Pulmonary tuberculosis

Improving diagnosis and management

Abstract

Tuberculosis (TB) is a major public health concern worldwide and the world's second most common cause of death from infectious disease after HIV/AIDS. With the emergence of resistant strains of tuberculosis and increase in immunosuppressed patients, clinicians must be familiar with the clinical presentation of this potentially deadly infection. This article reviews the pathology, signs and symptoms, diagnostics, and management of TB, focusing on recent advances in drug therapy for drug-sensitive and drug-resistant forms. A better understanding of TB will help clinicians identify the disease early, reduce transmission, and provide treatment to prevent complications and reduce patient morbidity and mortality.

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Box 1

Pulmonary tuberculosis (TB) remains a major cause of morbidity and mortality worldwide, with about one-third of the world's population infected.¹ Between 10% and 20% of those infected will progress to active TB, posing a serious health threat. The remaining patients will have latent TB, which can advance to active infection in times of immunosuppression. The CDC reported 9,588 new cases of TB in the United States in 2013, a decline of 4.2% compared with 2012 and the lowest number of cases recorded in the United States since 1953.² However, TB continues to be a major health threat, especially among foreign-born persons.² Worldwide, more than 1 million patients with TB are coinfected with HIV, and of the more than 1.5 million TB-related deaths reported in 2011, most resulted from multidrug-resistant or extensively drug-resistant strains.³ The increased prevalence of TB among HIV-infected patients, the evolution of multidrug-resistant strains, and a recent increase in international travel and immigration pose a serious threat to TB control. TB must be addressed more effectively in the United States to avoid a future epidemic of multidrug-resistant strains.³

This article reviews the pathology, clinical presentation, and diagnosis of TB, focusing on advances in drug therapy. A better understanding of TB can help clinicians make accurate diagnoses and better manage this potentially deadly contagious disease.

Box 2

PATHOGENESIS

TB is caused by the aerobic acid-fast rod-shaped bacterium Mycobacterium tuberculosis.⁴ This tiny bacterium, expelled from a contagious host, can remain suspended in air as droplet nuclei for hours.⁵ Speaking or a single cough or sneeze can generate many infective droplets, and as few as 10 bacilli can cause infection.⁵ If inhaled by a susceptible host, Mycobacterium can lodge in the alveoli and are eventually taken up by alveolar macrophages; if they contain the disease, the patient has latent TB. If the macrophages fail to contain the disease, the patient develops active TB. The risk of developing active TB depends on the patient's age, immunocompetence, and time since infection.⁶ Only patients with active disease are contagious.

Mucus-secreting goblet cells are the first line of defense, followed by alveolar macrophages of the innate immune system. The complement system assists in phagocytosis by producing protein C3, which binds to the bacterial cell wall, enhancing recognition and opsonization.⁶ The macrophages produce proteolytic enzymes and cytokines that further degrade bacteria, and attract T cells that spark a cell-mediated immune response, releasing interleukin-12 and -18.⁵ CD4 T lymphocytes release interferon gamma, resulting in further phagocytosis.⁵ Interferon gamma leads to the release of tumor necrosis factor alpha and granuloma formation, limiting bacteria replication. In the center of the granuloma is a necrotic, caseating substance characterized by low oxygen levels, low pH, and limited nutrient supply.⁶ Here the bacteria remain dormant and contained by an adequate host immune system until the granulomas undergo fibrosis and calcification.⁷

The initial cell-mediated immune response takes 2 to 12 weeks to develop in a patient with a normal immune system, and is identified by a positive tuberculin skin test. About 45% of close contacts exposed to a contagious patient with active TB will become infected and have a positive T-cell-mediated hypersensitivity response.⁸

About 5% of those infected will progress to active disease in the following 18 months of initial infection; the remaining 95% have a 5% risk of progressing to active disease in their lifetime.⁴ Progression to active disease can occur if the patient's immune system becomes compromised by comorbidities such as HIV, diabetes, renal failure, malignancy, chronic steroid use, chemotherapy, the use of tumor necrosis factor inhibitors, or reinfection. Reactivation of latent TB accounts for about 70% of active TB cases.⁹

A false-negative skin test result due to an impaired innate immune response is called anergy. Patients at risk for anergy are the young, older adults, and those with impaired immunity (such as in HIV infection).¹ In these patients, the initial infection can result in active primary TB because granuloma formation is suboptimal with loss of integrity.^8,10 Bacteria disseminate, leaving an air-filled fibrous cavity at the initial site of infection.⁶ If bacteria enter the bronchus, they can be expelled via a cough, sneeze, or speaking, resulting in airborne droplet nuclei and contagious spread of the pathogen. Bacteria that drain into blood vessels can cause extrapulmonary forms of TB.

