Tuberculosis

Author: Dr Charles L. Daley National Jewish Health 2008-07-28

Introduction

Tuberculosis is a disease that is spread from person-to-person through the air. It is caused by Mycobacterium tuberculosis, a slowly growing bacterium that is resistant to most antibiotics and, thus, difficult to treat. Despite the availability of effective therapy since the 1950’s, there are more cases of tuberculosis in the world today than in recorded history.
Left untreated, tuberculosis can kill approximately one half of patients within five years and produce significant morbidity (illness) in others. It is estimated that one-third of all HIV-infected patients die from tuberculosis and that it kills more adults than any other infectious disease. Inadequate therapy for tuberculosis can lead to drug-resistant strains of M. tuberculosis that are even more difficult to treat; the drugs needed to treat these strains are associated with more drug toxicities and greatly increased costs. This knol will review what is known about tuberculosis and how we diagnose and treat the disease.

What is tuberculosis?

Tuberculosis is a disease caused by infection with bacteria belonging to the Mycobacterium tuberculosis complex. These organisms include Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, and Mycobacterium canettii. Of these mycobacteria, M. tuberculosis is the most recognized and most common cause of tuberculosis, although all members of the complex (except M. microti) can cause disease (tuberculosis) in humans. Infection with the tubercle bacillus usually involves the lungs, but any area of the body can be involved. In the United States, approximately 18% of reported cases are extrapulmonary (outside of the lungs). The most common sites of involvement are depicted in Figure 1.

M. tuberculosis is a slowly growing bacterium that forms visible colonies on culture media after several days to weeks. The colonies are typically rough and nonpigmented on agar media (a sterile Petri dish with a medium that prompts growth) (Figure 2).

Tuberculosis, like all mycobacteria, has a thick lipid cell wall that resists staining with many dyes. The only true reservoir for the tubercle bacillus is the human; M. tuberculosis does not exist in the environment.

Tuberculosis – A historical perspective

Genetic studies suggest that M. tuberculosis has been present for at least 15,000 years. Evidence of tuberculosis in humans dates back to 2400-3400 B.C where mummies have been shown to have evidence of disease in their spines. Hippocrates created the term phithis, or consumption, in 460 BC, because of the significant weight loss associated with the disease. Despite its frequency at the time, the cause of tuberculosis was unknown.
By the 17^th century, anatomical and pathological descriptions of tuberculosis began to appear in the medical literature. The contagious nature of the disease was suspected as early as 1546 when Girolamo Tracastoro wrote that bed sheets and clothing of a consumptive could contain contagious particles. In 1720, Benjamin Marten, an English physician, was the first to suspect that tuberculosis could be caused by “minute leaving creatures” and that by coming into contact with a consumptive an individual could contract the disease.
In a landmark study, the French army physician Jean-Antoine Villemin demonstrated in 1865 that tuberculosis could be transmitted from humans to animals and hypothesized that a specific organism caused the disease. It was not until 1882, however, that Robert Koch convincingly demonstrated that M. tuberculosis was the cause of tuberculosis.
Despite the identification of the causative agent, treatment was elusive. The sanatorium movement, which had begun slowly in the mid 19^th century, became widespread during the early to mid 20^th century. In addition to bed rest and clean air, some patients had their lungs collapsed or surgically resected (partially removed). It was not until 1943 that Selman Waksman discovered a compound that acted against M. tuberculosis, called streptomycin. The compound was first given to a human patient in November 1949 and the patient was cured. Subsequently, it was noted that some patients who received streptomycin improved only to become ill again because the tubercle bacillus had developed resistance to the drug. It was not until the development of additional anti-tuberculosis drugs that truly effective therapy became a reality.

How does one get tuberculosis?

Tuberculosis is spread from person-to-person through the air. When someone with an infectious case of pulmonary tuberculosis coughs, they create an infectious aerosol containing small droplet nuclei. Each of these small droplet nuclei can contain tubercle bacilli and remain adrift in the air for hours. If an unsuspecting individual was to enter the same airspace and inhale these bacilli, they can become infected. The tubercle bacilli are usually deposited in the lower lung zones where ventilation is the greatest. A local inflammatory reaction develops in the lung, which is usually asymptomatic. With time the organisms make their way to the lymphatic system and blood stream where they can spread throughout the body. Once infected by the tubercle bacillus, one of two things will occur: 1) the individual’s immune system contains the spread of the infection and the person becomes latently infected or 2) the individual’s immune system is unable to contain the infection and the person develops active tuberculosis.
Studies have shown that about 10% of infected individuals will develop active disease during their lifetime (1). Of those who develop tuberculosis, approximately 50% will do so in the first 1-2 years after infection and this is referred to as primary tuberculosis. For the other 50% of infected individuals, disease develops years to decades later and this form of tuberculosis is referred to as post-primary or reactivation tuberculosis. If the tuberculosis is in the lungs, the bacilli can be expelled into the air, infect others, and continue the cycle of tuberculosis infection and disease.

