Tuberculosis

What every physician needs to know:

Tuberculosis is an infection that primarily affects the lungs but can also involve nearly every organ system in the body. It is caused by Mycobacterium tuberculosis, a slow-growing microorganism that is characteristically acid-fast; that is, it resists decolonization by acid after it has been stained. The microorganisms that cause the disease are transmitted from person to person almost exclusively by the airborne route; transmission through blood, bodily secretions, the oral/fecal route, sexual contact, casual contact, and fomites does not generally occur.

It is estimated that nearly a third of the world’s population, or some two billion people, have latent infection with M. tuberculosis. Persons with the latent form of the infection are not sick in any way, nor are they contagious; they simply harbor living organisms that are contained by their bodies’ immune systems. A person with latent infection has roughly a 5-10 percent lifetime risk of developing the active and contagious form of the disease. Treatment of latent tuberculosis, which is indicated for persons at highest risk for developing the active form of the disease, reduces the risk of progression by 60-80 percent.

Active tuberculosis on the other hand is contagious and can be fatal if untreated. Despite the availability of effective chemotherapy, tuberculosis still led to 1.3 million deaths in 2012.

Active tuberculosis is typically characterized by cardinal but somewhat non-specific clinical signs and symptoms: fever, cough and weight loss. If diagnosed promptly, most cases of active tuberculosis can be cured using a combination of antibiotics taken for 6-9 months.

Classification:

Tuberculosis exists in a latent form and an active form. Latent tuberculosis infection (LTBI) is a state of asymptomatic infection in which patients have no signs or symptoms of the disease and cannot transmit the organism to others. A small percentage of patients with LTBI will go on to develop active tuberculosis, but most will remain healthy throughout their lives.

The most common form of active tuberculosis is pulmonary tuberculosis. Eighty-five percent of all cases of tuberculosis involve the lung. Based on the appearance of tuberculosis on a plain chest radiograph, pulmonary tuberculosis is often classified as cavitary (associated with cavities, or holes, visible in the lung parenchyma) or non-cavitary.

Extra-pulmonary (outside the lung) cases of tuberculosis occur in 15 percent of patients, most often in combination with lung disease, although they may occur without lung involvement. The most common forms of extra-pulmonary tuberculosis are tuberculosis of the lymph nodes, especially the lymph nodes of the neck; tuberculosis of the bones and joints (usually the large bones and joints, such as the spine and hips); tuberculous pleuritis; disseminated (miliary) tuberculosis; genitourinary tuberculosis; and tuberculosis of the central nervous system, including tuberculous meningitis. Patients with immunocompromised states are more likely to develop TB and more likely to have extra-pulmonary manifestations.

Are you sure your patient has tuberculosis? What should you expect to find?

The principal symptoms and signs of pulmonary tuberculosis are common but somewhat non-specific. They begin slowly and so the presentation of tuberculosis is nearly always that of a sub-acute to chronic illness that develops over a period of weeks to months. The most important and common signs and symptoms are fever, cough, and weight loss. The fever is persistent and low-grade and has an insidious onset. The cough is generally productive, and in patients with the cavitary form of the disease, it may be accompanied by hemoptysis. Weight loss is responsible for the historical name for tuberculosis: consumption. Significant weight loss, to below 90 percent of ideal body weight is associated with advanced disease and a higher risk of mortality.

Patients with pulmonary tuberculosis may also complain of drenching night sweats that require a change of clothes or bedding, vague chest discomfort, or pleuritic-type pain if they have pleural involvement. Symptoms of extra-pulmonary tuberculosis are related to the organ involved: enlarged lymph nodes, back pain (from spine involvement), dysuria (in GU tuberculosis), prolonged and profound headache (with meningitis), and anemia (especially with disseminated or miliary tuberculosis).

Beware: there are other diseases that can mimic tuberculosis.

The differential diagnosis of pulmonary tuberculosis includes several other infectious diseases of the lung, as well as some non-infectious diseases. Several infections can present with the subacute to chronic illness that is typical of pulmonary tuberculosis. Overall, the differential diagnosis of tuberculosis includes infections such as pneumonia, chronic lung abscess, fungal infections of the lung, non-tuberculosis mycobacterial infections, melioidosis, and paragonimiasis, as well as lymphoma, sarcoidosis, granulomatosis with polyangiitis, hypersensitivity pneumonitis, and bronchogenic carcinoma.

How and/or why did the patient develop tuberculosis?