CLINICAL PRESENTATION

Active primary tuberculosis

Despite TB's overt clinical presentation, confirmation is a challenge. Positive diagnostic findings are the only evidence of infection in patients with asymptomatic primary TB. Subclinical disease can present as paratracheal lymphadenopathy if bacteria have spread to the patient's lymphatic system.⁶ As the primary lesion enlarges, and bacteria replicate, the patient will develop symptoms of respiratory distress (due to poor air exchange in affected tissue), chronic cough, crackles, sputum production, hemoptysis, pleuritic chest pain (due to inflamed parenchyma), fever, night sweats, and weight loss.⁶ The clinical picture is nonspecific and the patient may be diagnosed with pneumonia, lung cancer, or sarcoidosis, delaying accurate diagnosis.

Screen patients for TB if they have a history of persistent cough for more than 2 weeks and a history of possible TB exposure; recent travel in an endemic area; and symptoms of fever, night sweats, unintentional weight loss, shortness of breath, hemoptysis, or chest pain.^1,5 If the primary lesion is large, bacteria can infiltrate the pleural space, causing pleural effusion. Physical examination findings include dullness to percussion and decreased breath sounds in the affected area.⁶ Finger clubbing, a late sign, is associated with poor oxygenation. Wasting (loss of body fat and lean tissue) is the result of the inflammatory and immune response.⁶ Radiologic abnormalities include hilar or paratracheal adenopathy and cavitary or upper lobe infiltrates.^1,5

Disseminated disease results in lower lobe or miliary pattern infiltrates. Hematologic studies might show anemia and leukocytosis. Extrapulmonary disease can affect any organ in the body including bones, joints, and the genitourinary system, so maintain a high index of suspicion. Rapidly fatal forms include tuberculous meningitis, miliary TB, and lymphatic TB.⁶

Latent TB

This asymptomatic and nontransmittable infection is a consequence of exposure to droplet nuclei. Isolating bacteria in culture is not possible. Infection with latent TB is easily recognized as a positive test representing a delayed hypersensitivity response. This response indicates the host's ability to form granulomas around the site of infection containing the organism in a dormant, viable form. These patients are at risk of developing active TB in times of immunosuppression.⁸ Viable bacteria have been recovered from TB lesions discovered postmortem in patients who die from other causes.¹ Because of the threat of progression to active disease with potentially drug-resistant strains, latent TB must be identified and treated.¹

DIAGNOSIS

The first step in diagnosing TB is clinical suspicion. The distinction between active TB and latent infection is crucial from a clinical and epidemiologic point of view as management is dissimilar. Evaluate HIV status for all patients presenting with probable TB; patients with latent TB who become immunocompromised due to HIV can develop active TB, and coinfection with HIV accounts for the recent increase in TB worldwide.⁵ Other comorbidities that can result in progression to active disease include uncontrolled diabetes, sepsis, renal failure, malnutrition, smoking, chemotherapy, organ transplant, and long-term corticosteroid therapy.^3,4,9,11 Clinicians must identify these risk factors for progression in patients with latent TB.

No gold standard exists for confirming latent TB. Infection is suggested by a positive response to intradermal injection of a purified protein derivative of tuberculin, which contains more than 200 antigens found in both Mycobacterium and non-TB Mycobacterium (limiting specificity). Other limitations include low sensitivity in immunocompromised patients, and cross-reactivity with the BCG vaccine.⁵ In addition, patients must return in 48 to 72 hours to have the result read. Areas of induration (not redness) are measured in millimeters to determine a positive response (Table 1). The indurated response is consistent with a delayed type IV T-cell-mediated hypersensitivity response.¹

