Tuberculosis

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Tuberculosis Classification and external resources
Chest X-ray of a patient suffering from tuberculosis
ICD-10	A15.-A19.
ICD-9	010-018
OMIM	607948
DiseasesDB	8515
MedlinePlus	000077 000624
eMedicine	med/2324  emerg/618 radio/411
MeSH	C01.252.410.040.552.846

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Overview

Tuberculosis (abbreviated as TB for tubercle bacillus or Tuberculosis) is a common and deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis. Tuberculosis most commonly attacks the lungs (as pulmonary TB) but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, bones, joints and even the skin. Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti can also cause tuberculosis, but these species do not usually infect healthy adults.^[1]

Over one-third of the world's population has been exposed to the TB bacterium, and new infections occur at a rate of one per second.^[2] Not everyone infected develops the full-blown disease; asymptomatic, latent TB infection is most common. However, one in ten latent infections will progress to active TB disease, which, if left untreated, kills more than half of its victims.

In 2004, mortality and morbidity statistics included 14.6 million chronic active TB cases, 8.9 million new cases, and 1.6 million deaths, mostly in developing countries.^[2] In addition, a rising number of people in the developed world are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse, or HIV/AIDS.

The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis.^[3] The emergence of drug-resistant strains has also contributed to this new epidemic with, from 2000 to 2004, 20% of TB cases being resistant to standard treatments and 2% resistant to second-line drugs.^[4] TB incidence varies widely, even in neighboring countries, apparently because of differences in health care systems.^[5] The World Health Organization declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis aiming to save 14 million lives between 2006 and 2015.^[6]

Other names

In the past, tuberculosis was called consumption, because it seemed to consume people from within, with a bloody cough, fever, pallor, and long relentless wasting. Other names included phthisis (Greek for consumption) and phthisis pulmonalis; scrofula (in adults), affecting the lymphatic system and resulting in swollen neck glands; tabes mesenterica, TB of the abdomen and lupus vulgaris, TB of the skin; wasting disease; white plague, because sufferers appear markedly pale; king's evil, because it was believed that a king's touch would heal scrofula; and Pott's disease, or gibbus of the spine and joints.^[7][8] Miliary tuberculosis – now commonly known as disseminated TB– occurs when the infection invades the circulatory system resulting in lesions which have the appearance of millet seeds on X-ray.^[7][9]

Epidemiology and Demographics

• In U.S., only 5% multidrug-resistant (MDR) TB

Tuberculosis (TB) is one of the world’s deadliest diseases

• One third of the world’s population are infected with TB.
• Each year, nearly 9 million people around the world become sick with TB.
• Each year, there are almost 2 million TB-related deaths worldwide.
• TB is the leading killer of people who are HIV infected.

How many cases of tuberculosis (TB) were reported in the United States in 2005?

In total, 14,097 TB cases (a rate of 4.8 cases per 100,000 persons) were reported in the United States in 2005. This represents a 3.8% decline in the rate from 2004. The 2005 TB rate was the lowest recorded since national reporting began in 1953.

Is the rate of TB declining in the United States?

Yes. The TB rate is going down in the United States. But, the decrease in the percent change of the annual case rate has slowed, from an annual average of 5.6% for 1993 through 2002 to an average of 3.1% for 2003 through 2005.

How do the rates of TB compare between U.S.-born persons and foreign-born persons living in the United States?

In 2005, the TB rate in foreign-born persons in the United States (21.8 cases per 100,000 persons) was 8.7 times greater than that of U.S.-born persons (2.5 cases per 100,000 persons).

How many people died from TB in the United States?

There were 662 deaths from TB in 2004, a 6.9% decline from 711 deaths in 2003.

What are the rates of TB for different racial and ethnic populations†?

• American Indians or Alaska Natives: 6.9 cases per 100,000 persons
• Asians: 25.8 cases per 100,000 persons
• Blacks: 10.9 cases per 100,000 persons
• Native Hawaiians and other Pacific Islanders: 13.8 cases per 100,000 persons
• Hispanics or Latinos: 9.5 cases per 100,000 persons
• Whites: 1.3 cases per 100,000 persons

† For this report, persons identified as white, black, Asian, American Indian/Alaska Native, native Hawaiian or other Pacific Islander, or of multiple races are all non-Hispanic. Persons identified as Hispanic may be of any race.

Is multidrug-resistant tuberculosis (MDR TB) on the rise?

Among all reported TB cases in the United States, the percentage of multidrug-resistant (MDR) TB cases in persons with no previous history of TB that were reported in the United States decreased from 2.5% in 1993 to 1.0% in 2005.

Since 1998, the percentage of U.S.-born patients with MDR TB has remained ≤0.7%. However, of the total number of reported primary MDR TB cases, the proportion occurring in foreign-born persons increased from 26% (105 of 410) in 1993 to 80% (76 of 95) in 2005.

How are TB data collected?

The 50 states, the District of Columbia, New York City, Puerto Rico, and seven other U.S. jurisdictions in the Pacific and Caribbean, report all TB cases to CDC. These cases must meet the CDC/Council of State and Territorial Epidemiologists case definition. When cases are reported, the report includes specific information about the person with TB. This includes the patient's race, ethnicity (either Hispanic or non-Hispanic), treatment information, and, when available, drug-susceptibility test results. CDC calculates national and state TB rates and rates for foreign-born, U.S.-born, and racial/ethnic populations. These calculations use U.S. census population estimates for the years 1993 through 2005.

Pathophysiology

Bacterial species

Main article: Mycobacterium tuberculosis

The primary cause of TB , Mycobacterium tuberculosis (M. TB), is an aerobic bacterium that divides every 16 to 20 hours, an extremely slow rate compared with other bacteria, which usually divide in less than an hour.^[11] (For example, one of the fastest-growing bacteria is a strain of E. coli that can divide roughly every 20 minutes.) Since MTB has a cell wall but lacks a phospholipid outer membrane, it is classified as a Gram-positive bacterium. However, if a Gram stain is performed, MTB either stains very weakly Gram-positive or does not retain dye due to the high lipid & mycolic acid content of its cell wall.^[12] MTB is a small rod-like bacillus that can withstand weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in vitro.^[13]

Using certain histological techniques on expectorate samples from phlegm (also called sputum), scientists can identify MTB under a regular microscope. Since MTB retains certain stains after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB).^[12] The most common staining technique, the Ziehl-Neelsen stain, dyes AFBs a bright red that stands out clearly against a blue background. Other ways to visualize AFBs include an auramine-rhodamine stain and fluorescent microscopy.

The M. tuberculosis complex includes 3 other TB-causing mycobacteria: M. bovis, M. africanum and M. microti. The first two only very rarely cause disease in immunocompetent people. On the other hand, although M. microti is not usually pathogenic, it is possible that the prevalence of M. microti infections has been underestimated.^[14]

Other known pathogenic mycobacteria include Mycobacterium leprae, Mycobacterium avium and M. kansasii. The last two are part of the nontuberculous mycobacteria (NTM) group. Nontuberculous mycobacteria cause neither TB nor leprosy, but they do cause pulmonary diseases resembling TB.^[15]

Evolution

During its evolution, M. tuberculosis has lost numerous coding and non-coding regions in its genome, losses that can be used to distinguish between strains of the bacteria. The implication is that M. tuberculosis strains differ geographically, so their genetic differences can be used to track the origins and movement of each strain.^[16]

Transmission

Further information: Transmission (medicine)

When people suffering from active pulmonary TB cough, sneeze, speak, kiss, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze, for instance, can release up to 40,000 droplets.^[17] Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very low and the inhalation of just a single bacterium can cause a new infection.^[18]

People with prolonged, frequent, or intense contact are at particularly high risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis can infect 10–15 other people per year.^[2] Others at risk include people in areas where TB is common, people who inject illicit drugs (especially when sharing needles), residents and employees of high-risk congregate settings, medically under-served and low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, patients immunocompromised by conditions such as HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving these high-risk clients.^[19]