Tuberculosis occurs throughout the world, although twenty-two countries (the “high burden” countries) account for more than 80 percent of all cases. There are 8-12 million new cases of tuberculosis in the world each year, the vast majority of which occur in Southeast Asia (58%) and the African region (27%). China and India alone account for 40 percent of all the cases in the world each year. In general, case rates are highest in countries that have lower levels of economic development, higher levels of malnutrition, and overcrowding. In many African countries, more than half of those with tuberculosis are also infected with HIV. An estimated 0.5 million are children and 2.9 million (2.7 –3.1 million) cases occur in women.

In the developed West, tuberculosis case rates are much lower. In the United States in 2016, for example, the incidence of tuberculosis was 2.9/100,000 persons. By contrast, in the high-burden countries, case rates range between 150 and 1700 per 100,000 persons.

Tuberculosis is acquired almost exclusively by the airborne route. A person exposed to an infectious case of tuberculosis inhales organisms into the respiratory tract. In some cases, the body’s innate immune system eliminates the mycobacterium immediately and completely, and no state of latent infection develops. In many other cases, an immune response ensues that results in a state of latent infection, in which living bacteria are contained in an area of granulomatous inflammation and the patient is completely asymptomatic and not contagious. In most instances, this latent state is maintained indefinitely and no clinical illness will ever occur. However, in some cases (often if there is coincident immunosuppression), the well-formed granuloma breaks down, and the mycobacteria begin to grow and divide, causing clinical illness.

Which individuals are at greatest risk of developing tuberculosis?

Individuals at highest risk for contracting active tuberculosis include the following:

• Persons with compromised immune systems, including HIV infection (even if the individual is on anti-retroviral medications), prolonged treatment with higher doses of prednisone (more than 15 mg/day for more than 30 days), treatment with other immunosuppressives (especially TNF-alpha antagonists), and organ transplant recipients who are receiving anti-rejection therapies

• Persons who have been in close contact with someone who has active tuberculosis

• Persons who have recent evidence (within two years) of having acquired latent tuberculosis infection (e.g., health care workers whose annual testing for latent tuberculosis infection is newly positive)

• Recent (within five years) immigrants to the U.S. from high-burden countries, as more than half of all cases of tuberculosis in the U.S. occur in persons born outside the U.S.

• Persons with evidence of latent tuberculosis infection, an old tuberculosis scar on chest radiograph (e.g., an upper-lobe fibrotic scar), and no prior history of treatment for tuberculosis

• Persons with end-stage renal failure

• Persons with poorly controlled diabetes mellitus

All persons in these categories should be tested for latent tuberculosis. However, there will still be patients who present with signs and symptoms of active tuberculosis who do not fall into any of these categories, and tuberculosis should still be considered as a diagnostic possibility in those cases.

Although children and the elderly are at increased risk for tuberculosis, the mode of the age distribution for tuberculosis cases in the U.S. and around the world is in the 25-44 age group.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

The initial evaluation for most patients suspected of having tuberculosis should include a plain chest radiograph and a sputum smear examination. Sputum can be obtained through simple expectoration or by sputum induction if the patient is unable to produce an expectorated sample. Induction by inhaling nebulized hypertonic saline will often produce a satisfactory specimen. Samples may also be obtained by early-morning gastric aspiration, as organisms may migrate up the respiratory tree during sleep and be swallowed. Several studies have indicated that samples obtained via bronchoalveolar lavage are no more sensitive for diagnosis than samples obtained by sputum induction.

Conventional histology and microbiology

Sputum should be examined by microscopy for the presence of M. tuberculosis organisms either after Ziehl-Neelsen or after auramine-rhodamine staining with fluorescent microscopy. (Figure 1) The former technique is more widely available and perhaps more specific, but the latter technique is more sensitive. Overall, the sensitivity of sputum smear examination for the diagnosis of tuberculosis is roughly 50-60 percent if three samples are collected on three consecutive days. The sensitivity is higher in cases of extensive and cavitary tuberculosis and lower in non-cavitary disease.

Figure 1.

When there is a reasonable clinical suspicion of tuberculosis, a negative sputum smear examination does not rule out the diagnosis. A sample should be sent to culture at the same time sputum is sent for smear examination. Culture has excellent sensitivity (90-95%), although positive results take 10-28 days to develop if broth-based systems like mycobacterial growth indicator tubes (MGIT) are used, and longer if a solid medium like Lowenstein-Jensen agar is used. Drug-susceptibility testing should be obtained for any specimens that are culture positive so the antibiotic regimen can be adjusted if necessary.

