Tuberculosis

Tuberculosis; active and latent tuberculosis

Also known as: Mycobacterium tuberculosis, M tb, TB, phthisis, positive PPD

Related conditions: Pulmonary TB, Pott’s disease

1. Description of the problem

What every clinician needs to know

One third of the world’s population is infected with Mycobacterium tuberculosis (M tb) In the United States, clinicians may miss the diagnosis in critically ill patients because it is uncommon in people born in the United States and may present in atypical ways in the intensive care unit (ICU). Clinicians need to consider tuberculosis (TB) in the differential diagnosis in any patient from an endemic area who presents with a pulmonary or systemic, infectious or inflammatory process that eludes diagnosis by routine bacterial cultures and other testing.

Clinical features

Systemic symptoms of TB include fever, cough hemoptysis, night sweats, anorexia, weight loss, and anemia (of chronic disease). Some patients are asymptomatic or do not realize that they have symptoms due to the long course of the illness. About 80% of patients have lung-related symptoms and the rest have extrapulmonary TB.

Extrapulmonary TB may affect the bones, genitourinary tract, lymph nodes, bone marrow, intestines, central nervous system, or skin and soft tissue (Figure 1, Figure 2, Figure 3).

Some patients, including those who are immunocompromised, may have disseminated disease often called “miliary TB” with millet-seed-size lesions in the lungs and TB in almost all organ systems including positive blood cultures.

Figure 1.

Figure 2.

Figure 3.

Factors that should prompt consideration of TB in the differential diagnosis

• History of TB infection (positive tuberculin test)
• History of TB disease, particularly if never or inadequately treated
• Contact with known or suspected TB case
• Presence of fibrotic lung lesions or upper lobe scars compatible with inactive TB
• Immigration from countries with high risk for TB
• Advanced age
• Institutional exposure (congregate living)
• Known or suspected HIV infection
• Other immunosuppressed states

2. Emergency management

When the clinician suspects TB, the primary emergency is to collect specimens that will help diagnose the infection. The second problem is to quarantine the patient in a way that protects others from being infected with this mycobacteria. It is almost never an emergency to deal with a positive tuberculin skin test (TST or PPD).

If the patient has an abnormal chest x-ray, suggesting active TB, then it is necessary to find out if the patient has TB in a contagious form. That requires sputum collection for AFB smear and culture, and sometimes the best place for the patient is at home, as long as there are no children under 5 years old. If patients with a suspicion of TB are admitted to a medical facility, then they should be placed in a negative-pressure room and staff should use N-95 respirators (masks or other personal protective devices).

Chest radiographs

Routine chest radiography is an invaluable diagnostic and screening test for patients at risk for TB. Patients with intact immunity and pulmonary TB usually have an abnormal chest x-ray; however, patients with HIV infection may occasionally have culture-positive pulmonary TB despite normal pulmonary radiographs.

The usual radiographic pattern of primary TB is a lower lobe infiltrate with ipsilateral hilar adenopathy in primary TB (especially in children) or in reactivation disease a classic pattern of fibrotic and cavitary infiltrates in the apical segment of the upper lobe or superior segment of the lower lobes (Figure 4).

Figure 4.

It is important for clinicians to recognize the radiographic patterns of upper lobe parenchymal scars or calcified granulomas representing fibrotic foci of healed inactive tuberculosis. In contrast, in patients with miliary tuberculosis, radiographs may initially be normal or show miliary nodules of 1 to 3 mm in diameter. Chest radiographs or CT scans may show cavitary lesions (Figure 5).

Figure 5.

3. Diagnosis

TB infection (Active TB)

Screening for tuberculosis includes history, physical examination, and chest imaging. Confirmation of active TB requires positive acid fast bacilli (AFB) on direct smear, DNA probe for M tb, positive culture or demonstration of typical organisms or typical pathology findings on biopsy. AFB smears and cultures may be collected from expectorated sputum, endotracheal specimens, or bronchoalveolar lavage. A culture may take up to 8 weeks of incubation to grow M tuberculosis in the laboratory.

