM are ubiquitous in the environment. The disease pathogenesis likely results from microtrauma caused by shaving the legs prior to pedicures and footbath water that is heavily contaminated with RGM due to failure to routinely clear the footbath filters. High-Performance Liquid Chromatography (HPLC) of mycolic acids may be used in large reference laboratories but it can identify only a few species adequately. Restriction fragment length polymorphism analysis of selected gene targets such as hsp65 are currently used in some larger reference laboratories. Currently, the only nucleic acid probe available for identification of the RGM but not yet cleared by the Food and Drug Administration in the United States is the INNO- LiPA multiplex probe assay. Current antimicrobial regimens for treatment of disease caused by the RGM are based upon their unique in vitro susceptibility patterns. Finally, the chapter describes common clinical diseases caused due to RGM.

In contrast to other common nontuberculous mycobacteria, Mycobacterium kansasii is infrequently isolated from natural water sources or soil. The major reservoir appears to be tap water. Infection is likely acquired through the aerosol route, with low infectivity in regions of endemicity. Human-to-human transmission is not thought to occur despite few case reports of familial clustering. Clinically significant disease is occasionally discovered incidentally on radiology, but these patients are often symptomatic and represent less than 20% of cases in most published series. Disseminated disease is an uncommon presentation in HIV-negative patients and usually associated with severe immunosuppression. The majority of patients with M. kansasii pulmonary disease have underlying pulmonary comorbidities, such as smoking, chronic obstructive pulmonary disease, bronchiectasis, and prior or concurrent M. tuberculosis infection. A survey in Great Britain, however, noted higher rates, with 9% of M. kansasii infections presenting with extrapulmonary disease. Common sites of extrapulmonary disease include lymph nodes, skin, musculoskeletal, and genitourinary systems. The specificity of gamma interferon release assays (IGRAs) for M. tuberculosis may be reduced by M. kansasii infection, as M. kansasii encodes for CFP-10 and ESAT-6, two antigens targeted by IGRAs. In a study conducted to evaluate the therapy in rifampin-resistant disease, it was found that patients with acquired rifampin resistance were treated with daily high-dose ethambutol, isoniazid, sulfamethoxazole, and pyridoxine combined with aminoglycoside therapy. Given the potential toxicities, particularly with aminoglycoside therapy, clarithromycin and/or moxifloxacin therapy could be considered as alternatives.

Mycobacterium marinum is a pathogenic mycobacterium, which makes it, along with its related species M. ulcerans, distinct from the other nontuberculous mycobacterium (NTM) that are opportunistic pathogens. The Esx secretion system is critical for virulence of both Mycobacterium tuberculosis and M. marinum and is highly conserved between the two species. When multilocus sequence analysis applied to 22 M. marinum strains, it was found that significant molecular differences separated clinical isolates from the piscine isolates. Molecular biology techniques have been successfully applied to identification of mycobacteria. Scarce cases of M. marinum infection occurring in patients treated with tumor necrosis factor alpha inhibitor therapy have been reported since 2002. Therefore, it is not possible to draw any conclusions regarding the frequency or the severity of M. marinum infection in this population. Instead, preventive strategies are recommended especially for those patients. Distal aspects of the upper limbs, such as the finger/hand, are the most common sites of infection in relation to fish/water animal exposure. From the studies dealing with a large number of strains and applying a standard method of testing, M. marinum has a natural multidrug resistance pattern. Broth microdilution susceptibility testing is recommended by CLSI and may use the commercially available Sensititre MIC plates. Patients infected with M. marinum are usually treated with antibiotics. A variety of antibiotics have been used, including tetracyclines, co-trimoxazole, rifampin plus ethambutol, and more rarely clarithromycin, levofloxacin, and amikacin. The chapter describes epidemiology and prevention of M. marinum.