Epidemiology

Tuberculosis remains one of the most deadly diseases in the world affecting a staggering number of the world’s population. It is estimated that each year more than 8-9 million new cases of tuberculosis occur and approximately 2-3 million persons die from the disease, including approximately one-third of HIV-infected patients (2). Ninety-five percent of the tuberculosis cases occur in developing countries where there are few resources and where HIV infection may be common. The large number of tuberculosis cases arises from an even larger population of persons infected with the causative agent, M. tuberculosis. It is estimated that one-third of the world’s population has tuberculous infection.
 Areas that have a high incidence of HIV infection are particularly vulnerable to increases in tuberculosis case rates. Not surprisingly, some of the highest rates of tuberculosis occur in sub-Saharan Africa where the prevalence of HIV-infection is very high.
In the United States, the number of tuberculosis cases has been declining since 1992, however the decline in cases has begun to plateau (3) .
Although there has been a decrease in the number of cases that are reported in U.S.-born individuals, the number of cases in people born outside of the U.S. has failed to decline .

Why is there so much drug-resistant tuberculosis?

Recent reports of patients with highly resistant forms of tuberculosis have highlighted the emergence of drug-resistance globally and the need for improved tuberculosis control (4). During the 1990’s multidrug-resistant tuberculosis (MDR-TB), defined as resistance to isoniazid and rifampin (our two best drugs for treatment of tuberculosis), began to emerge both in the United States and worldwide. Today, it is estimated that there are 400,000 cases of MDR-TB, globally. An outbreak of extensively drug-resistant tuberculosis (XDR-TB), (defined as MDR-TB with additional resistance to fluoroquinolones and at least one of the following injectables: capreomycin, amikacin, or kanamycin) in South Africa highlighted the fact that even more resistant strains are spreading. Reports have documented XDR-TB in over 40 countries and it is estimated that there are nearly 30,000 XDR-TB cases, globally. Between 1993 and 2006, there were 49 cases of XDR-TB reported in the United States (5).
Drug resistance is created when patients with tuberculosis are not treated adequately either because:

• The patient does not take the drug treatment regimen as prescribed (nonadherent) or
• The treating physician or program does not treat the patient with the appropriate drug regimen.

Once drug-resistant tuberculosis is created it can then be spread to other susceptible individuals. HIV-infected patients have helped to amplify the global drug resistance problem because HIV-infected patients with tuberculosis are more likely to acquire drug resistant tuberculosis (particularly rifampin-resistant) and are more likely to develop tuberculosis once infected.

Despite the availability of effective treatment regimens there are more drug-resistant cases of tuberculosis today than at any time in history. Ineffective tuberculosis control programs in resource poor areas have contributed to the spread of the disease.

What are the risk factors for getting tuberculosis?

Anyone can become infected with M. tuberculosis simply by breathing in the bacillus that has been expelled into the air by an infectious patient. However, the probability that infection would occur is based on the prevalence of tuberculosis in someone’s environment. Someone living in a crowded high incidence area is more likely to come in contact with an infectious case than is someone living in a remote low incidence area where the chance of coming into contact with an infectious case is very low. Individuals or groups that are more likely to be exposed to tuberculosis and/or become infected include (6):

• Close contacts of persons known or suspected to have TB
• People born outside of the United States, including children, from areas that have a high incidence of TB
• Residents and employees of high-risk congregate settings
• Health care workers who serve high-risk clients
• Some medically underserved, low income populations, defined locally as having an increased prevalence of TB
• Infants, children, and adolescents exposed to adults in high-risk categories
• Persons who inject illicit drugs and other locally identified high-risk substance abusers like crack cocaine users.

About 30% of those in contact with infectious cases of pulmonary tuberculosis will become infected with M. tuberculosis. However, as noted previously not all infected persons will develop tuberculosis. Some individuals have a higher probability of progressing to active disease such as:

• Persons with HIV infection
• Persons who were recently infected with M. tuberculosis (within the past two years), particularly infants and very young children
• Persons who have certain medical conditions known to increase the risk of disease if infection occurs (see below)
• Persons who inject illicit drugs and other locally identified high-risk substance abusers like crack cocaine users.
• Persons with a history of inadequately treated TB

There are certain medical conditions that increase the risk of developing tuberculosis once infected with M. tuberculosis. The condition that confers the greatest risk of progressing to tuberculosis is underlying HIV infection. HIV-infected persons have a much greater risk of developing tuberculosis than those not infected with HIV. HIV-infected persons are more likely to progress rapidly to disease, develop post-primary disease, and become re-infected with a new strain of M. tuberculosis than those not infected with HIV.
Others at high risk for developing tuberculosis once infected with M. tuberculosis include:

• People taking immunosuppressive drugs (e.g., steroids, tumor necrosis alpha antagonists)
• People with one or more of the following conditions:
• diabetes mellitus
• silicosis (lung disease caused by inhaling silicon dust)
• end-stage renal disease
• head and neck carcinoma
• hematogenous malignancies (e.g, leukemia, lymphoma)
• malignancies of the head and neck
• gastric/intestinal bypass
• weight loss of ≥ 10% of ideal body weight

How is tuberculosis diagnosed?