AFB smear and culture

Sputum or other respiratory specimens: Sputum should be obtained from patients who have a productive cough, sputum induced with warm hypertonic saline may be used for ambulatory patients and suctioned secretions or bronchoscopy should be used for intubated patients. Three successive first-morning deep-coughed specimens are recommended; however, the CDC has approved using at least one morning specimen and then specimens every 8 hours as adequate for hospitalized patients.

Sensitivity for diagnosis of the smear is around 80% and culture around 95%. A direct probe assay is available.

Urine: Three first-morning voiding specimens are recommended (not 24-hour collections) to diagnose genitourinary TB.

Gastric aspirate: May be useful in children or patients from whom it is difficult to obtain good respiratory specimens. Three successive first-morning specimens are recommended.

Cerebral spinal fluid (CSF): 3 to 10 mL of spinal fluid should be obtained. Sensitivity of a single smear is less than 5% to 10% and culture around 50% to 80%.

Tissue (bone, lymph node, pleural biopsy), other fluids, and bone marrow may be used to diagnose active TB and are appropriate to culture.

Mycobacterial culture (AFB culture)

Specimens are planted onto egg-based medium (eg, Lowenstein-Jensen), semisynthetic medium (eg, Middlebrook 7H10) and/or broth medium (eg, Middlebrook 7H9) to grow M tb. Mycobacteria grow slowly so cultures need to be incubated for up to 8 weeks before reporting as negative.

Mycobacterial identification/rapid testing

Rapid DNA probe tests are available for confirmation of the identity of an organism from a positive culture or from a direct sputum smear. These molecular probes, using rRNA sequences from M tb, M avium-intracellulare (MAI) and the nonpathogenic (but frequently isolated) M gordonae can be used to test suspicious colonies with final results available within several days of colony isolation.

The history is specifically directed towards prior TB exposures, history of active TB, travel to or residence in endemic regions, and past tuberculin skin test results. Physical examination for unexplained lymphadenopathy or pneumonia, and chest imaging for evidence of prior TB exposure or active infection are also part of ICU evaluation.

TB infection (latent TB)

The currently Food and Drug Administration (FDA)-approved methods of diagnosis for latent TB infection in the United States include the tuberculin skin test (TST) and the interferon gamma release assays (IGRAs): Quantiferon Gold (QFT-G), Quantiferon Gold in-tube (QFT-G in tube), and T.SPOT.TB.

Tuberculin skin test

The TST has been used for decades and is based on a delayed type IV hypersensitivity reaction. 5TU of purified protein derivative (PPD) is placed intradermally on the volar surface of the forearm and the reaction is read in 48 to 72 hours; 10% to 25% of people with active TB do not react to PPD with 5mm or greater of induration, the criteria for a positive TST in active or suspected TB. Patients with disseminated TB have a rate of false negativity of about 50%. At a prevalence of 25%, the TST has a positive predictive value range between 86% and 97%.

The tuberculin skin test is the test used for screening populations for infection with M tb. The skin test is not specific for infection with M tb, as exposure to atypical mycobacteria can cause a positive test. For this reason, the criteria for a positive test vary depending on the prevalence of TB infection in the population being tested and with the level of cellular immunity in the subject.

IGRAs measure the patient’s immune response to TB antigens after stimulation of the patient’s white blood cells in vitro. The Centers for Disease Control and Prevention (CDC) issued revised guidelines in June 2010 outlining the use of QFT-G, QFT-G in tube), and T.SPOT.TB. These assays use antigens that are not present in the BCG vaccine strain, so false positive tests due to BCG vaccination are rare.

These assays may be more specific than the TST, and debate exists as to whether they are more or less sensitive in various patient populations, being the least sensitive in patients who are immunocompromised or have reasons for T cell suppression such as being on steroids or critically ill. There are conflicting data on use in healthcare workers or for serial testing.