Transmission can only occur from people with active—not latent—TB. The probability of transmission from one person to another depends upon the number of infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of exposure, and the virulence of the M. tuberculosis strain.^[20] The chain of transmission can therefore be broken by isolating patients with active disease and starting effective anti-tuberculous therapy. After two weeks of such treatment, people with non-resistant active TB generally cease to be contagious.^[21]

Pathogenesis

About 90% of those infected with Mycobacterium tuberculosis have asymptomatic, latent TB infection (sometimes called LTBI), with only a 10% lifetime chance that a latent infection will progress to TB disease. However, if untreated, the death rate for these active TB cases is more than 50%.^[22]

TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within alveolar macrophages.^[23] The primary site of infection in the lungs is called the Ghon focus. Bacteria are picked up by dendritic cells, which do not allow replication, although these cells can transport the bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to the more distant tissues and organs where secondary TB lesions can develop in lung apices, peripheral lymph nodes, kidneys, brain, and bone.^[24] All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.^[25]

Tuberculosis is classified as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes and fibroblasts are among the cells that aggregate to form a granuloma, with lymphocytes surrounding the infected macrophages. The granuloma functions not only to prevent dissemination of the mycobacteria, but also provides a local environment for communication of cells of the immune system. Within the granuloma, T lymphocytes (CD4+) secrete cytokines such as interferon gamma, which activates macrophages to destroy the bacteria with which they are infected.^[26] T lymphocytes (CD8+) can also directly kill infected cells.^[23]

Importantly, bacteria are not always eliminated within the granuloma, but can become dormant, resulting in a latent infection. Another feature of the granulomas of human tuberculosis is the development of cell death, also called necrosis, in the center of tubercles. To the naked eye this has the texture of soft white cheese and was termed caseous necrosis.^[27]

If TB bacteria gain entry to the bloodstream from an area of damaged tissue they spread through the body and set up many foci of infection, all appearing as tiny white tubercles in the tissues. This severe form of TB disease is most common in infants and the elderly and is called miliary tuberculosis. Patients with this disseminated TB have a fatality rate of approximately 20%, even with intensive treatment.^[28]

In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis.^[27] Affected tissue is replaced by scarring and cavities filled with cheese-like white necrotic material. During active disease, some of these cavities are joined to the air passages bronchi and this material can be coughed up. It contains living bacteria and can therefore pass on infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.^[27]

Diagnosis

For more details on this topic, see Tuberculosis diagnosis.

Tuberculosis can be a difficult disease to diagnose, due mainly to the difficulty in culturing this slow-growing organism in the laboratory. A complete medical evaluation for TB must include a medical history, a chest X-ray, and a physical examination.

When Should You Suspect Tuberculosis (TB)?

When the disease becomes active, 75% of the cases are pulmonary TB. Pulmonary TB disease should be suspected in persons who have the following symptoms^[2]:

• Chest pain
• Hemoptysis (Coughing up blood)
• Productive, prolonged cough for more than three weeks
• Unexplained weight loss
• Loss of appetite
• Night sweats
• Chills
• Fever
• Fatigue
• Pallor

In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB more common in immunosuppressed persons and young children. Extrapulmonary infection sites include:

• Pleura
• Central nervous system in meningitis
• Lymphatic system in scrofula of the neck
• Genitourinary system in urogenital tuberculosis
• Bones and joints in Pott's disease of the spine

An especially serious form is disseminated TB, more commonly known as miliary tuberculosis. Although extrapulmonary TB is not contagious, it may co-exist with pulmonary TB, which is contagious.^[20]

How Do You Evaluate Persons Suspected of Having TB Disease?

A complete medical evaluation for TB includes the following:

• Medical History: Clinicians should ask about the patient’s history of TB exposure, infection, or disease. It is also important to consider demographic factors (e.g., country of origin, age, ethnic or racial group, occupation) that may increase the patient’s risk for exposure to TB or to drug-resistant TB. Also, clinicians should determine whether the patient has medical conditions, especially HIV infection, that increase the risk of latent TB infection progressing to TB disease.

• Mantoux Tuberculin Skin Test and/or QuantiFERON®-TB Gold In Tube[4] Test: The Mantoux tuberculin skin test (TST) and the QuantiFERON®-TB Gold In Tube test (QFT-GIT) are used to test for M. tuberculosis infection. Additional tests are required to confirm TB disease. The Mantoux tuberculin skin test is performed by injecting a small amount of fluid called tuberculin into the skin in the lower part of the arm. The test is read within 48 to 72 hours by a trained health care worker, who looks for a reaction (induration) on the arm. The QFT-GIT is a blood test. It measures the patient’s immune system reaction to M. tuberculosis. Once the blood samples are taken, they must be processed within 16 hours. Interpretation of QFT-GIT results is influenced by the patient’s estimated risk for TB infection.

• Chest Radiograph: A posterior-anterior chest radiograph is used to detect chest abnormalities. Lesions may appear anywhere in the lungs and may differ in size, shape, density, and cavitation. These abnormalities may suggest TB, but cannot be used to definitively diagnose TB. However, a chest radiograph may be used to rule out the possibility of pulmonary TB in a person who has had a positive reaction to a TST or QFT-G and no symptoms of disease.

• Physical Examination: A physical exam can provide valuable information about the patient’s overall condition and other factors that may affect how TB is treated, such as HIV infection or other illnesses.

• Diagnostic Microbiology (sputum): The presence of acid-fast-bacilli (AFB) on a sputum smear or other specimen often indicates TB disease (at least 10,000c is needed on the smear to get a postive acid fast bacilli (AFB) stain). Acid-fast microscopy is easy and quick, but it does not confirm a diagnosis of TB because some acid-fast-bacilli are not M. tuberculosis. Therefore, a culture is done on all initial samples to confirm the diagnosis. However, a positive culture is not always necessary to begin or continue treatment for TB because cultures can take up to 3 weeks to yield definite results. A positive culture for M. tuberculosis confirms the diagnosis of TB disease. Culture examinations should be completed on all specimens, regardless of AFB smear results. Laboratories should report positive results on smears and cultures within 24 hours by telephone or fax to the primary health care provider and to the state or local TB control program, as required by law. A mycobacterium tuberculosis direct test (MTD) of nucleic acid amplification can also be performed to diagnose TB. An MTD test is similar to a polymerase chain reaction (pcr) and is very specific. The test is more sensitive than a smear but it is less senstive than a culture, and has the benefit of same day results.

• Diagnostic Microbiology (pleural fluid): A sample of pleural exudate can be analyzed by cytopathology or at a cell count lab. Samples are usually lymphocyte predominant, and cytopathology is more accurate than cell count labs at detecting lymphs. If there is more fluid present, then an AFB lab is more appropriate. A pleural exudate lab test may find sterile pyuria (especially in HIV positive patients), but overall this finding is fairly uncommon. Note: most extra-pulmonary TB is pauci-bacillary, so the yield of tests is very low. This means that negative cultures do not mean no disease (e.g. negative cerebrospinal fluid AFB or even MTD is not that sensitive).

• Drug Resistance: For all patients, the initial M. tuberculosis isolate should be tested for drug resistance. It is crucial to identify drug resistance as early as possible to ensure effective treatment. Drug susceptibility patterns should be repeated for patients who do not respond adequately to treatment or who have positive culture results despite 3 months of therapy. Susceptibility results from laboratories should be promptly reported to the primary health care provider and the state or local TB control program.

• Electrocardiogram: Patients can develop a pericardial effusion secondary to TB and this might be manifested as low voltage and tachycardia.

• Echocardiography or Ultrasound: Patients can develop a pericardial effusion secondary to TB.