Nucleic acid-based approaches

A useful adjunct to sputum smear examinations are recent molecular technologies that have allowed for the detection of M. tuberculosis complex DNA and common mutations that are associated with drug resistance. This includes two major types of molecular assays – (1) probe-based (non-sequencing) tests and (2) sequence-based assays.

The probe-based nucleic acid amplification testing (NAAT) confirms the presence of mycobacteria by identifying nucleic acid sequences that are unique to M. tuberculosis in sputum samples. This technique detects nearly all smear-positive cases of tuberculosis and about half of the smear-negative cases, for an overall sensitivity of 80-85 percent, and results are usually available within twenty-four hours. In addition to improved sensitivity over smear alone, NAAT confirms whether a positive sputum smear is caused by M. tuberculosis and not by another non-tuberculous mycobacteria species.

The Xpert MTB/RIF assay is another probe-based assay for detection of M. tuberculosis and rifampin resistance mutations in a region of the rpoB gene known as the rifampicin resistance–determining region. The assay may be used for sputum from adults with suspected pulmonary TB who have received fewer than three days of anti-mycobacterial therapy. Results can be available within two hours and the assay is relatively simple to perform with minimal training. The Xpert MTB/RIF assay has greater sensitivity (high 90%) than smear microscopy and very high specificity. The next generation of Xpert (Ultra) which has been endorsed by WHO and will start to be available sometime in late 2017, has a sensitivity that approaches that of culture.

Recently, highly automated technologies for nucleic acid amplification have been developed that also have the capability of rapidly identifying mutations in M. tuberculosis that are associated with drug resistance, particularly resistance to rifampin. There are also sequence-based assays under investigation that can provide more genetic information of the mutations with greater accuracy to help detect and predict drug resistance.

TST and IGRA

Tests for prior exposure to M. tuberculosis, such as tuberculin skin tests (TST) and interferon gamma release assays (IGRA), are positive in 70-80 percent of patients with active tuberculosis, but a negative test result from a TST or IGRA does not exclude tuberculosis as a diagnostic possibility, so these tests have limited utility in the evaluation of a patient with suspected active disease. Similarly, serological tests for tuberculosis, which identify antibodies against cell wall components and other antigens of M. tuberculosis, lack good sensitivity and specificity for diagnosis of active disease and should not be used.

Routine blood tests, such as complete blood counts, electrolytes, liver function tests, and erythrocyte sedimentation rate, are often useful in monitoring patients who are being treated for tuberculosis, but they are not useful diagnostically, as abnormalities in all these parameters are common in but not specific to tuberculosis patients.

What imaging studies will be helpful in making or excluding the diagnosis of tuberculosis?

Although routine chest radiography is not available in many resource-limited settings, plain chest radiograph should be obtained in every patient suspected of having tuberculosis.

The radiographic findings in tuberculosis have been well-known and well-described for many years: the classic location for abnormalities in patients with tuberculosis is in the upper lobes (Figure 2, Figure 3). Infiltrates may be unilateral or bilateral, and lesions may be cavitary (Figure 4), although many are not, and the lack of cavitation does not in any way make an upper-lobe infiltrate less likely to represent tuberculosis. Cavities tend to be thick-walled and air-fluid levels in the cavities are uncommon. At times, the lesions in the upper lobes may be subtle, in which case lordotic views can be helpful in obtaining a clearer view of the apices of the lungs. Certainly, infiltrates may occur in areas other than the upper lobes, especially in patients who are immunocompromised. A miliary pattern can be seen on plain chest radiographs in cases of disseminated tuberculosis. (Figure 5) Miliary nodules are small (1-2 mm in diameter) and are distributed throughout the lungs with a predilection for the lower lung zones.

Figure 2

Figure 3.

Figure 4.

Figure 5.

Other than parenchymal infiltrates, several other radiographic findings can represent tuberculosis. Pleural effusion is a common finding, and effusions in tuberculosis are typically small to moderate in size. At times the effusions will accompany parenchymal infiltrates, but effusions often occur with no other changes. Mediastinal or hilar adenopathy can also be the sole manifestation of tuberculosis, particularly in patients with compromised immune systems. (Figure 6) The differential diagnosis of the adenopathy includes sarcoidosis, lymphoma and metastatic carcinoma. Tuberculous lymph nodes may become necrotic (Figure 7).

Figure 6.

Figure 7.