Case presentation

The patient is an 85-year-old woman admitted to a hospital with what was thought to be community acquired pneumonia on December 27. The patient was afebrile, had a cough and reported weight loss. She was treated with levofloxacin and seemed to improve. She was was readmitted a few weeks later for continued cough and had bronchoscopy on January 11. She was treated with levofloxacin and was discharged to home.

In March, she was still coughing and thru a Cambodian interpreter, she complained of fatigue, shortness of breath (SOB), and decreased appetite. After about 7 weeks, the cultures taken from the bronchoscopy grew
M tb. The patient was seen in a public health TB clinic on March 14 and started on four-drug therapy, including isoniazid, rifampin, pyrazinamide, ethambutol, and vitamin B6. Her sputum grew
M tuberculosis susceptible to all agents tested (Figure 6).

Figure 6.

When the patient initially presented, her physicians failed to consider TB in the diferential diagnosis and gave her a quinolone antibiotic. This resulted in some improvement as levofloxacin has activity against TB. Her physicians may not have seen many cases of TB in the United States. Since she was from Cambodia, they should have considered TB in their differential diagnosis.

The patient could have had community acquired pneumonia due to a bacterial infection, or may have had a viral process. Alternatively given the several weeks to a month of a cough, she could have had a lung tumor.

The most important thing is to think of TB when a person with risk factors comes into care with a pulmonary complaint. The next most important thing is to order sputum smear and culture for AFB. This is the way to diagnose TB. In addition, it is important to alert the radiologist that you are considering the diagnosis of TB.

4. Specific Treatment

First-line and other therapies

Current recommendations for treatment of cavitary TB rely on the use of four drugs initially for 2 months followed by two drugs (usually isoniazid and rifampin) for an additional 4 to 7 months for susceptible strains. Retreatment or resistant cases may require other drugs and/or more prolonged therapy.

The first-line therapeutic agents are as follows:

Isoniazid (INH) at a dose of 10mg/kg daily or maximum adult dose 300mg daily, given orally (although INH is available for intravenous [IV] use).

Rifampin (RIF) at a dose of 10mg/kg daily or 600mg daily as the usual adult dose, given orally.

Pyrazinamide (PZA) at a dose of 20 to 25mg/kg daily with 2000mg daily the adult maximum, given orally.

Ethambutol 15 to 25mg/kg given orally daily or streptomycin given intravenously are added until susceptibility results are available to avoid development of resistance in case the patient has been infected with a drug-resistant strain.

In patients infected with multiply resistant strains, second-line anti-tuberculosis medications may be used according to laboratory susceptibility results. In extensively drug-resistant cases, sometimes surgery to remove the infected lung tissue is required.

5. Disease monitoring, follow-up and disposition

Expected results of treatment

The prognosis for a patient with active TB is good unless the disease is disseminated widely such as to the central nervous system or so-called “miliary” TB, involving almost every organ in the body.

Incorrect diagnosis

One should suspect that they have made the wrong diagnosis if the patient’s X-ray or clinical symptoms are not improving. One possibility is that the patient’s organism may be resistant to the first-line antimicrobial agents.

Follow-up

The patient should be followed at home with directly observed TB therapy by a public health nurse and monthly by the physician. Each month a chest X-ray should be ordered until improvement is noted, as well as a sputum for AFB smear and culture until sputum converts to negative. The physician should look for improvement in symptoms and should assess the patient for side effects of therapy.

The patient’s contacts should be screened for TB infection with a TST and a symptom screen. Contact investigation should start with the family, and the circle of contacts needs to broaden until no new TST conversions are found.

Pathophysiology

Infection with M tb produces tuberculosis. The most common site involved is the lung, but tuberculosis may involve any organ, may be disseminated or may be asymptomatic. The pathogenesis of tuberculosis is a two-stage process. The skin test becomes positive 2 to 10 weeks after the onset of TB infection. The pathology depends on the host with a granulomatous reaction in immunocompetent patients and less host response and more acid fast bacilli in the tissues in patients with impaired cell-mediated immunity.