Diagnostic Findings

Chest x-ray: Disseminated Tuberculosis

Chest x-ray: Disseminated Tuberculosis

CT:Disseminated Tuberculosis

CT:Disseminated Tuberculosis

CT:Disseminated Tuberculosis

Progression

Progression from TB infection to TB disease occurs when the TB bacilli overcome the immune system defenses and begin to multiply. In primary TB disease—1 to 5% of cases—this occurs soon after infection. However, in the majority of cases, a latent infection occurs that has no obvious symptoms. These dormant bacilli can produce tuberculosis in 2 to 23% of these latent cases, often many years after infection.^[29] The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In patients co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.^[22]

Other conditions that increase risk include drug injection, mainly due to the lifestyle of IV drug users; recent TB infection or a history of inadequately treated TB; chest X-ray suggestive of previous TB, showing fibrotic lesions and nodules; diabetes mellitus; silicosis; prolonged corticosteroid therapy and other immunosuppressive therapy; head and neck cancers; hematologic and reticuloendothelial diseases, such as leukemia and Hodgkin's disease; end-stage kidney disease; intestinal bypass or gastrectomy; chronic malabsorption syndromes; or low body weight.^[20]

Twin studies in the 1950's showed that the course of TB infection was highly dependent on the genetics of the patient. At that time, it was rare that one identical twin would die and the other live.^[30]

Some drugs, including rheumatoid arthritis drugs that work by blocking tumor necrosis factor-alpha (an inflammation-causing cytokine), raise the risk of activating a latent infection due to the importance of this cytokine in the immune defense against TB.^[31]

Risk Stratification and Prognosis

The results of a Mantoux tuberculin skin test must be interpreted carefully. The person's medical risk factors determine at which increment (5 mm, 10 mm, or 15 mm) of induration the result is considered positive.^[32] A positive result indicates TB exposure.

• 5 mm or more is positive in
  • HIV-positive person
  • Recent contacts of TB case
  • Persons with nodular or fibrotic changes on chest x-ray consistent with old healed TB
  • Patients with organ transplants and other immunosuppressed patients

• 10 mm or more is positive in
  • Recent arrivals (less than 5 years) from high-prevalence countries
  • Injection drug users
  • Residents and employees of high-risk congregate settings (e.g., prisons, nursing homes, hospitals, homeless shelters, etc.)
  • Mycobacteriology lab personnel
  • Persons with clinical conditions that place them at high risk (e.g., diabetes, prolonged corticosteroid therapy, leukemia, end-stage renal disease, chronic malabsorption syndromes, low body weight, etc)
  • Children less than 4 years of age, or children and adolescents exposed to adults in high-risk categories

• 15 mm or more is positive in
  • Persons with no known risk factors for TB
  • (Note: Targeted skin testing programs should only be conducted among high-risk groups)

A few important notes about Mantoux tuberculin skin tests:

• A tuberculin test conversion is defined as an increase of 10 mm or more within a 2-year period, regardless of age.
• Mycobacterium avium intracellulare (MAI) or other mycobacterium cause 5 mm induration, but TB is what causes ≥10mm.
• Decision to test is decision to treat.
• If a patient is treated fully, then re-exposed, they should only be retreated if they are HIV positive (immunocompromised) or the risk of reinfection is high.

Treatment

If their is a high probability of infection, presumptively treat the patient even if the stain is negative, while waiting for the culture results. The patient should be brought back in few weeks. Patients usually feel better a few weeks post-treatment. In the U.S., all TB is tested for drug resistance. Isoniazid (INH) resistant TB can be treated in same way as non-MDR TB

Responsibility for Successful Treatment

The overall goals for treatment of tuberculosis are: 1) to cure the individual patient, and 2) to minimize the transmission of Mycobacterium tuberculosis to other persons. Thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides. For this reason the prescribing physician, be he/she in the public or private sector, is carrying out a public health function with responsibility not only for prescribing an appropriate regimen but also for successful completion of therapy. Prescribing physician responsibility for treatment completion is a fundamental principle in tuberculosis control. However, given a clear understanding of roles and responsibilities, oversight of treatment may be shared between a public health program and a private physician.

Organization and Supervision of Treatment

Treatment of patients with tuberculosis is most successful within a comprehensive framework that addresses both clinical and social issues of relevance to the patient. It is essential that treatment be tailored and supervision be based on each patient's clinical and social circumstances (patient-centered care). Patients may be managed in the private sector, by public health departments, or jointly, but in all cases the health department is ultimately responsible for ensuring that adequate, appropriate diagnostic and treatment services are available, and for monitoring the results of therapy.

It is strongly recommended that patient-centered care be the initial management strategy, regardless of the source of supervision. This strategy should always include an adherence plan that emphasizes directly observed therapy (DOT), in which patients are observed to ingest each dose of antituberculosis medications, to maximize the likelihood of completion of therapy. Programs utilizing DOT as the central element in a comprehensive, patient-centered approach to case management (enhanced DOT) have higher rates of treatment completion than less intensive strategies. Each patient's management plan should be individualized to incorporate measures that facilitate adherence to the drug regimen. Such measures may include, for example, social service support, treatment incentives and enablers, housing assistance, referral for treatment of substance abuse, and coordination of tuberculosis services with those of other providers.

Acute Pharmacotherapies

• Typical treatment for active pulmonary disease:

  • RIPE for 6 months; all for first 2 months, then just INH & rifampin for last 4 months

    • Rifampin little upfront activity, more active vs. latent TB; good at sterilizing tissues
    • INH rapidly kills TB (always give with vitamin B6 because of risk peripheral neuropathy)
    • Prazoloacridine (Pza) has upfront ability to kill bacteriain people with disease, only drug which can shorten duration of treatment from 9 to 6 months
    • Ethambutol does nothing but protect vs. resistance to other drugs

• First-Line Drugs

  • Isoniazid
  • Rifampin
  • Rifabutin
  • Rifapentine
  • Pyrazinamide
  • Ethambutol
  • Fixed-dose combination preparations: Two combined preparations, INH and RIF (Rifamate®) and INH, RIF, and PZA (Rifater®).

• Second-Line Drugs

  • Cycloserine
  • Ethionamide
  • Streptomycin
  • Amikacin and kanamycin
  • Capreomycin
  • p-Aminosalicylic acid
  • Fluoroquinolones

Recommended Treatment Regimens

The recommended treatment regimens are, in large part, based on evidence from clinical trials and are rated on the basis of a system developed by the United States Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA).

There are four recommended regimens for treating patients with tuberculosis caused by drug-susceptible organisms. Although these regimens are broadly applicable, there are modifications that should be made under specified circumstances, described subsequently. Each regimen has an initial phase of 2 months followed by a choice of several options for the continuation phase of either 4 or 7 months.

Because of the relatively high proportion of adult patients with tuberculosis caused by organisms that are resistant to isoniazid, four drugs are necessary in the initial phase for the 6-month regimen to be maximally effective. Thus, in most circumstances, the treatment regimen for all adults with previously untreated tuberculosis should consist of a 2-month initial phase of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). If (when) drug susceptibility test results are known and the organisms are fully susceptible, EMB need not be included. For children whose visual acuity cannot be monitored, EMB is usually not recommended except when there is an increased likelihood of the disease being caused by INH-resistant organisms or when the child has "adult-type" (upper lobe infiltration, cavity formation) tuberculosis. If PZA cannot be included in the initial phase of treatment, or if the isolate is resistant to PZA alone (an unusual circumstance), the initial phase should consist of INH, RIF, and EMB given daily for 2 months. Examples of circumstances in which PZA may be withheld include severe liver disease, gout, and, perhaps, pregnancy.

The initial phase may be given daily for 2 weeks and then twice weekly for 6 weeks, or three times weekly. For patients receiving daily therapy, EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF. When the patient is receiving less than daily drug administration, expert opinion suggests that EMB can be discontinued safely in less than 2 months (i.e., when susceptibility test results are known), but there is no evidence to support this approach.