CT of the chest is usually not required in the evaluation of patients with suspected tuberculosis when the plain radiograph shows advanced or typical findings, but it can be a useful adjunct when the plain radiograph findings are subtle or when an alternative diagnosis of the findings on plain radiography is suspected. CT is more sensitive than chest radiography for early or subtle parenchymal and nodal processes. There is no role for routine positron emission tomography (PET) scans to evaluate for TB as PET does not differentiate infection from tumor.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of tuberculosis?

Other than the laboratory tests listed above, other non-invasive tests have little role in the diagnosis of tuberculosis. Pulmonary function testing is not only generally unhelpful, but such tests should be avoided while patients are infectious. Cardiopulmonary exercise testing is also not helpful.

What diagnostic procedures will be helpful in making or excluding the diagnosis of tuberculosis?

Several tests are useful in making the diagnosis of tuberculosis, including testing for tuberculosis infection with tuberculin skin testing (TST) or by interferon gamma release assays (IGRA). IGRA are more specific than TST, but neither is sensitive or specific enough to establish a diagnosis of active tuberculosis on its own.

Sputum smear examination and sputum culture are also useful. The sensitivity of sputum smear examination is 50-60 percent, while specificity depends on the background prevalence of non-tuberculous mycobacteria in the population. Sputum culture has high sensitivity and specificity, but there are cases of active tuberculosis in which sputum cultures will be negative. Therefore, if there is a high clinical suspicion based on clinical and radiographic findings, and the patient responds to treatment, a diagnosis of tuberculosis should be considered confirmed even if cultures are negative. Up to 10 percent of cases of tuberculosis will be culture-negative.

Chest radiography is extremely helpful in diagnosing tuberculosis, although radiographic findings are not specific, and radiography alone cannot establish a diagnosis.

Flexible bronchoscopy and transbronchial biopsy have little role to play in the diagnosis of tuberculosis, as it has been convincingly demonstrated that induced sputum samples have the same diagnostic yield as bronchoalveolar lavage fluid obtained by bronchoscopy. These procedures are sometimes performed if there is significant diagnostic uncertainty and the clinician finds it necessary to rule out other diseases, such as sarcoidosis or lung cancer, or if expectorated or induced sputum samples are unavailable.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of tuberculosis?

If a tissue biopsy is performed, the typical finding of tuberculosis is necrotizing granulomas, which may also stain positive for acid-fast organisms. However, the causes of granulomatous inflammation are many, and this finding (without the presence of acid-fast organisms) in and of itself does not establish the diagnosis.

If you decide the patient has tuberculosis, how should the patient be managed?

Because of the disease’s infectious nature, the treatment of a patient with tuberculosis requires both medical and public health approaches. In the U.S., tuberculosis is a reportable condition; that is, a physician is obligated to report any case to the local health department. The health department will conduct a contact investigation so persons exposed to the patient prior to diagnosis and at the institution of treatment can have a proper medical evaluation. Case management strategies are recommended for TB care that involves case managers to help with patient education, counseling, care coordination, reminders, treatment assessments and home visits.

Because of the infectious nature of the disease, consideration should be given to protecting the general public from infection. Hospitalization is not always required, but patients should not resume work or other activities until they are no longer infectious. Patients are usually considered non-infectious when they have been on therapy for at least two weeks AND their sputum smears are negative for acid-fast organisms.

Antibiotic therapy is the only treatment that can cure tuberculosis. In cases of drug-susceptible tuberculosis (still the vast majority of all tuberculosis cases in the world), treatment consists of an intensive phase of four-drug induction phase given for two months followed by a continuation phase of four months of therapy that usually consists of two drugs. The intensive phase usually requires that the drugs isoniazid, rifampin, pyrazinamide, and ethambutol be given daily, while the continuation phase consists of isoniazid and rifampin. Daily rather than intermittent dosing in the intensive phase of therapy for drug-susceptible TB is recommended. Pyridoxine is administered with isoniazid to all patients at risk of developing neuropathy.

During therapy, patients should be examined at least once a month to assess for treatment response and adverse drug effects, and they should have sputum samples collected monthly until cultures revert to negative for at least two consecutive months. Components of the routine visit should include a history, a physical exam, vision testing for patients who are taking ethambutol, and liver function testing.

As the therapy for tuberculosis is prolonged and is often accompanied by side effects, the treating physician should pay particular attention to ensuring adherence to the therapy. Directly observed therapy (DOT) is recommended over self-administered therapy for nearly all patients who are undergoing treatment. In addition to providing medications, the best DOT programs offer medical, social, and nursing supportive care to patients; DOT has been shown to be successful in the U.S. even in difficult-to-treat populations.