TABLE 1: Positive tuberculin skin tests

Interferon-gamma release assays, an alternate screening examination, use specific M. tuberculosis antigens not found in the BCG vaccine and nontuberculous Mycobacteria, and should be used for patients who have had the BCG vaccine.¹ They detect the presence of interferon gamma released by sensitized white blood cells after whole blood is incubated with synthetic peptides of strains of mycobacterium, or by the enzyme-linked immunospot technique (requiring isolation of peripheral blood mononuclear cells before incubation).¹ Although these tests have improved specificity, they cannot distinguish latent from active disease.^4,6 Interferon-gamma release assays are recommended by the CDC for identifying TB infection.^1,6

Any patient with a CD4 count less than 200 with atypical pulmonary infiltrates, pleural effusion, and/or lymphadenopathy should undergo TB screening. If the patient's CD4 count is less than 75, pulmonary findings consistent with TB might not be apparent.⁴ Consider the possibility of disseminated extrapulmonary TB if the patient has advanced HIV infection.¹¹

The definitive diagnosis of TB requires culture of acid-fast bacteria Mycobacterium from respiratory secretions with sensitivity testing.¹² Flexible bronchoscopy with bronchial washings is recommended when expectorated sputum samples are inadequate, or produce negative results.¹³ Sputum culture is inexpensive with high specificity. The downfall is that the sample concentration of the bacteria can vary depending on timing of collection. Mycobacterium bacilli grow very slowly, with up to 6 weeks needed for detectable growth.⁶ The sensitivity of the sputum smear for detection by microscopic examination is 32% to 97%, further emphasizing the need for culture identification.^1,12

Nucleic acid (DNA/RNA) tests such as the polymerase chain reaction (PCR) assay can help diagnose TB. The PCR assay detects small quantities of DNA via amplification methods, and results are available within as little as 2 hours, which can help with early treatment initiation.^1,4,6,13 Limitations include high cost, low sensitivity, and low availability worldwide.^6,13 A new molecular diagnostic test called Xpert MTB/RIF assay detects the M. tuberculosis complex within 2 hours, and has a sensitivity higher than smear microscopy.⁴ This test is not approved in the United States but also can identify drug resistance to isoniazid and rifampin, an advantage in countries with high rates of extremely drug-resistant TB.⁴

TREATMENT

Latent TB

Screening and treatment of latent TB is a cornerstone in the strategy to eliminate TB in the United States.⁹ Because patients with latent TB are at risk for progression to active TB, a positive skin test warrants a preventive 9-month regimen of isoniazid, or longer therapy for patients who are immunosuppressed or live in areas of high TB prevalence.⁴ Preventive therapy is recommended for patients who are HIV-positive (including pregnant patients); and those in close contact with patients with active TB, infants, and young children.¹⁴ Monotherapy is usually sufficient as bacillary load is low, and resistant mutants are not likely; however, complications with patient adherence to a long regimen are common.⁸ Other adverse reactions to isoniazid include drug-related hepatitis resulting in hepatotoxicity and therapy discontinuation.

An effective alternative to daily administration of isoniazid for 9 months is once-weekly directly observed 12 doses of isoniazid and rifapentine. This regimen should not be used in children under age 12 years, patients with HIV on antiretroviral therapy, pregnant women, or women expecting to become pregnant (because of the additional risk for hepatotoxicity).¹⁵ The regimen is recommended for patients who have had recent contact with patients with infectious TB, and for those with positive screening results.¹⁵ This regimen increases compliance up to 90%.¹⁶ A 4-month regimen of rifampin can be considered for patients who cannot take isoniazid and patients exposed to isoniazid-resistant strains.¹⁵ Rifampin is associated with hepatotoxicity and contraindicated in patients on antiretroviral therapy.

Monitor the patient's aminotransferase levels, and evaluate the patient monthly for signs of hepatitis. Asymptomatic elevations in liver enzyme concentrations can occur in 10% to 20% of patients receiving isoniazid.¹⁵ Discontinue treatment if aminotransferase levels exceed three times the upper limit in symptomatic patients, or five times the upper limit in asymptomatic patients.¹⁵

Peripheral neuropathy can occur in 0.2% of patients on isoniazid therapy; the risk is greater in patients who have diabetes, HIV, renal failure, abuse alcohol, or are pregnant.¹⁵ Daily pyridoxine supplementation is recommended for these patients.¹⁵

Active TB

Treatment of active TB is imperative to reducing the prevalence and incidence of TB.¹⁷ The goal of therapy is to reduce mortality and the emergence of drug-resistant strains.^5,16 Treatment effectiveness depends on early identification, awareness of resistant strains, the patient's HIV status, and adherence to a tolerable regimen.⁴ Practices that include monotherapy to treat active disease, or addition of a single agent to failing regimens can result in growth of mutations and resistance.⁴

