Evidence of TB dating back 6,500 years has been found in archaeologic digs. There are signs of the organism in the remains of mummified Egyptians and mention of it in ancient Chinese and Sanskrit written records. Hippocrates made the first clinically detailed description between 460 and 375 B.C.E. He called the disease "phthisis." During the 16th to the 19th centuries, TB was epidemic in Europe, causing the death of as many as one in four persons.

Starting in Northern Europe more than 500 years ago, the disease spread steadily across the continent but did not move into Russia until the late 1800s. New Guinea, the last place left uninfected, developed TB for the first time in the 1940s.

Inhaled droplet nuclei are deposited along the tracheobronchial mucosa and into the alveoli of the middle and lower lobes. Following a period of active replication, the infection spreads to regional lymphatic channels and mediastinal lymph nodes; from here, bacilli released into the thoracic duct reach the bloodstream and are disseminated throughout the body. In response, the immune system targets these scattered vascular foci of infection, first with macrophages that surround and engulf the organisms, then lymphocytes, and finally a characteristic, focal inflammatory reaction termed a granuloma. A healthy granulomatous reaction terminates active infection, usually before the person is symptomatic, though it does not eliminate all bacilli. In time, the granuloma becomes encapsulated, effectively sealing off any remaining viable organisms. Encapsulated granulomas are termed tubercles. With age, they usually calcify, and larger ones are visible later by chest x-ray and tissue scans. Most healthy persons remain asymptomatic throughout life, the only evidence of prior infection being the calcified granuloma or positive skin test.

However, compared with other infectious diseases, TB is not easy to contract. The average time from ongoing exposure (e.g., family contact) until established infection is about two months. There have been reports of infection occurring in much less time. In one well-reported incident, a passenger on an airline was very ill with TB and coughed throughout the entire flight. Later, it was learned that fellow passengers on the plane had become infected with TB [7]. This is a rare occurrence, but it serves as a reminder to those in the healthcare professions. Caring for patients with TB can be a health risk, and proper isolation techniques for prevention must be employed when working with known or suspected cases of active infection [7].

If the immune process works well and stops the proliferation of bacilli after the initial primary infection, healing occurs in the lungs, in the lymph nodes, and in the metastatic sites of infection. Depending upon the patient's age and presence of other infections, a latent period ensues. This period lasts a lifetime in 85% to 90% of those infected. During this asymptomatic phase, the only evidence of infection with M. tuberculosis may be skin-test reactivity to tuberculin [22]. Some patients will have fine, linear scarring in the lung or a focal calcification (Ghon lesion) visible usually in a middle or lower lobe, a sign of the struggle between M. tuberculosis and the cellular immune response.

An estimated 13 million persons in the United States have an asymptomatic, latent form tuberculous infection [57]. Recurrence of active disease occurs in 10% to 15% of infected persons, half of whom reactivate within two years after primary infection. The cause of the reactivation is usually related to waning of the patient's immune surveillance rather than reinfection from newly inhaled bacteria. In the United States, the highest frequency of recurrent or reactivation TB is in middle-aged and older adults and immigrants [3].

An estimated 13 million persons in the United States have an asymptomatic, latent form tuberculous infection [57]. Recurrence of active disease occurs in 10% to 15% of infected persons, half of whom reactivate within two years after primary infection. The cause of the reactivation is usually related to waning of the patient's immune surveillance rather than reinfection from newly inhaled bacteria. In the United States, the highest frequency of recurrent or reactivation TB is in middle-aged and older adults and immigrants [3].

The early symptoms of active pulmonary TB are often so subtle as to be missed at first by most patients. Because of this, they will frequently have difficulty pinpointing exactly when their illness began. Some patients without obvious symptoms are diagnosed solely by a routine chest x-ray. For those who do have symptoms, the most common manifestations are gradual onset and progression of fever, malaise, cough, anorexia, and weight loss. The fever is low-grade, often not so high as to be noticed or disquieting. When the fever breaks during the early morning hours, it is often associated with "night sweats." Weight loss may result from the infectious process itself, or it can be a sign that malnutrition and depletion of immune reserves preceded, and to some extent caused, the infection.

The optimal time to collect a specimen is early morning, after the patient has had nothing by mouth for about eight hours. The mouth should be rinsed with water to reduce contamination of the sample with the normal flora of the mouth, but the teeth should not be brushed prior to the collection.

There are two U.S. Food and Drug Administration (FDA) approved, commercially available nucleic acid amplification tests (NAATs) for use in confirming M. tuberculosis in procured specimens [71]. The Xpert MTB/RIF Assay, which is able to detect the presence of M. tuberculosis organisms as well as resistance to rifampin, is an automated, cartridge-based system (GeneXpert platform) that requires a sputum sample [55]. Results are available within two hours. The second approved probe is the amplified M. tuberculosis direct (Hologic Amplified MTD) test, which uses transcription-mediated amplification in order to identify and magnify the RNA target. Results are generally available within three to four hours. This test is approved for the detection of tuberculosis in both smear-positive and smear-negative cultures [26]. Non-FDA approved NAATs (often called "in-house" tests) may be used to diagnose TB and to test for drug-resistant TB [46,58]. The Xpert MTB/RIF Ultra and the Xpert MTB/XDR tests are two examples, the latter of which is a drug susceptibility test that can identify resistance to isoniazid, fluoroquinolones, second-line injectable drugs (e.g., amikacin, capreomycin, kanamycin), and ethionamide [72].