Although clinical trials have shown that the efficacy of streptomycin (SM) is approximately equal to that of EMB in the initial phase of treatment, the increasing frequency of resistance to SM globally has made the drug less useful. Thus, SM is not recommended as being interchangeable with EMB unless the organism is known to be susceptible to the drug or the patient is from a population in which SM resistance is unlikely.

The continuation phase of treatment is given for either 4 or 7 months. The 4-month continuation phase should be used in the large majority of patients. The 7-month continuation phase is recommended only for three groups: patients with cavitary pulmonary tuberculosis caused by drug-susceptible organisms and whose sputum culture obtained at the time of completion of 2 months of treatment is positive; patients whose initial phase of treatment did not include PZA; and patients being treated with once weekly INH and rifapentine and whose sputum culture obtained at the time of completion of the initial phase is positive. The continuation phase may be given daily, two times weekly by DOT, or three times weekly by DOT. For human immunodeficiency virus (HIV)-seronegative patients with noncavitary pulmonary tuberculosis (as determined by standard chest radiography), and negative sputum smears at completion of 2 months of treatment, the continuation phase may consist of rifapentine and INH given once weekly for 4 months by DOT. If the culture at completion of the initial phase of treatment is positive, the once weekly INH and rifapentine continuation phase should be extended to 7 months. All of the 6-month regimens, except the INH--rifapentine once weekly continuation phase for persons with HIV infection, are rated as AI or AII, or BI or BII, in both HIV-infected and uninfected patients. The once-weekly continuation phase is contraindicated (Rating EI) in patients with HIV infection because of an unacceptable rate of failure/relapse, often with rifamycin-resistant organisms. For the same reason twice weekly treatment, either as part of the initial phase or continuation phase is not recommended for HIV-infected patients with CD4+ cell counts <100 cells/µl. These patients should receive either daily or three times weekly (continuation phase) treatment.

Deciding To Initiate Treatment

The decision to initiate combination antituberculosis chemotherapy should be based on epidemiologic information; clinical, pathological, and radiographic findings; and the results of microscopic examination of acid-fast bacilli (AFB)--stained sputum (smears) (as well as other appropriately collected diagnostic specimens) and cultures for mycobacteria. A purified protein derivative (PPD)-tuberculin skin test may be done at the time of initial evaluation, but a negative PPD-tuberculin skin test does not exclude the diagnosis of active tuberculosis. However, a positive PPD-tuberculin skin test supports the diagnosis of culture-negative pulmonary tuberculosis, as well as latent tuberculosis infection in persons with stable abnormal chest radiographs consistent with inactive tuberculosis.

If the suspicion of tuberculosis is high or the patient is seriously ill with a disorder, either pulmonary or extrapulmonary, that is thought possibly to be tuberculosis, combination chemotherapy using one of the recommended regimens should be initiated promptly, often before AFB smear results are known and usually before mycobacterial culture results have been obtained. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive nucleic acid amplification test, treatment can be continued to complete a standard course of therapy. When the initial AFB smears and cultures are negative, a diagnosis other than tuberculosis should be considered and appropriate evaluations undertaken. If no other diagnosis is established and the PPD-tuberculin skin test is positive (in this circumstance a reaction of 5 mm or greater induration is considered positive), empirical combination chemotherapy should be initiated. If there is a clinical or radiographic response within 2 months of initiation of therapy and no other diagnosis has been established, a diagnosis of culture-negative pulmonary tuberculosis can be made and treatment continued with an additional 2 months of INH and RIF to complete a total of 4 months of treatment, an adequate regimen for culture-negative pulmonary tuberculosis. If there is no clinical or radiographic response by 2 months, treatment can be stopped and other diagnoses including inactive tuberculosis considered.

If AFB smears are negative and suspicion for active tuberculosis is low, treatment can be deferred until the results of mycobacterial cultures are known and a comparison chest radiograph is available (usually within 2 months). In low-suspicion patients not initially being treated, if cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the chest radiograph is unchanged after 2 months, one of the three regimens recommended for the treatment of latent tuberculosis infection could be used. These include INH for a total of 9 months, RIF with or without INH for a total of 4 months, or RIF and PZA for a total of 2 months. Because of reports of an increased rate of hepatotoxicity with the RIF--PZA regimen, it should be reserved for patients who are not likely to complete a longer course of treatment, can be monitored closely, and do not have contraindications to the use of this egimen.

Baseline and Follow-Up Evaluations

Patients suspected of having tuberculosis should have appropriate specimens collected for microscopic examination and mycobacterial culture. When the lung is the site of disease, three sputum specimens should be obtained. Sputum induction with hypertonic saline may be necessary to obtain specimens and bronchoscopy (both performed under appropriate infection control measures) may be considered for patients who are unable to produce sputum, depending on the clinical circumstances. Susceptibility testing for INH, RIF, and EMB should be performed on a positive initial culture, regardless of the source of the specimen. Second-line drug susceptibility testing should be done only in reference laboratories and be limited to specimens from patients who have had prior therapy, who are contacts of patients with drug-resistant tuberculosis, who have demonstrated resistance to rifampin or to other first-line drugs, or who have positive cultures after more than 3 months of treatment.

It is recommended that all patients with tuberculosis have counseling and testing for HIV infection, at least by the time treatment is initiated, if not earlier. For patients with HIV infection, a CD4+ lymphocyte count should be obtained. Patients with risk factors for hepatitis B or C viruses (e.g., injection drug use, foreign birth in Asia or Africa, HIV infection) should have serologic tests for these viruses. For all adult patients baseline measurements of serum amino transferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained. Testing of visual acuity and red-green color discrimination should be obtained when EMB is to be used.

During treatment of patients with pulmonary tuberculosis, a sputum specimen for microscopic examination and culture should be obtained at a minimum of monthly intervals until two consecutive specimens are negative on culture. More frequent AFB smears may be useful to assess the early response to treatment and to provide an indication of infectiousness. For patients with extrapulmonary tuberculosis the frequency and kinds of evaluations will depend on the site involved. In addition, it is critical that patients have clinical evaluations at least monthly to identify possible adverse effects of the antituberculosis medications and to assess adherence. Generally, patients do not require follow-up after completion of therapy but should be instructed to seek care promptly if signs or symptoms recur.

Routine measurements of hepatic and renal function and platelet count are not necessary during treatment unless patients have baseline abnormalities or are at increased risk of hepatotoxicity (e.g., hepatitis B or C virus infection, alcohol abuse).

Identification and Management of Patients at Increased Risk of Treatment Failure and Relapse

The presence of cavitation on the initial chest radiograph combined with having a positive sputum culture at the time the initial phase of treatment is completed has been shown in clinical trials to identify patients at high risk for adverse outcomes (treatment failure, usually defined by positive cultures after 4 months of treatment, or relapse, defined by recurrent tuberculosis at any time after completion of treatment and apparent cure). For this reason it is particularly important to conduct a microbiological evaluation 2 months after initiation of treatment (Figure 1). Approximately 80% of patients with pulmonary tuberculosis caused by drug-susceptible organisms who are started on standard four-drug therapy will have negative sputum cultures at this time. Patients with positive cultures after 2 months of treatment should undergo careful evaluation to determine the cause. For patients who have positive cultures after 2 months of treatment and have not been receiving DOT, the most common reason is nonadherence to the regimen. Other possibilities, especially for patients receiving DOT, include extensive cavitary disease at the time of diagnosis, drug resistance, malabsorption of drugs, laboratory error, and biological variation in response.