 In order to diagnose tuberculosis, the clinician must first suspect it. Symptoms that would lead a clinician to consider tuberculosis would include fever, chills, night sweats, appetite loss, weight loss, and cough (usually of 3 weeks duration or more). When extrapulmonary tuberculosis occurs, the symptoms will vary depending on the involved site.
When a clinician suspects tuberculosis, he or she should assess whether the patient has had contact with a case of infectious tuberculosis, whether they have had tuberculosis or latent infection in the past, and what risk factors they may have for tuberculosis, especially HIV infection.
A physical examination may detect enlargement of lymph nodes, particularly in the cervical area (neck). Evidence of weight loss is consistent with a diagnosis of tuberculosis, but none of these signs can rule in or rule out tuberculosis.

A chest x-ray should be obtained in persons suspected of having tuberculosis. Most adults have evidence of upper lobe abnormalities on the chest x-ray with cavities (holes in the lung) (Figure 8). In children and patients with HIV-infection, enlargement of the lymph nodes is common and the disease may be seen in the lower lung zones.
When someone is suspected of having pulmonary tuberculosis, three sputum specimens are collected and examined to try to identify M. tuberculosis (7). Specimens are collected on three separate days, usually in the morning. Alternatively, specimens can be collected every eight hours with at least one early morning specimen. For patients unable to cough up sputum, coughing can be induced by inhalation of hypertonic saline (three to 10%). Bronchoscopy can be performed if respiratory specimens cannot be obtained through coughing although the chance of identifying M. tuberculosis in specimens obtained by bronchoscopy is similar to that of specimens obtained through sputum induction.
Young children often cannot cough up sputum and bronchoscopy has been shown to have a relatively low chance of identifying M. tuberculosis. Therefore, aspirates (samples) of gastric fluids are obtained and cultured. Typically, the aspirate is obtained in the early morning before the child gets out of bed or eats.
In patients with extrapulmonary tuberculosis, clinical specimens are obtained from whatever site is involved. Aspiration or biopsy of cervical lymph nodes has a high probability of finding acid-fast bacilli (AFB) on a smear and in culture whereas the chance of finding AFB in cerebrospinal fluid is relatively low. Similarly, the chance of obtaining mycobacteria from pleural (the area around the lungs) fluid is low, but the yield can be increased (close to 80%) if a biopsy of the pleura is obtained.
In most of the world, sputum specimens (and other respiratory specimens) are examined by smear microscopy to identify evidence of AFB . Because all mycobacteria are acid-fast, the presence of AFB in the clinical specimen only provides preliminary evidence of tuberculosis. Moreover, many cases of tuberculosis are smear negative. In high incidence areas, a positive AFB smear is almost always due to tuberculosis. However, in low incidence areas, a positive AFB smear is likely due to nontuberculous mycobacteria. Consequently, fluorochrome staining with auramine-rhodamine is the preferred method because it is faster and more sensitive than traditional methods such as Ziehl-Neelsen or Kinyoun stains.
Definitive diagnosis of tuberculosis depends on isolation of M. tuberculosis from persons suspected of having the disease.  Cultures of respiratory specimens will detect M. tuberculosis in over 85% of cases of pulmonary tuberculosis with results becoming available within seven to 14 days in liquid culture systems and three to eight weeks with solid media (7). However, cultures are often not available in many resource-poor countries, which are the countries that often have the highest incidence of tuberculosis.
Once growth has been detected, the species of mycobacteria must be identified. Species identification can occur through biochemical means but this can take up six to 12 weeks. More rapid tests, such as the AccuProbeÒ test (Gen-Probe, Inc., San Diego, CA), that detect specific nucleic acid sequences in the culture material can provide species-specific identification in two to four hours (7).
Nucleic acid amplification tests, such as the polymerase chain reaction and other methods of amplifying DNA or RNA, can facilitate rapid detection of M. tuberculosis directly in a sputum specimen (without having to wait for a culture to become positive). In the United States there are two commercial assays that are available, the Amplified MTD (Mycobacterium Tuberculosis Direct) test (Gen-Probe, Inc., San Diego, CA) and the Amplicor MTB test and COBAS Amplicor MTB test (Roche Molecular Diagnostics, Pleasonton, CA). These tests can rapidly determine whether the clinical specimen has nucleic acids from M. tuberculosis versus another mycobacterial species. In general both perform best in AFB smear positive cases compared with smear negative cases. Only the Amplified MTD test is FDA approved for use in both AFB smear positive and negative specimens.
In persons who have a positive culture, drug susceptibility tests are performed in order to detect the possibility of drug resistance.  By growing the bacilli in media containing different concentrations of anti-tuberculosis drugs, we are able to determine which drugs have activity against a patient’s isolate (strain) of M. tuberculosis. We can then tailor therapy to the individual’s specific isolate of M. tuberculosis.