These tests are able to differentiate the DNA of different species of M. tuberculosis, also called DNA fingerprinting or genotyping. Because most strains of bacteria share patterns, it has been difficult to follow the person-to-person transmission of certain strains. Using genotyping, researchers have shown that each strain has a distinct DNA fingerprint and that all samples sharing the same DNA fingerprint were isolated from people who live together. This will help track the path of transmission and aid public health researchers to pinpoint patterns of infection, which in turn helps to plan prevention programs that target the areas of heightened infection rates.

A task force supported by the CDC and pulmonary/infectious disease subspecialty societies recommends that a NAAT should be performed on at least one respiratory specimen from each patient with signs and symptoms of pulmonary TB for whom a diagnosis of TB is being considered but has not yet been established and for whom the test result would alter case management or TB control activities [46].

The kidney is the most common site for extrapulmonary TB. From there, the bacilli spread to the bladder and, in men, to the prostate, seminal vesicles, and epididymis. Often, the first sign of the infection is an enlarging scrotal mass. Pyelography will then often reveal a cavitary lesion of the renal parenchyma and irregularities of the ureters. Diagnosis is easily confirmed by urine smear and culture.

Under conditions of poor immune function or trauma, previously quiescent TB foci may destabilize, releasing viable bacilli into the bloodstream. Unchecked, this leads to a sustained, active systemic infection with small metastatic lesions throughout the body. Although not immediately evident on chest x-ray, eventually the films will show multitudes of small nodules spread throughout both lungs, having the appearance of millet seeds. Prominent symptoms include chronic fever, night sweats, weakness, malaise, weight loss, and dyspnea. Bone marrow and liver biopsies are often taken to complete the diagnosis.

Preventive therapy is recommended for all persons, regardless of age, with a positive TB blood test (IGRA) [57]. Persons in the following risk groups should be given high priority for preventive therapy if their reaction to the tuberculin skin test result is 5 mm or greater [57]:

Persons with no known risk factors may be considered for preventive therapy if they have a positive tuberculin test result of 15 mm or greater or a positive IGRA test result [57]. However, testing for TB should generally only be performed among high-risk groups.

Although not recommended or routinely used in the United States, many other countries, particularly developing countries with limited financial resources, have used the BCG vaccine to control TB [20]. The WHO estimates that more than 1 billion people have received BCG, making it one of the most widely used vaccines in the world. Studies have shown BCG to have variable efficacy against all TB strains. Analysis of these studies is difficult due to the fact that several different strains of the vaccine are used worldwide. There are serious concerns about its use in immunocompromised patients [20].

Generally, the vaccine is given to infants and children who have (1) a negative tuberculin skin test; (2) are at high risk of continuing exposure to persons with infectious TB; (3) cannot be placed on long-term preventive therapy; or (4) are continually exposed to persons with INH- or rifampin-resistant disease. As BCG is a live, attenuated vaccine, administration will cause a person to convert from a negative TB skin test to a positive one, requiring any subsequent skin testing to be confirmed by blood test.

Prophylactic antituberculosis treatment is highly recommended for children of patients diagnosed with active TB. The treatment regimens most effective for children are limited, compared with those used for adult patients with TB. However, the once-weekly, three-month regimen of isoniazid-rifapentine is now approved for use in children 2 to 17 years of age, thereby permitting a relatively brief and more manageable course of antituberculous prophylaxis [65]. Nine-month treatment with INH alone has proved to be successful in most children and is also recommended [52]. Children taking INH do not seem to develop the transient elevation of liver enzymes seen in adults, so liver function does not have to be monitored unless the patient has a history of other liver disease. When INH is not tolerated, the American Academy of Pediatrics recommends six months of daily rifabutin at a dosage of 10–20 mg/kg [52]. As noted, ethambutol is usually avoided in children younger than 7 years of age because it is difficult to properly monitor visual acuity and color perception in children that young. It is rare for children to develop drug-induced hepatitis, so monthly follow-ups do not include liver function studies, as in adults. Good indicators of improvement are increased appetite, weight gain, and lower evening temperatures.

It is important for healthcare professionals to give both the patient and the caregiver explicit verbal and written instructions outlining which medications should be taken and how often. Some even make a poster with sample tablets glued to it, so the patient has a constant visual reminder of what needs to be taken. These instructions should also include the name and telephone number of a physician or nurse to call if questions arise.

Patients' health literacy is typically low, and an inability to follow a prescription is the foremost problem associated with poor health literacy [19]. Patients whose primary language is not English, racial/ethnic minorities, and patients older than 60 years of age have the lowest health literacy, which is unfortunate given that most cases of TB occur in these populations [19,23,54]. Many patients report that the clinician did not provide information in words they could understand, and some individuals feel shame about their lack of understanding and fail to ask for clarification due to embarrassment. Non-English-proficient patients require a professional translator (i.e., not a family member) to be present at each visit. It is vital that the patient understand the importance of precisely following the drug regimen.

Patients and caregivers should be taught the signs and symptoms of drug toxicity and side effects, such as those with rifampin, which causes feces, saliva, tears, and urine to be a red-orange color. It is important to strongly reinforce that they must not stop taking the medications without permission.