Isolates of Mycobacterium scrofulaceum, according to early reports, were identified in raw milk, oysters, soil, and water. Dunn and Hodgson were able to isolate M. scrofulaceum, among other species of nontuberculous mycobacteria (NTM), from raw milk but not from samples of pasteurized milk. The distribution of mycobacterial species in childhood cervical lymphadenitis has changed over the years. Differentiating NTM lymphadenitis from tuberculosis is usually not difficult. Age from 1 to 5 years, unilateral nodes, lack of systemic illness, no history of contact with active tuberculosis, normal chest radiograph, no or weak response to intermediate-strength tuberculin skin test, nonreactive tuberculin skin tests in siblings, early suppuration, and no response to antituberculous antibiotics are all points which favor NTM disease. Wedge biopsy of one of the nodules revealed caseating granulomas and acid-fast bacilli, with M. scrofulaceum isolated from culture. Yamamoto et al. reported six cases of meningitis due to NTM, five of which were due to scotochromogens. There are several reports of cutaneous disease. The sensitivity of M. scrofulaceum to antituberculous antibiotics has been reported sporadically. It is one of the most resistant of all NTM species. The organism is resistant to isoniazid, para-aminosalicylic acid, and kanamycin. A large body of anecdotal evidence suggests that antibiotic therapy has no benefit in lymphadenitis and that node resection usually suffices for complete cure.

The species Mycobacterium tuberculosis along with other organisms together form the so- called Mycobacterium tuberculosis complex, with important differences among these organisms in epidemiology, microbiology, and even therapy. Human disease caused by Mycobacterium bovis is indistinguishable clinically or pathologically from the disease caused by M. tuberculosis. In the last decades, DNA probes became the most common molecular-based tool for identification of pathogenic mycobacterial isolates. The current recommended regimen for the treatment of tuberculosis includes the use of isoniazid, rifampin, and pyrazinamide for 2 months, followed by isoniazid and rifampin for 4 months. The bacille Calmette-Guérin (BCG) strain of M. bovis is a laboratory-obtained attenuated strain described by Albert Calmette and Camille Guérin in 1922. Mycobacterium africanum is a species from the M. tuberculosis complex that includes strains which share phenotypic characteristics with M. bovis and M. tuberculosis. Strains of this species have been isolated in sub- Saharan African countries, where it is the cause of human tuberculosis with variable percentages. However, in developed countries, M. africanum isolation is uncommon and is associated with immigrant patients from Africa; such patients can infect immigrants from other countries and even autochthonous patients. Disease caused by M. africanum is identical to that caused by M. tuberculosis. There are reports which evaluate both diseases: one of them showed no differences between the two species, except for less clustering of M. africanum cases than M. tuberculosis cases, and the appearance of lower lobe lung disease less frequently in M. africanum cases.

The list of clinically important nontuberculous mycobacteria (NTM) is growing as new species continue to be identified and older ones are found to be pathogenic. Molecular techniques such as real-time PCR and gene amplification and restriction length polymorphism are promising tools for rapid identification of NTM. Optimal therapy for a documented Mycobacterium gordonae infection remains undefined. The majority of isolates tested have been resistant in vitro to isoniazid and pyrazinamide, whereas many are susceptible to ethambutol, rifampin, clarithromycin, linezolid, and the fluoroquinolones. Unlike other nontuberculous mycobacteria, M. simiae produces niacin and thus may be confused with M. tuberculosis. M. simiae can colonize the respiratory tract, and the lung is the most commonly reported site of infection. The majority of reported infections have occurred in persons living near rivers or stagnant bodies of water. A recent open-label randomized trial conducted in Ghana compared two regimens for early, limited M. ulcerans infections. In this study, 73 of 76 patients who received streptomycin and rifampin for 8 weeks and 68 of 75 patients who received 4 weeks of streptomycin and rifampin followed by 4 weeks of rifampin and clarithromycin had healed lesions at 1 year after the start of treatment. Infections with M. xenopi have shown variable responses to drug therapy. Recommendations for initial therapy include isoniazid, a rifamycin, ethambutol, and clarithromycin with or without an initial course of streptomycin. Pyrazinamide and ciprofloxacin have been included in some successful regimens.