In USPHS Study 22, nearly 21% of patients in the control arm of the study (a continuation phase of twice weekly INH and RIF) who had both cavitation on the initial chest radiograph and a positive culture at the 2-month juncture relapsed. Patients who had only one of these factors (either cavitation or a positive 2-month culture) had relapse rates of 5--6% compared with 2% for patients who had neither risk factor. In view of this evidence, it is recommended that, for patients who have cavitation on the initial chest radiograph and whose 2-month culture is positive, the minimum duration of treatment should be 9 months (a total of 84--273 doses depending on whether the drugs are given daily or intermittently) (Figure 1 and Table 2). The recommendation to lengthen the continuation phase of treatment is based on expert opinion and on the results of a study of the optimal treatment duration for patients with silicotuberculosis showing that extending treatment from 6 to 8 months greatly reduced the rate of relapse (Rating AIII). The recommendation is also supported by the results of a trial in which the once weekly INH--rifapentine continuation phase was extended to 7 months for patients at high risk of relapse. The rate of relapse was reduced significantly compared with historical control subjects from another trial in which the continuation phase was 4 months.

For patients who have either cavitation on the initial film or a positive culture after completing the initial phase of treatment (i.e., at 2 months), the rates of relapse were 5--6%. In this group decisions to prolong the continuation phase should be made on an individual basis.

Completion of Treatment

A full course of therapy (completion of treatment) is determined more accurately by the total number of doses taken, not solely by the duration of therapy. For example, the "6-month" daily regimen (given 7 days/week; see below) should consist of at least 182 doses of INH and RIF, and 56 doses of PZA. Thus, 6 months is the minimum duration of treatment and accurately indicates the amount of time the drugs are given only if there are no interruptions in drug administration. In some cases, either because of drug toxicity or nonadherence to the treatment regimen, the specified number of doses cannot be administered within the targeted period. In such cases the goal is to deliver the specified number of doses within a recommended maximum time. For example, for a 6-month daily regimen the 182 doses should be administered within 9 months of beginning treatment. If treatment is not completed within this period, the patient should be assessed to determine the appropriate action to take---continuing treatment for a longer duration or restarting treatment from the beginning, either of which may require more restrictive measures to be used to ensure completion.

Clinical experience suggests that patients being managed by DOT administered 5 days/week have a rate of successful therapy equivalent to those being given drugs 7 days/week. Thus, "daily therapy" may be interpreted to mean DOT given 5 days/week and the required number of doses adjusted accordingly. For example, for the 6-month "daily" regimen given 5 days/week the planned total number of doses is 130. As an option, patients might be given the medications to take without DOT on weekends.

Interruptions in treatment may have a significant effect on the duration of therapy. Reinstitution of treatment must take into account the bacillary load of the patient, the point in time when the interruption occurred, and the duration of the interruption. In general, the earlier in treatment and the longer the duration of the interruption, the more serious the effect and the greater the need to restart therapy from the beginning.

Treatment in Special Situations

HIV infection

Recommendations for the treatment of tuberculosis in HIV-infected adults are, with a few exceptions, the same as those for HIV-uninfected adults. The INH--rifapentine once weekly continuation phase is contraindicated in HIV-infected patients because of an unacceptably high rate of relapse, frequently with organisms that have acquired resistance to rifamycins. The development of acquired rifampin resistance has also been noted among HIV-infected patients with advanced immunosuppression treated with twice weekly rifampin- or rifabutin-based regimens. Consequently, patients with CD4+ cell counts <100/µl should receive daily or three times weekly treatment. DOT and other adherence-promoting strategies are especially important for patients with HIV-related tuberculosis.

Management of HIV-related tuberculosis is complex and requires expertise in the management of both HIV disease and tuberculosis. Because HIV-infected patients are often taking numerous medications, some of which interact with antituberculosis medications, it is strongly encouraged that experts in the treatment of HIV-related tuberculosis be consulted. A particular concern is the interaction of rifamycins with antiretroviral agents and other antiinfective drugs. Rifampin can be used for the treatment of tuberculosis with certain combinations of antiretroviral agents. Rifabutin, which has fewer problematic drug interactions, may also be used in place of rifampin and appears to be equally effective although the doses of rifabutin and antiretroviral agents may require adjustment. As new antiretroviral agents and more pharmacokinetic data become available, these recommendations are likely to be modified.

On occasion, patients with HIV-related tuberculosis may experience a temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis while receiving antituberculosis treatment. This clinical or radiographic worsening (paradoxical reaction) occurs in HIV-infected patients with active tuberculosis and is thought to be the result of immune reconstitution as a consequence of effective antiretroviral therapy. Symptoms and signs may include high fevers, lymphadenopathy, expanding central nervous system lesions, and worsening of chest radiographic findings. The diagnosis of a paradoxical reaction should be made only after a thorough evaluation has excluded other etiologies, particularly tuberculosis treatment failure. Nonsteroidal antiinflammatory agents may be useful for symptomatic relief. For severe paradoxical reactions, prednisone (1--2 mg/kg per day for 1--2 weeks, then in gradually decreasing doses) may be used, although there are no data from controlled trials to support this approach.

Children

Because of the high risk of disseminated tuberculosis in infants and children younger than 4 years of age, treatment should be started as soon as the diagnosis of tuberculosis is suspected. In general, the regimens recommended for adults are also the regimens of choice for infants, children, and adolescents with tuberculosis, with the exception that ethambutol is not used routinely in children. Because there is a lower bacillary burden in childhood-type tuberculosis there is less concern with the development of acquired drug resistance. However, children and adolescents may develop "adult-type" tuberculosis with upper lobe infiltration, cavitation, and sputum production. In such situations an initial phase of four drugs should be given until susceptibility is proven. When clinical or epidemiologic circumstances suggest an increased probability of INH resistance, EMB can be used safely at a dose of 15--20 mg/kg per day, even in children too young for routine eye testing. Streptomycin, kanamycin, or amikacin also can be used as the fourth drug, when necessary.

Most studies of treatment in children have used 6 months of INH and RIF supplemented during the first 2 months with PZA. This three-drug combination has a success rate of greater than 95% and an adverse drug reaction rate of less than 2%. Most treatment studies of intermittent dosing in children have used daily drug administration for the first 2 weeks to 2 months. DOT should always be used in treating children.

Because it is difficult to isolate M. tuberculosis from a child with pulmonary tuberculosis, it is frequently necessary to rely on the results of drug susceptibility tests of the organisms isolated from the presumed source case to guide the choice of drugs for the child. In cases of suspected drug-resistant tuberculosis in a child or when a source case isolate is not available, specimens for microbiological evaluation should be obtained via early morning gastric aspiration, bronchoalveolar lavage, or biopsy.

In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions are disseminated tuberculosis and tuberculous meningitis, for which there are inadequate data to support 6-month therapy; thus 9--12 months of treatment is recommended.

The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs, and the total duration of therapy should be at least 9 months, although there are no data to support this recommendation.

Extrapulmonary tuberculosis

The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary forms of the disease. Although relatively few studies have examined treatment of extrapulmonary tuberculosis, increasing evidence suggests that 6- to 9-month regimens that include INH and RIF are effective. Thus, a 6-month course of therapy is recommended for treating tuberculosis involving any site with the exception of the meninges, for which a 9- 12-month regimen is recommended. Prolongation of therapy also should be considered for patients with tuberculosis in any site that is slow to respond. The addition of corticosteroids is recommended for patients with tuberculous pericarditis and tuberculous meningitis.

Culture-negative pulmonary tuberculosis and radiographic evidence of prior pulmonary tuberculosis

Failure to isolate M. tuberculosis from persons suspected of having pulmonary tuberculosis on the basis of clinical features and chest radiographic examination does not exclude a diagnosis of active tuberculosis. Alternative diagnoses should be considered carefully and further appropriate diagnostic studies undertaken in persons with apparent culture-negative tuberculosis. The general approach to management is shown in Figure 2. A diagnosis of tuberculosis can be strongly inferred by the clinical and radiographic response to antituberculosis treatment. Careful reevaluation should be performed after 2 months of therapy to determine whether there has been a response attributable to antituberculosis treatment. If either clinical or radiographic improvement is noted and no other etiology is identified, treatment should be continued for active tuberculosis. Treatment regimens in this circumstance include one of the standard 6-month chemotherapy regimens or INH, RIF, PZA, and EMB for 2 months followed by INH and RIF for an additional 2 months (4 months total). However, HIV-infected patients with culture-negative pulmonary tuberculosis should be treated for a minimum of 6 months.