How is latent tuberculosis infection diagnosed?

For decades, evidence of skin test reactivity to tuberculous antigens has been used to determine if someone has latent tuberculosis infection (LTBI) (6). The Mantoux tuberculin skin test (TST) has been the standard method of identifying persons with LTBI. The Mantoux tuberculin skin test is performed by injecting 0.1 ml of purified protein derivative (PPD) intradermally (between layers of skin) into the volar (inner) surface of the forearm (http://www2a.cdc.gov/podcasts/player.asp?f=3739). An individual who has been trained to read skin tests should read the test 48 to 72 hours later. The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis). The amount of erythema (redness) is not measured.
The appropriate cutoff for defining a positive TST depends on the individual’s risk factors for tuberculosis (6) (Table 1). For persons who are severely immunocompromised, have scarring on the chest x-ray, or have had recent contact with infectious cases, a reaction size of ≥ 5 mm is considered positive. If an individual has no risk factors for tuberculosis, ≥ 15 mm is considered positive and ≥ 10 mm is considered positive for everyone in between (some risk factors, but not all of the ones listed above).

Table 1. Classification of the Tuberculin Reaction

≥ 5 mm	≥ 10 mm	≥ 15 mm
HIV positive person	Recent arrivals (< 5 years) from high prevalence countries	Persons with no known risk factors
Recent contacts of TB case	Injection drug users
Persons with fibrotic lesions on the chest x-ray consistent with TB	Residents and employees of high-risk congregate settings
Patients with organ transplants and other immunosuppressed patients	Mycobacteriology laboratory personnel
	Persons with medical conditions that place them at high- risk
	Children < 4 years of age, or children and adolescents exposed to adults in high-risk categories

Delayed type hypersensitivity reactions to tuberculin can decrease over time. If a person is skin tested years after their initial infection, the reaction may be falsely negative. However, a TST may stimulate or “boost” immune recall to the tuberculin antigens so that a repeat TST will be positive. This is considered a true positive reaction. Repeated skin testing in persons who are not infected with M. tuberculosis or other cross-reacting antigens should not induce a positive TST result. A boosted reaction can sometimes be misinterpreted as a skin test conversion (changing from a negative to a positive reaction) that would suggest recent infection with M. tuberculosis. In actuality, the person was not recently infected but had been infected in the remote past and their immune system had “forgotten” that it had seen the tuberculosis antigens previously.
Two-step testing is used to reduce the likelihood that a boosted reaction is misinterpreted as a recent infection. In two-step testing, an initial TST is placed and read after 48 to 72 hours. If the TST reaction is classified as negative, another TST is placed in 1-3 weeks and read as usual. If the second TST is negative, the individual is considered TST negative and not infected with M. tuberculosis. However, if the second TST is positive, the person is considered to have LTBI but not as a result of recent infection. A positive reaction to subsequent TST would be considered a new infection. Two-step testing is recommended in the initial assessment of adults who will be retested periodically, such as health care workers.
As with any test, there can be false positive and false negative results. False negative results can occur in persons who are immunocompromised (e.g, HIV infection, on immunosuppressive drugs), in persons who have recent TB infection, in very young children (< 6 months), for several weeks after live virus vaccination, and with overwhelming tuberculosis. False positive tests can be caused by cross-reactive antigens such as those contained in other mycobacterial species and Bacillus of Calmette and Guérin (BCG) vaccine. Because BCG is widely used in countries with a high incidence of TB, it is a common cause of false positive TST results.
More recently, new blood-based tests referred to as interferon-gamma release assays have been developed to identify latent infection (8). These assays utilize specific antigens found almost exclusively in organisms in the M. tuberculosis complex and not M. bovis BCG (the organism used to create the BCG vaccine). Therefore, unlike with the TST, past BCG vaccination should not cause a false positive result.
There are two commercially available interferon-gamma release assays, the QuantiFERON-TB Gold (QFT) test (Cellestis, Carnegie, Victoria, Australia) and the T-Spot.TB Test (Oxford Immunotec, Oxford, United Kingdom). The QFT test works by stimulating peripheral blood monocytes (PBMCs) with three specific antigens (TB 7.7, ESAT-6, CFP-10) and measuring the amount of interferon-gamma that is released into the plasma. The T-Spot.TB Test uses ESAT-6 and CFP-10 to stimulate PBMCs and identifies the number of cells that are producing interferon-gamma. Based on numerous studies, it appears that the QFT and T-Spot.TB assays are more sensitive and specific than the TST. The T-Spot.TB assay is more sensitive than the QFT but less specific. However, there are still question regarding the performance of these new assays in young children and immunocompromised individuals.

How is tuberculosis treated?