In cases of drug-resistance, particularly multi-drug resistance (MDR-TB, defined as tuberculosis that is resistant to isoniazid and rifampin), therapy is prolonged and individualized, and consultation with an expert in the treatment of drug-resistant tuberculosis is strongly advised. Treatment of MDR-TB relies on several drugs that are difficult to administer and/or that have significant side effects. The most useful of the second-line anti-tuberculosis drugs are the advanced quinolones (levofloxacin and moxifloxacin) and the injectable agents (streptomycin, amikacin, and kanamycin). Recently, a relatively short (9-month) regimen for treatment of MDR TB, the so-called Bangladesh regimen, has been endorsed by WHO in selected patient populations. This regimen contains a large number of drugs and should not be used in pregnant women or persons previously treated for tuberculosis.

In some cases of MDR-TB, surgery may be a useful adjunct to antibiotics if the disease is relatively confined to a lobe or segment of the lung. Empiric therapy for MDR-TB is usually not warranted. Cases in which there should be a high index of suspicion for MDR-TB include those in which there is a prior history of self-administered treatment for tuberculosis or in which the patient is known to have been in contact with another person with active MDR-TB.

What is the prognosis for patients managed in the recommended ways?

Most patients with tuberculosis respond well to therapy and are completely cured of their disease. Cure rates for drug-susceptible tuberculosis approach 100 percent, and the relapse rate is only on the order of 3-5 percent. However, in certain cases of drug-susceptible tuberculosis, a higher relapse rate can be predicted and treatment should be prolonged to nine months. Predictors of a high relapse rate include extensive bilateral cavitary disease, persistent positive sputum culture beyond the first two months of therapy, and initial body weight that is less than 90 percent of predicted ideal body weight. Any two of these three risk factors raise the chance for relapse to 10-15 percent if treatment is discontinued after six months.

Special mention should be made of patients with HIV infection. In the era preceding the use of highly active antiretroviral therapy, mortality rates for HIV-infected patients with tuberculosis were in the range of 20 percent in the first year following diagnosis of tuberculosis. Several recent studies have shown that mortality rates can be reduced to well below 5 percent if antiretroviral therapy is instituted soon after therapy for tuberculosis is also instituted.

However, simultaneous treatment of tuberculosis and HIV infection is difficult for several reasons: the sheer number of medications (at least seven, in most cases) involved creates adherence issues, a multiplicity of drugs leads to a multiplicity of side effects, drug-drug interactions that are due mostly to rifampin’s potent activity as a cytochrome P450 inducer create problems in maintaining adequate blood levels for several of the HIV drugs, and immune reconstitution inflammatory syndrome (IRIS) can occur. Therefore, treatment of simultaneous TB and HIV infection should be undertaken with the close guidance of someone knowledgeable and experienced in this area.

For HIV-infected patients receiving antiretroviral therapy, it is suggested by the 2016 ATS/CDC/IDSA guideline to institute a standard 6-month daily regimen consisting of an intensive phase of 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a continuation phase of 4 months of isoniazid and rifampin for the treatment of drug-susceptible TB. For HIV patients not on antiretroviral therapy, it is recommended to initiate antiretroviral treatment, ideally within the first 2 weeks of TB treatment for those with CD4 cell counts of less than 50/microliter and within 8-12 weeks of TB treatment for those with CD4 cell counts of greater than 50/microliter.

Therapy is much more complicated and outcomes may be poorer for patients with MDR-TB than for those with drug-susceptible tuberculosis. If there is resistance to isoniazid and rifampin alone, the best medical therapy, sometimes combined with surgery, can achieve cure rates approaching 90 percent. For extensively drug-resistant tuberculosis (XDR-TB), which is often associated with HIV infection, outcomes have been poor and mortality rates have been high.

Patients who present with advanced pulmonary tuberculosis may have considerable residual lung damage even after they are treated and cured. Scarring of the lungs, volume loss, and bronchiectasis are all common in patients who present with extensive disease at the time of diagnosis. As a result, loss of lung capacity and chronic respiratory disease may be seen in some patients who have been cured of their tuberculosis.

What other considerations exist for patients with tuberculosis?

Patients with tuberculosis are often faced with an unfortunate and unfair social stigma of which caregivers should be aware, as it has the potential to affect the patient adversely in many ways. Many patients with tuberculosis live at the margins of society, and caregivers should be sensitive to their economic and social circumstances. Patients may need referral to a range of social services, including those for housing, substance abuse counseling, legal services, and mental health.

All patients with tuberculosis should receive HIV testing.

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