Persons with a positive tuberculin skin test who have radiographic evidence of prior tuberculosis (e.g., upper lobe fibronodular infiltrations) but who have not received adequate therapy are at increased risk for the subsequent development of tuberculosis. Unless previous radiographs are available showing that the abnormality is stable, it is recommended that sputum examination (using sputum induction if necessary) be performed to assess the possibility of active tuberculosis being present. Also, if the patient has symptoms of tuberculosis related to an extrapulmonary site, an appropriate evaluation should be undertaken. Once active tuberculosis has been excluded (i.e., by negative cultures and a stable chest radiograph), the treatment regimens are those used for latent tuberculosis infection: INH for 9 months, RIF (with or without INH) for 4 months, or RIF and PZA for 2 months (for patients who are unlikely to complete a longer course and who can be monitored closely).

Renal insufficiency and end-stage renal disease

For patients undergoing hemodialysis, administration of all drugs after dialysis is preferred to facilitate DOT and to avoid premature removal of drugs such as PZA and cycloserine. To avoid toxicity it is important to monitor serum drug concentrations in persons with renal failure who are taking cycloserine or EMB. There is little information concerning the effects of peritoneal dialysis on clearance of antituberculosis drugs.

Liver disease

INH, RIF, and PZA all can cause hepatitis that may result in additional liver damage in patients with preexisting liver disease. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used if at all possible, even in the presence of preexisting liver disease. If serum AST is more than three times normal before the initiation of treatment (and the abnormalities are not thought to be caused by tuberculosis), several treatment options exist. One option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH. A second option is to treat with INH and RIF for 9 months, supplemented by EMB until INH and RIF susceptibility are demonstrated, thereby avoiding PZA. For patients with severe liver disease a regimen with only one hepatotoxic agent, generally RIF plus EMB, could be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months; however, there are no data to support this recommendation.

In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced hepatic injury.

Pregnancy and breastfeeding

Because of the risk of tuberculosis to the fetus, treatment of tuberculosis in pregnant women should be initiated whenever the probability of maternal disease is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. Although all of these drugs cross the placenta, they do not appear to have teratogenic effects. Streptomycin is the only antituberculosis drug documented to have harmful effects on the human fetus (congenital deafness) and should not be used. Although detailed teratogenicity data are not available, PZA can probably be used safely during pregnancy and is recommended by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months.

Breastfeeding should not be discouraged for women being treated with the first-line antituberculosis agents because the small concentrations of these drugs in breast milk do not produce toxicity in the nursing newborn. Conversely, drugs in breast milk should not be considered to serve as effective treatment for tuberculosis or for latent tuberculosis infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is recommended for all women taking INH who are either pregnant or breastfeeding. The amount of pyridoxine in multivitamins is variable but generally less than the needed amount.

Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and Guidelines from the IUATLD

To place the current guidelines in an international context it is necessary to have an understanding of the approaches to treatment of tuberculosis in high-incidence, low-income countries. It is important to recognize that the American Thoracic Society/CDC/Infectious Diseases Society of America (ATS/CDC/IDSA) recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront the disease to an important extent determine the approaches used. Given the increasing proportion of patients in low-incidence countries who were born in high-incidence countries, it is also important for persons managing these cases to be familiar with the approaches used in the countries of origin.

The major international recommendations and guidelines for treating tuberculosis are those of the WHO and of the IUATLD. The WHO document was developed by an expert committee whereas the IUATLD document is a distillation of IUATLD practice, validated in the field.

The WHO and IUATLD documents target, in general, countries in which mycobacterial culture, drug susceptibility testing, radiographic facilities, and second-line drugs are not widely available as a routine. A number of differences exist between these new ATS/CDC/IDSA recommendations, and the current tuberculosis treatment recommendations of the WHO and guidelines of the IUATLD. Both international sets of recommendations are built around a national case management strategy called "DOTS," the acronym for "directly observed therapy, short course," in which direct observation of therapy (DOT) is only one of five key elements. The five components of DOTS are 1) government commitment to sustained tuberculosis control activities, 2) case detection by sputum smear microscopy among symptomatic patients self-reporting to health services, 3) a standardized treatment regimen of 6--8 months for at least all confirmed sputum smear--positive cases, with DOT for at least the initial 2 months, 4) a regular, uninterrupted supply of all essential antituberculosis drugs, and 5) a standardized recording and reporting system that enables assessment of treatment results for each patient and of the tuberculosis control program overall.

A number of other differences exist as well

The WHO and the IUATLD recommend diagnosis and classification of tuberculosis cases and assessment of response based on sputum AFB smears. Culture and susceptibility testing for new patients is not recommended because of cost, limited applicability, and lack of facilities. Chest radiography is recommended by both the WHO and IUATLD only for patients with negative sputum smears and is not recommended at all for follow-up. Both 6- and 8-month treatment regimens are recommended by the WHO. The IUATLD recommends an 8-month regimen with thioacetazone in the continuation phase for HIV-negative patients. For patients suspected of having or known to have HIV infection, ethambutol is substituted for thioacetazone The WHO and the IUATLD recommend a standardized 8-month regimen for patients who have relapsed, had interrupted treatment, or have failed treatment. Patients who have failed supervised retreatment are considered "chronic" cases and are highly likely to have tuberculosis caused by MDR organisms. Susceptibility testing and a tailored regimen using second-line drugs based on the test results are recommended by the WHO, if testing and second-line drugs are available. The IUATLD recommendations do not address the issue. Neither baseline nor follow-up biochemical testing is recommended by the WHO and the IUATLD. It is recommended that patients be taught to recognize the symptoms associated with drug toxicity and to report them promptly.

A Research Agenda for Tuberculosis Treatment

New antituberculosis drugs are needed for three main reasons: 1) to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, 2) to improve treatment of drug-resistant tuberculosis, and 3) to provide more efficient and effective treatment of latent tuberculosis infection. No truly novel compounds that are likely to have a significant impact on tuberculosis treatment are close to clinical trials. However, further work to optimize the effectiveness of once-a-week rifapentine regimens using higher doses of the drug and using rifapentine in combination with moxifloxacin is warranted, on the basis of experimental data.

New categories of drugs that have shown promise for use in treating tuberculosis include the nitroimidazopyrans and the oxazolidinones. Experimental data also suggest that a drug to inhibit an enzyme, isocitrate lyase, thought to be necessary for maintaining the latent state, might be useful for treatment of latent tuberculosis infection.

A number of other interventions that might lead to improved treatment outcome have been suggested, although none has undergone rigorous clinical testing. These include various drug delivery systems, cytokine inhibitors, administration of "protective" cytokines such as interferon-g and interleukin-2, and nutritional supplements, especially vitamin A and zinc.

Research is also needed to identify factors that are predictive of a greater or lesser risk of relapse to determine optimal length of treatment. Identification of such factors would enable more efficient targeting of resources to supervise treatment. In addition, identification of behavioral factors that identify patients at greater or lesser likelihood of being adherent to therapy would also enable more efficient use of DOT.

Prevention

Primary Prevention

Many countries use BCG vaccine as part of their TB control programs, especially for infants. This was the first vaccine for TB and developed at the Pasteur Institute in France between 1905 and 1921.^[33] However, mass vaccination with BCG did not start until after World War II.^[34] The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in children is greater than 80%; its protective efficacy for preventing pulmonary TB in adolescents and adults is variable, ranging from 0 to 80%.^[35]

In South Africa, the country with the highest prevalence of TB, BCG is given to all children under the age of three.^[36] However, the effectiveness of BCG is lower in areas where mycobacteria are less prevalent, therefore BCG is not given to the entire population in these countries. In the USA, for example, BCG vaccine is not recommended except for people who meet specific criteria:^[20]

• Infants or children with negative skin-test results who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.
• Healthcare workers considered on an individual basis in settings in which a high percentage of MDR-TB patients has been found, transmission of MDR-TB is likely, and TB control precautions have been implemented and were not successful.