General Concepts

Drug resistance occurs in M. tuberculosis through random mutations in the organism’s genome. In any population of M. tuberculosis, the frequency of these mutations varies depending on the drug. If a patient with active tuberculosis is treated with only one drug, the drug-resistant mutants survive and grow to become the predominant population. Studies have shown that if a patient with pulmonary tuberculosis is treated with isoniazid alone, approximately 70% of the patients will develop isoniazid-resistant tuberculosis in a matter of weeks to months (9). Thus, all patients with active tuberculosis must be treated with two or more anti-tuberculosis drugs in order to prevent drug resistance.
The anti-tuberculosis drugs that are available work through different mechanisms and at different sites in the body. For example, isoniazid is most active in extracellular (outside the cell) locations and exerts its activity on organisms that are dividing rapidly. Rifampin works in both intra- and extracellular locations and is able to kill M. tuberculosis when it is growing is spurts. Pyrazinamide works in acid environments. Thus, the anti-tuberculosis drugs are able to kill the tubercle bacilli in different compartments within the body and at different growth rates.

Anti-tuberculosis drugs

The anti-tuberculosis drugs are typically divided into several groups based on their activity against M. tuberculosis. The “first-line” drugs, which are used to treat drug susceptible tuberculosis, include isoniazid, rifampin, ethambutol, and pyrazinamide. These are some of the most potent and best tolerated of the anti-tuberculosis drugs. When patients have drug-resistant tuberculosis, other drugs often referred to as “second-line” drugs are needed. These drugs include the fluoroquionlones, cycloserine, ethionamide or prothionamide, para-aminosalicylic acid, and several injectable agents such as streptomycin, capreomycin, kanamycin, and amikacin. In patients with highly drug-resistant tuberculosis, “third-line” drugs are used which are usually less potent, have more side effects, and are more expensive than first and second-line drugs.

• Isoniazid is one of the most potent anti-tuberculosis drugs and is effective at preventing the emergence of drug resistance when given with another anti-tuberculosis drug. Side effects include nausea and vomiting, skin rash, liver inflammation (hepatitis), and tingling and numbness of the hands and feet (neuropathy).
• Rifampin is also a potent anti-tuberculosis drug that not only prevents the emergence of resistance when given with another drug, but also allows for shortening of the treatment regimen. The typical duration of therapy for drug resistant tuberculosis is six months but if rifampin is not used, the duration of therapy increases to 12-18 months! Side effects include nausea and vomiting, diarrhea, skin rash, liver inflammation (hepatitis), flu-like symptoms, and an orange discoloration of body fluids, including tears, which can permanently stain soft contact lenses. Rifampin is metabolized in the liver and can interact with numerous drugs in such a way as to lower the serum concentration of those drugs. Therefore it is very important to review any drugs that are being taken with rifampin.
• Ethambutol is a less potent drug than isoniazid or rifampin but helps prevent the emergence of drug resistance. Side effects include skin rashes, decreased visual acuity and red-green color blindness (optic neuritis), and tingling and numbness in the hands and feet (neuropathy). At the currently used doses, the visual problems are rare.
• Pyrazinamide, like rifampin, allows for shortening of the treatment regimen. When pyrazinamide is not used, the treatment duration increases from six to nine months. Side effects include skin rashes, joint aches, and liver inflammation.

Treatment Regimen

Patients with drug susceptible tuberculosis are treated with a four-drug regimen that is administered for six months (9). The regimen includes the first-line drugs isoniazid, rifampin, ethambutol, and pyrazinamide. After the first two months of therapy, pyrazinamide and ethambutol are discontinued. Isoniazid and rifampin are continued for another four months to complete the 6-month regimen. Medications can be administered daily, twice a week, or three times a week, with similar results. The expected outcomes with this treatment regimen are excellent with few treatment failures and relapse rates of only 2-3%.
A health care worker usually administers the treatment regimen under direct observation. This directly observed therapy (DOT) ensures that each drug is taken as prescribed and allows for close monitoring for response to therapy and drug-related side effects and toxicities. DOT can be provided in the clinic or in the field at the patient’s home or place of work. In some circumstances patients take the medicine themselves and this form of therapy is referred to as self-administered therapy.
Patients are monitored closely during therapy to ensure adherence to the treatment regimen and to monitor for response and potential drug toxicities. Each drug has specific drug side effects and potential drug toxicities as noted previously. Three of the four anti-tuberculosis drugs can produce inflammation in the liver (hepatitis) so patients are monitored for evidence of hepatitis by periodic blood examinations. Rifampin causes an orange discoloration of body fluids, which resolves when the drug is no longer being taken. Ethambutol can produce inflammation in the optic nerve so periodic assessments of visual acuity and red/green color blindness are performed. Pyrazinamide commonly causes some aching of the joints and, rarely, it can incite an attack of gout.  In addition, pyrazinamide can produce hepatitis.
Most patients who have pulmonary tuberculosis will respond quickly to therapy with improvement in symptoms and eventually conversion of sputum cultures to negative. After two months of treatment, approximately 80% of pulmonary cases will have negative sputum cultures.