Why is directly observed therapy (DOT) the preferred public health practice in therapy of TB?

Partial treatment of infection selects for drug-resistant survivors. In New York City, the rate of drug resistance is 50% for relapse cases. Therefore, it is important for drugs taken religiously for full course (about 9 m), even though patients may feel better very early in the treatment course. The use of DOT is key to getting patients to take a complicated regimen for 6 months. In countries where anti-TB drugs are taken without supervision, higher incidence of resistance occurs. Thus, the state is willing to support the staff needed for DOT to protect the public health.

Epidemiology

Tuberculosis is most common in the developing world: one third of the world’s population harbors M tb. Cases in the United States are more common in foreign-born persons.

Prognosis

Most patients who are treated for TB with the recommended course of antimicrobials recover without relapse. Patients need to take all the medications for the entire 6 to 9 months of therapy. DOT is the preferred strategy.

What’s the evidence?

Trends in Tuberculosis. 2006.

“WHO/HTM/TB/2009.420 1.Antitubercular agents – administration and dosage. 2.Tuberculosis, Pulmonary – drug therapy. 3. National health programs. 4.Patient compliance. 5.Guidelines”. Treatment of tuberculosis: guidelines. (This on line reference gives the current guidelines for treatment of tuberculosis.)

“The difference between latent TB infection and active TB disease”. Available at: . (This reference can be used to help educate patients and their families about the difference between latent and active tuberculosis.)

“Targeted tuberculin testing and treatment of latent tuberculosis infection”. MMWR Recommendations and Reports. vol. 44. 2000. pp. 1-54. (This reference gives the rationale for a major change in testing for, and therapy of, latent tuberculosis. It is a consensus statement that created the guideline to stop using the tuberculin skin test in patients who are not at increased risk of tuberculosis and put forward the idea that to do a skin test is to be ready to offer treatment if the patient is found to have active or latent tuberculosis.)

Maldonado, RA, Yarnell, CT, Holbert, D. “Safety and completion rate of short-course therapy for treatment of latent tuberculosis infection”. CID. vol. 43. 2006. pp. 271-5. (This reference outlines the difficulty of getting patients to complete therapy for latent tuberculosis.)

Spyridis, NP, Spyridis, PG, Gelesme, A. “The effectiveness of a 9-month regimen of isoniazid alone versus 3- and 4-month regimens of isoniazid plus rifampin for treatment of latent tuberculosis infection in children: Results of an 11-year randomized study”. CID. vol. 45. 2007. pp. 715-22. (This reference compares the effectiveness of isoniazid versus a shorter regimen in children. The overall consensus is that for children isoniazid for 9 months is preferred.)

Jasmer, RM, Nahid, P, Hopewell, PC. “Clinical practice: Latent tuberculosis infection”. N Engl J Med. vol. 347. 2002. pp. 1860-6. (Practical review of treatment for latent tubeculosis.)

“Treatment of tuberculosis”. MMWR Recommendations and Reports. vol. 52. 2003. pp. 1-77. (This is a comprehensive reference to use when treating active tuberculosis.)

Saukkonen, JJ, Cohn, DL, Jasmer, RM. “An official ATS statement: Hepatotoxicity of antituberculosis therapy”. Am J Respir Crit Care Med. vol. 174. 2006. pp. 935-52. (A review of hepatotoxicity of the medications used to treat tuberculosis.)

Mazurek, GH, Jereb, J, Vernon, A, LoBue, P, Goldberg, S, Castro, K. “IGRA Expert Committee; Centers for Disease Control and Prevention (CDC). Updated guidelines for using interferon gamma release assays to detect infection–United States, 2010”. MMWR Recomm Rep. vol. 59. 2010 Jun 25. pp. 1-25.

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