Several new vaccines to prevent TB infection are being developed. The first recombinant tuberculosis vaccine entered clinical trials in the United States in 2004, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).^[37] A 2005 study showed that a DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protect against re-infection in mice; it may take four to five years to be available in humans.^[38] A very promising TB vaccine, MVA85A, is currently in phase II trials in South Africa by a group led by Oxford University,^[39] and is based on a genetically modified vaccinia virus. Because of the limitations of current vaccines, researchers and policymakers are promoting new economic models of vaccine development including prizes, tax incentives and advance market commitments.^[40][41]

Secondary Prevention

Implementing a Respiratory Protection Program

If respirators are used in a health-care setting, the Occupational Safety and Health Administration (OSHA) requires the development, implementation, administration, and periodic reevaluation of a respiratory protection program. The most critical elements of a respiratory protection program include 1) assignment of responsibility, 2) training, and 3) fit testing. All HCWs who use respirators for protection against M. tuberculosis infection should be included in the respiratory protection program.

The health-care setting should develop a policy on the use of respirators by visitors. Visitors to AII rooms and other areas with patients who have suspected or confirmed infectious TB disease may be offered respirators (e.g., N95 disposable respirators) and should be instructed by an HCW on the use of the respirator before entering an AII room.

To be effective and reliable, respiratory protection programs must include at least the following elements:

• Assignment of responsibility to one person with sufficient knowledge who is given the authority and responsibility to manage all aspects of the program.
• Standard operating procedures that include information and guidance for the proper selection, use, and care of respirators.
• Screening by a physician or other licensed health-care professional of all HCWs who might need to use a respirator for pertinent medical conditions at the time they are hired, and then re-screening periodically.
• Annual training of HCWs with specific focus on prevention, transmission, and symptoms.
• Selection of filtering facepiece respirators approved by CDC/NIOSH.
• Fit testing performed during the initial respiratory protection program training and periodically thereafter, in accordance with federal, state, and local regulations.
• Inspection and maintenance of respirators according to manufacturer instructions.
• Evaluation of the respirator program periodically to ensure its continued effectiveness.
• Information on the development and management of a respiratory protection program is available in technical training courses that cover the basics of respiratory protection. Such courses are offered by OSHA, the American Industrial Hygiene Association, the American Conference of Governmental Industrial Hygienists, universities, manufacturers, and private contractors

Infection Control in Health-Care Settings

All health-care settings need an infection-control program designed to ensure prompt:

• detection
• airborne precautions
• treatment

of persons who have suspected or confirmed tuberculosis (TB) disease (or prompt referral of persons who have suspected TB disease for settings where persons with TB disease are not expected to be encountered). In order to be effective, the primary emphasis of the TB infection-control program should be on achieving these three goals.

In all health-care settings, particularly those in which persons who are at high risk for exposure to Mycobacterium tuberculosis work or receive care, policies and procedures for TB control should be developed, reviewed periodically, and evaluated for effectiveness to determine the actions necessary to minimize the risk for transmission of M. tuberculosis.

Overview of TB Infection-Control Measures

The TB infection-control program should be based on a three-level hierarchy of control measures. The first and most important level of the hierarchy, administrative measures, affects the largest number of persons and is intended primarily to reduce the risk of uninfected persons exposed to persons who have TB disease. These measures include the following activities:

• Assigning responsibility for TB infection control in the setting.
• Conducting a TB risk assessment of the setting.
• Developing and instituting a written TB infection-control plan to ensure prompt detection, airborne precautions, and treatment of persons who have suspected or confirmed TB disease.
• Ensuring the timely availability of recommended laboratory processing, testing, and reporting of results to the ordering physician.
• Implementing effective work practices for the management of patients with suspected or confirmed TB disease.
• Ensuring proper cleaning and sterilization or disinfection of potentially contaminated equipment (e.g., bronchoscopes, endoscopes).
• Training and educating health-care workers (HCWs) regarding TB, with specific focus on prevention, transmission, and symptoms.
• Screening and evaluating HCWs who are at risk for TB disease or who might be exposed to M. tuberculosi.
• Applying epidemiologic-based prevention principles, including the use of setting-related infection-control data.
• Using appropriate signage advising respiratory hygiene and cough etiquette.
• Coordinating efforts with the local or state health department.

The second level of the hierarchy is the use of environmental controls to prevent the spread and reduce the concentration of infectious droplet nuclei in ambient air. Primary environmental controls control the source of infection by using local exhaust ventilation (hoods, tents, or booths) and dilute and remove contaminated air by using general ventilation. Secondary environmental controls control the airflow to prevent contamination of air in areas adjacent to the source (airborne infection isolation [AII] rooms) and clean the air by using high efficiency particulate air (HEPA) filtration, or ultraviolet germicidal irradiation.

The first two control levels of the hierarchy minimize the number of areas in the health-care setting where exposure to M. tuberculosis may occur.

They reduce, but do not eliminate, the risk in those few areas where exposure to M. tuberculosis can still occur (e.g., AII rooms housing TB patients and treatment rooms in which cough-inducing or aerosol-generating procedures are performed on TB patients). Therefore, the third level of the hierarchy is the use of respiratory protective equipment in situations that pose a high risk of exposure to M. tuberculosis.

Use of respiratory protection equipment can further reduce risk for exposure of HCWs to infectious droplet nuclei that have been expelled into the air from a patient with infectious TB disease. The following measures can be taken to reduce the risk for exposure:

• Implementing a respiratory protection program
• Training HCWs on respiratory protection
• Training patients on respiratory hygiene and cough etiquette procedures.
• Determining the Infectiousness of TB Patients
• In general, patients who have suspected or confirmed TB disease should be considered infectious if (a) they are coughing, undergoing cough-inducing procedures, or have positive sputum smear results for acid-fast bacilli (AFB); and (b) they are not receiving adequate antituberculosis therapy, have just started therapy, or have a poor clinical or bacteriologic response to therapy.

For patients placed under airborne precautions because of suspected infectious TB disease of the lungs, airway, or larynx, airborne precautions can be discontinued when infectious TB disease is considered unlikely and either

• Another diagnosis is made that explains the clinical syndrome, or
• The patient produces three consecutive negative sputum smears collected in 8- to 24-hour intervals (one should be an early morning specimen).

Patients for whom the suspicion of infectious TB disease remains after the collection of three negative sputum smear results should not be released from airborne precautions until they:

• Receive standard multidrug antituberculosis treatment (minimum of 2 weeks) and
• Demonstrate clinical improvement.

For these patients, additional diagnostic approaches (e.g., sputum induction) and, after sufficient time on treatment, bronchoscopy may need to be considered.

Patients who have drug-susceptible TB of the lung, airway, or larynx, should remain under airborne precautions until they:

• Produce three consecutive negative sputum smears collected in 8- to 24-hour intervals (one should be an early morning specimen).
• Receive standard multidrug antituberculosis treatment (minimum of 2 weeks).
• Demonstrate clinical improvement.