Special Situations

HIV Infection
HIV-infected patients are treated with the same treatment regimen and for the same duration as HIV-uninfected patients with tuberculosis with two exceptions:

• 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 rifampin.
• HIV-infected patients with CD4 cell counts <100/ml should receive daily or three times weekly treatment because acquired rifampin resistance has been noted among HIV-infected patients with advanced disease who received twice-weekly therapy.

Management of HIV-related tuberculosis is complex because of possible drug interactions between anti-tuberculosis drugs and anti-retroviral drugs. The rifamycins (rifampin and rifabutin) induce certain enzymes (cytochrome P450 isoenzymes) that increase the metabolism of anti-retroviral drugs, reducing the serum concentration of the drug and possibly leading to the development of resistance to the anti-retroviral drugs (10). Some of the anti-retroviral drugs can either inhibit or induce these same enzymes affecting the metabolism of some rifamycins. Thus, appropriate dosing of both the rifamycins and anti-retroviral medications can be very complex. The reader is directed to specific recommendations at the CDC website,
http://cdc.gov/tb/TB_HIV_Drugs/default.htm
Some HIV infected patients will experience a worsening of symptoms after starting therapy for tuberculosis. This worsening is called a paradoxical reaction or immune reconstitution and presumably occurs as a consequence of improvement in the immune system caused by anti-retroviral drugs and/or treatment of the tuberculosis itself. Signs of a paradoxical reaction may include fever (often high), increase in the size of lymph nodes, new lymph node enlargement, expanding central nervous system lesions (tissue damage) or appearance of new ones, and worsening of pulmonary infiltrations or pleural effusions (excessive fluid in the space that surrounds the lungs). It is important to rule out other possible causes for the worsening such as other opportunistic infections or treatment failure.
Most patients who experience a paradoxical reaction can be treated with assurance and antipyretic (fever-reducing) medications. However, when the reaction is severe or life-threatening corticosteroids are indicated.
Extrapulmonary tuberculosis
Tuberculosis can involve any organ or tissue in the body. Extrapulmonary sites tend to be more common in persons with impaired immunity and young children. The basic principles that underlie the treatment of pulmonary tuberculosis also apply to the treatment of extrapulmonary tuberculosis and thus the treatment regimen and duration of therapy are generally the same regardless of the site of disease.

There are two exceptions to this generalization, however. In persons who have tuberculosis of the central nervous system (meningitis) some experts recommend that treatment be extended to 9-12 months. Also, when tuberculosis involves the bone and joints, treatment should continue for six to nine months. 

     Corticosteroid treatment may be a useful adjunct in two forms of extrapulmonary tuberculosis: 1) central nervous system tuberculosis, including meningitis, and 2) disease involving the pericardium (thin layer of tissue surrounding the heart).
Children
In most of the world, children are treated with the same treatment regimen and for the same duration as adults. In the United States, some experts prefer to treat children with a three-drug regimen (excluding ethambutol) for several reasons:

• The bacillary population is lower than in adults
• The pill burden is less than with four drugs
• It is difficult to assess visual acuity to in young children being treated with ethambutol

However, it is important to use a four-drug regimen in any child suspected of having underlying drug-resistant tuberculosis, in children and adolescents who have adult-type tuberculosis, or disseminated disease. DOT should be used for all children and adolescents. The treatment duration should be extended to 9-12 months in children who have disseminated disease or meningitis. The American Academy of Pediatrics recommends that HIV-infected children should be treated for at least nine months.
Pregnancy
Untreated tuberculosis represents a far greater risk to a pregnant women and her fetus than does treatment of the disease. Infants born to women with untreated tuberculosis may have a lower body weight than usual and, in rare instances, the infant may be born with congenital tuberculosis. Therefore, treatment of tuberculosis disease is recommended when tuberculosis is considered highly likely in a pregnant woman.
In most of the world, the standard four-drug treatment regimen is used. However, in most places in the United States, a three-drug regimen is used with exclusion of pyrazinamide because of insufficient data to determine safety. When pyrazinamide is not used in the treatment regimen the duration of therapy should be nine months. Pyridoxine (B6) should be given to pregnant women who are receiving isoniazid.
Renal failure
Renal insufficiency can complicate the management of tuberculosis because the kidneys clear some anti-tuberculosis drugs. In addition, some anti-tuberculosis drugs are removed during hemodialysis. Therefore, alternation in dosing of anti-tuberculosis medications is required in patients with renal insufficiency and end-stage renal disease requiring hemodialysis. Instead of decreasing the dose of the drug, increasing the dosing interval is recommended.
Rifampin and isoniazid are metabolized by the liver so no change in dosing is required. However, ethambutol is about 80% cleared by the kidneys so a longer interval between doses is recommended (e.g., three times per week). Pyrazinamide is metabolized by the liver but its metabolites may accumulate in the setting of renal disease so a longer interval between doses is recommended. In general, anti-tuberculosis drugs should be administered after hemodialysis to avoid drug loss and facilitate DOT.
Liver disease
The treatment of tuberculosis in patients with liver disease can be complicated for several reasons:

• The risk of drug-induced hepatitis may be greater.
• The implications for worsening hepatic function are greater in someone with marginal function.
• It is more difficult to monitor for hepatic injury because of fluctuating biochemical indicators of liver disease.

There are several possible treatment options in persons with significant underlying liver disease:

• Treatment without isoniazid – Treatment with rifampin, ethambutol and pyrazinamide would still have two hepatoxic drugs (rifampin and pyrazinamide) but it would still allow for a six-month treatment duration.
• Treatment without pyrazinamide – Treatment with isoniazid, rifampin and ethambutol would require extending the duration of treatment to nine months.
• Treatment with regimens that include only one hepatotoxic drug – An example regimen might include rifampin (the least hepatotoxic), ethambutol, a fluoroquinolone, and cycloserine.
• Treatment with a regimen that includes no hepatotoxic drugs – In patients with severe unstable liver disease, a regimen that contains no hepatotoxic drugs may be necessary. Such a regimen might include an injectable drug like streptomycin, ethambutol, a fluoroquinolone, and another second-line drug. These patients are very difficult to treat so consultation with an expert is recommended.

Drug-resistant tuberculosis
Drug-resistant tuberculosis is more difficult and more costly to treat than drug susceptible disease. Once drug resistance occurs, less potent and more toxic medications are needed. The drugs used and duration of therapy will depend on the pattern of drug resistance. For example, when someone has isoniazid-resistant tuberculosis, he or she can still be treated for six months. However, with rifampin- resistance, the duration of therapy is 12-18 months depending on the regimen that is used to treat the patient. Multidrug-resistant tuberculosis (MDR-TB) typically requires treatment with at least four drugs (and often six or seven) including an injectable agent and the duration of treatment is typically 18 to 24 months beyond the time that the sputum culture becomes negative. Cure rates for MDR-TB are significantly lower than for drug susceptible disease, often averaging around 75%. XDR-TB is even more difficult to treat with cure rates as low as 30%.

When is a patient with pulmonary tuberculosis no longer considered infectious?

Infectiousness is directly related to the number of tubercle bacilli expelled into the air. Thus, only pulmonary and laryngeal tuberculosis are considered infectious (9, 11). Patients with either of these forms of tuberculosis should be considered infectious if they are:

• Coughing, are undergoing cough-inducing or aerosol-generating procedures, or have sputum smears containing AFB, AND
• Not receiving therapy, have just started therapy, or have a poor clinical or bacteriological response to therapy.

Treatment rapidly renders infectious persons noninfectious but the exact point that a person becomes noninfectious is not known. The CDC recommends that patients with drug-susceptible pulmonary tuberculosis are no longer considered infectious if they meet all of the following criteria:

• They are on adequate therapy
• They have had a significant clinical response to therapy
• They have had three consecutive negative sputum smear results from sputum collected on different days

In patients with multi-drug resistant tuberculosis, many experts recommend that the patient’s cultures must convert to negative before they are considered noninfectious.

How is latent tuberculosis infection treated?

When a high-risk person is found to have evidence of LTBI treatment may be indicated. There are at least three treatment regimens that can be considered. In the United States, latently infected individuals are treated with isoniazid alone for 6-9 months. In some cases, either because of underlying drug resistance or intolerance to isoniazid, rifampin is given for four months. The combination of isoniazid plus rifampin is also an option and can be administered for three to four months. Completion of isoniazid therapy has been shown to decrease the risk of developing tuberculosis by 70 to 95%. A careful assessment to rule out the possibility of active tuberculosis is necessary before treatment for LTBI is started.
Close contacts of patients with infectious tuberculosis may become infected but have a negative TST immediately after infection has occurred. In this setting, the contact may be treated with isoniazid or rifampin and the skin test repeated in 10 to 12 weeks. This is referred to as “window prophylaxis.” If the second TST is negative, the contact is not infected and the anti-tuberculosis drug stopped. On the other hand, if the TST becomes positive, the treatment regimen should be continued.
The risk of developing hepatitis in persons taking isoniazid is low unless they have additional risk factors for hepatitis such as alcohol use, underlying liver disease, or are taking other medications that can cause liver damage.  Similarly, peripheral neuropathy is uncommon unless other conditions such as diabetes mellitus, HIV-infection, end-stage renal disease, alcohol abuse, and malnutrition are present. For people with these conditions who are given isoniazid, as well as for pregnant women or persons with a seizure disorder, pyridoxine (10-50 mg/day) is recommended.

Is there a vaccine against tuberculosis?