History

Tuberculosis has been present in humans since antiquity. The earliest unambiguous detection of Mycobacterium tuberculosis is in the remains of bison dated 18,000 years before the present.^[42] However, whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor, is currently unclear.^[43] Skeletal remains show prehistoric humans (4000 BC) had TB, and tubercular decay has been found in the spines of mummies from 3000-2400 BC.^[44] Phthisis is a Greek term for tuberculosis; around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times involving coughing up blood and fever, which was almost always fatal.^[45] Genetic studies suggest that TB was present in South America for about 2,000 years.^[46] In South America, the earliest evidence of tuberculosis is associated with the Paracas-Caverna culture (circa 750 BC to circa 100 AD).^[47]

Folklore

Before the Industrial Revolution, tuberculosis may sometimes have been regarded as vampirism. When one member of a family died from it, the other members that were infected would lose their health slowly. People believed that this was caused by the original victim draining the life from the other family members. Furthermore, people who had TB exhibited symptoms similar to what people considered to be vampire traits. People with TB often have symptoms such as red, swollen eyes (which also creates a sensitivity to bright light), pale skin and coughing blood, suggesting the idea that the only way for the afflicted to replenish this loss of blood was by sucking blood.^[48] Another folk belief attributed it to being forced, nightly, to attend fairy revels, so that the victim wasted away owing to lack of rest; this belief was most common when a strong connection was seen between the fairies and the dead.^[49] Similarly, but less commonly, it was attributed to the victims being "hagridden"—being transformed into horses by witches (hags) to travel to their nightly meetings, again resulting in a lack of rest.^[49]

TB was romanticized in the nineteenth century. Many at the time believed TB produced feelings of euphoria referred to as "Spes phthisica" or "hope of the consumptive". It was believed that TB sufferers who were artists had bursts of creativity as the disease progressed. It was also believed that TB sufferers acquired a final burst of energy just before they died which made women more beautiful and men more creative.^[50]

Study and treatment

The study of tuberculosis dates back to The Canon of Medicine written by Ibn Sina (Avicenna) in the 1020s. He was the first physician to identify pulmonary tuberculosis as a contagious disease and suggest that it could spread through contact with soil and water.^[51][52] He developed the method of quarantine in order to limit the spread of tuberculosis.^[53]

Although it was established that the pulmonary form was associated with 'tubercles' by Dr Richard Morton in 1689,^[54][55] due to the variety of its symptoms, TB was not identified as a single disease until the 1820s and was not named 'tuberculosis' until 1839 by J. L. Schönlein.^[56] During the years 1838–1845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of tuberculosis sufferers into the cave in the hope of curing the disease with the constant temperature and purity of the cave air: they died within a year.^[57] The first TB sanatorium opened in 1859 in Görbersdorf, Germany (today Sokołowsko, Poland) by Hermann Brehmer.^[58]

In regard to this claim, The Times for January 15, 1859, page 5, column 5, carries an advertisement seeking funds for the Bournemouth Sanatorium for Consumption, referring to the balance sheet for the past year, and offering an annual report to prospective donors, implying that this sanatorium was in existence at least in 1858.

The bacillus causing tuberculosis, Mycobacterium tuberculosis, was identified and described on March 24, 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine in 1905 for this discovery.^[59] Koch did not believe that bovine (cattle) and human tuberculosis were similar, which delayed the recognition of infected milk as a source of infection. Later, this source was eliminated by the pasteurization process. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it 'tuberculin'. It was not effective, but was later adapted as a test for pre-symptomatic tuberculosis.^[60]

The first genuine success in immunizing against tuberculosis was developed from attenuated bovine-strain tuberculosis by Albert Calmette and Camille Guerin in 1906. It was called 'BCG' (Bacillus of Calmette and Guerin). The BCG vaccine was first used on humans in 1921 in France,^[33] but it wasn't until after World War II that BCG received widespread acceptance in the USA, Great Britain, and Germany.^[34]

Tuberculosis, or 'consumption' as it was commonly known, caused the most widespread public concern in the 19th and early 20th centuries as an endemic disease of the urban poor. In 1815, one in four deaths in England was of consumption; by 1918 one in six deaths in France were still caused by TB. In the 20th century, tuberculosis killed an estimated 100 million people.^[61] After the establishment in the 1880s that the disease was contagious, TB was made a notifiable disease in Britain; there were campaigns to stop spitting in public places, and the infected poor were "encouraged" to enter sanatoria that resembled prisons; the sanatoria for the middle and upper classes offered excellent care and constant medical attention.^[58] Whatever the purported benefits of the fresh air and labor in the sanatoria, even under the best conditions, 50% of those who entered were dead within five years (1916).^[58]

The promotion of Christmas Seals began in Denmark during 1904 as a way to raise money for tuberculosis programs. It expanded to the United States and Canada in 1907–08 to help the National Tuberculosis Association (later called the American Lung Association).

In the United States, concern about the spread of tuberculosis played a role in the movement to prohibit public spitting except into spittoons.

In Europe, deaths from TB fell from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. Improvements in public health were reducing tuberculosis even before the arrival of antibiotics, although the disease remained a significant threat to public health, such that when the Medical Research Council was formed in Britain in 1913 its initial focus was tuberculosis research.^[62]

It was not until 1946 with the development of the antibiotic streptomycin that effective treatment and cure became possible. Prior to the introduction of this drug, the only treatment besides sanatoria were surgical interventions, including the pneumothorax technique—collapsing an infected lung to "rest" it and allow lesions to heal—a technique that was of little benefit and was largely discontinued by the 1950s.^[63] The emergence of multidrug-resistant TB has again introduced surgery as part of the treatment for these infections. Here, surgical removal of chest cavities will reduce the number of bacteria in the lungs, as well as increasing the exposure of the remaining bacteria to drugs in the bloodstream, and is therefore thought to increase the effectiveness of the chemotherapy.^[64]

Hopes that the disease could be completely eliminated have been dashed since the rise of drug-resistant strains in the 1980s. For example, tuberculosis cases in Britain, numbering around 117,000 in 1913, had fallen to around 5,000 in 1987, but cases rose again, reaching 6,300 in 2000 and 7,600 cases in 2005.^[65] Due to the elimination of public health facilities in New York and the emergence of HIV, there was a resurgence in the late 1980s.^[66] The number of those failing to complete their course of drugs is high. NY had to cope with more than 20,000 "unnecessary" TB-patients with multidrug-resistant strains (resistant to, at least, both Rifampin and Isoniazid). The resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization in 1993.^[67]

See also

• 2007 tuberculosis scare
• Abreugraphy
• ATC code J04 Drugs for treatment of TB
• Buruli ulcer and leprosy: other diseases caused by mycobacteria
• Latent tuberculosis
• Mycobacterium Tuberculosis Structural Genomics Consortium
• National Center for HIV, STD, and TB Prevention
• Nontuberculous mycobacteria
• Philip D'Arcy Hart
• UNITAID
• Nosocomial infection

Further reading

External links

• Tuberculosis at the Open Directory Project
• Centers for Disease Control and Prevention (CDC), Division of Tuberculosis Elimination. Core Curriculum on Tuberculosis: What the Clinician Should Know. 4th edition (2000). Updated Aug 2003.
• (CDC) - Division of Tuberculosis Elimination News and updates.
• (CDC) - Questions and Answers About TB, 2007.
• Health Protection Agency, England - [5]
• BioHealthBase Bioinformatics Resource Center. Database of Mycobacterium tuberculosis genome sequences and related information.
• Kaiser Family Foundation. Tuberculosis. Globalhealthfacts.org.
• The Nobel Prize Website. Tuberculosis Educational Game
• United States Agency for International Development (USAID). The Tuberculosis Coalition for Technical Assistance (TBCTA).
• World Health Organization (WHO). Tuberculosis.
• Tuberculosis and HIV: HIV InSite Knowledge Base chapter and related resources.
• (CDC) Respiratory Protection in Health-Care Settings
• (CDC) Infection Control in Health-Care Settings
• (CDC) Diagnosis of Tuberculosis Disease
• (CDC) Treatment of Tuberculosis: American Thoracic Society, CDC, and Infectious Diseases Society of America
• (CDC) Tuberculosis Information for International Travelers
• (CDC) Trends in Tuberculosis, 2006 – United States

References

Acknowledgements

The content on this page was first contributed by: Ben Steinberg and members of the Osler House Staff

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