The Bacille of Calmette and Guérin (BCG) vaccine is the only tuberculosis vaccine (12). BCG vaccines are live vaccines derived from a strain of M. bovis that was attenuated (made less virulent) by Calmette and Guérin at the Pasteur Institute in Lille, France in the early part of the 20^th century. The vaccine was first administered to humans in 1921. There are many different BCG vaccines available today but all were derived from the original strain. The vaccine is not used as a routine component of tuberculosis control in the United States, the Netherlands, and an increasing number of countries. Meta-analyses (analyses that review the published literature and provide summary statistics) have described a wide range of efficacy among the many BCG vaccines that have been studied ranging from 0% to 80%. In other words, in some studies BCG vaccinated persons had 80% less tuberculosis than nonBCG vaccinated persons, whereas in others no protection was provided by the vaccine. These same meta-analyses confirmed that there was protective efficacy of BCG in preventing serious forms of tuberculosis in children (> 80% protection) and represent the primary reason BCG is still used in many countries.
BCG is usually administered in the lower deltoid area (upper arm) via percutaneous injection. Normal reactions to the vaccine include a bluish-red pustule within two to three weeks of injection. After about six weeks, the pustule ulcerates forming a lesion approximately five millimeters in diameter. Scabs eventually form and the lesion heals within three months of vaccination, forming a permanent scar.
Because BCG is a live vaccine, it is contraindicated in persons who have an impaired immune response or who are immunosuppressed because of medications like corticosteroids. Although BCG vaccination can result in local adverse reactions, serious complications are rare. Reactions that can be expected are pustule formation at the injection site and enlargement of lymph nodes in the axillae (armpit). These reactions can persist for up to three months. More serious complications like disseminated BCG infection and infection of the bone are rare.
In the United States, BCG is rarely used. BCG vaccination should be considered for an infant or child who has a negative tuberculin skin test result in the following circumstances:

• The child is exposed continually to an untreated or ineffectively treated patient who has infectious pulmonary tuberculosis, and the child cannot be separated from the infectious patient or given long-term primary preventative therapy; or
• The child is exposed continually to a patient who has infectious pulmonary tuberculosis caused by a strain of M. tuberculosis resistant to isoniazid and rifampin (MDR-TB), and the child cannot be separated from the infectious patient

In rare occasions health care workers or other individuals who will be exposed to MDR-TB frequently have been vaccinated although there is not evidence that this practice is effective.

More information

Web resources

1. American Thoracic Society, www.thoracic.org
2. Centers for Disease Control and Prevention, www.cdc.org
3. World Health Organization, Stop TB Partnership, www.stoptb.org
4.  Francis J. Curry National Tuberculosis Center, www.nationaltbcenter.edu
5. Heartland National Tuberculosis Center, www.heartlandntbc.org
6. International Union Against Tuberculosis and Lung Disease, www.iuatld.org
7. Johns Hopkins Center for Tuberculosis Research, www.jhsph.edu/dept/IH/Centers/TB_Research.html
8. National Jewish Medical and Research Center, www.nationaljewish.org
9. Northeastern Regional Training and Medical Consultation Consortium, www.umdnj.edu/globaltb/home.htm
10. Southeastern National Tuberculosis Center, sntc.medicine.ufl.edu

Books about tuberculosis

1. Lee Reichman, Timebomb
2. Frank Ryan, The Forgotten Plague
3. Renee and Jean Dubois, The White Plague-Tuberculosis, Man and Society
4. Thomas Daniel, Captain of Death: The Story of Tuberculosis
5. Toney Allman, Tuberculosis
6. Ending Neglect: The Elimination of Tuberculosis in the United States, Institute of Medicine

References
1. Hopewell PC. Factors influencing the transmission and infectivity of Mycobacterium tuberculosis: implications for clinical and public health management. Respiratory Infections. Churchill Livingstone, New York. 1986:191-216.
2. World Health Organization. Global tuberculosis control. surveillance, planning, financing. WHO report 2007 (WHO/HTM/TB/2007.376).
3. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2006. Atlanta, GA: U.S. Department of Health and Human Servies, CDC, September 2007.
4 Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs, worldwide, 2000-2004. MMWR 2006;55(No.11):301-305.
5. Centers for Disease Control and Prevention. Extensively drug-resistant tuberculosis, United States, 1993-2006. MMWR 2007;56:1-6.
6. Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(No. RR-6):1-51.
7. Dunlap NE, Bass J, Fujiwara P, Hopewell P, Horsburgh CR, Salfinger M, Simone PM. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:1376-1395.
8. Centers for Disease Control and Prevention. Guidelines for the investigation of contacts of persons with infectious tuberculosis; recommendations from the National Tuberculosis Controllers Association and CDC and Guidelines for using the QuantiFERON®-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR 2005;54(No. RR-15):1-55.
9. Centers for Disease Control and Prevention, American Thoracic Society, and Infectious Diseases Society of America. Treatment of Tuberculosis. MMWR 2003;52 (No. RR-11)1-77.
10. Centers for Disease Control and Prevention. Updates guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2004;53:37.
11. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR 2005;54(No.-17):1-141.
12. Centers for Disease Control and Prevention. The role of BCG vaccine in the prevention and control of tuberculosis in the United States: a joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. MMWR 1996;45(No. RR-4):1-18.