The initial empiric treatment regimen for drug-susceptible TB consists of two phases, with a cure rate of 95% for direct observation therapy.⁴ The initial four-drug regimen: isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) is administered over 2 months (Table 2).¹⁴ This intensive phase is designed to kill active and dormant bacteria. Monitor patients weekly for culture conversion, which takes 2 weeks to 3 months in 80% to 90% of patients.^5,14 Patients on pyrazinamide need baseline and periodic serum uric acid assessment and assessment of hepatic function. Elevations in uric acid can lead to hyperuricemia, arthralgias, and gout. Treat elevated levels of uric acid only if the patient is symptomatic.⁵ Patients on ethambutol need baseline and periodic tests for visual acuity, blurred vision, reduced red-green color discrimination, and optic neuritis.⁵ These adverse reactions are dose-related and reversible; discontinue the medication if the patient develops these symptoms.^5,14 Avoid using these medications in young children who cannot participate in visual screening examinations.

TABLE 2: Adverse reactions and recommended monitoring of primary TB medications⁶

If the organism is resistant to isoniazid, continue rifampin, pyrazinamide, and ethambutol for 6 months. If the organism is susceptible, follow this therapy with the continuation phase: Discontinue pyrazinamide and ethambutol and continue isoniazid and rifampicin for 4 months, unless cultures remain positive.^4,14 This phase reduces the likelihood of the development of drug-resistant mutations (because fewer drugs are needed), eliminates residual bacteria, and prevents reinfection.⁵ The regimen is effective for pulmonary and extrapulmonary TB, regardless of the patient's HIV status.⁴ Drug-drug interactions can occur between HIV and TB medications, resulting in intolerance, loss of efficacy, toxicity, and treatment disruptions.⁴

Although isoniazid, rifampin, and ethambutol are pregnancy category C, they are considered nonteratogenic in pregnancy.⁵ Advise patients of the risks and benefits of the medication before treatment. Pyrazinamide may be used in pregnant patients with suspected multidrug-resistant TB, or if alternatives are not available or are less effective.⁵

Anti-TB regimens that are comprehensive, effective, and tolerable with fewer drug interactions are urgently needed. Significant effort is being invested into the development of regimens for drug-susceptible TB. Trials are in progress to add fluoroquinolones, or increased doses of rifamycins to shorten regimens to 4 months rather than the current 6.⁴

Multidrug-resistant tuberculosis

Multidrug resistance is a challenge to controlling TB worldwide because of inadequate treatment and detection.³ Multidrug-resistant TB is resistant to at least rifampicin and isoniazid.¹⁸ Isoniazid is known for its strong antibactericidal activity and rifampin for action against dormant bacteria not actively replicating.¹⁴ Multidrug-resistant TB treatment regimens are recommended if the patient has not responded to current treatments, has recurrent TB, has confirmed rifampicin-resistant TB, or has contact with patients with multidrug-resistant TB.⁴ The choice of agents is determined by geographic patterns of resistance, previous regimens, underlying medical conditions, and adverse reactions.⁴ Empiric treatment should begin after sputum samples are retrieved and without waiting for susceptibility information. The initial intensive phase is 8 months of treatment with at least four second-line drugs daily under direct observation therapy.⁴ The continuation phase lasts 20 months if the patient has no history of previous treatment for multidrug-resistant TB, and up to 28 months for patients with recurrent TB, with direct observation therapy to monitor for adherence.⁴

Second-line drugs have weak bacteriostatic activity, are less well tolerated, less effective, and have increased toxicity over standard regimens (Table 3).^4,18 Never add a single medication to a failing regimen.¹⁴ Bedaquiline fumarate was recently approved by the FDA for combination therapy for adults with multidrug-resistant TB when an effective regimen is not available.^14,19 The drug's effectiveness and safety profile is unclear.¹⁹ Other drugs are in phase II and III clinical trials.^4,18 Linezolid, clofazimine, and moxifloxacin are in the pipeline for possible treatment of multidrug-resistant TB.¹⁸

TABLE 3: First- and second-line antimycobacterial drugs^4,15

Surgical resection is an option and may reduce bacillary burden in patients with multidrug-resistant TB who do not respond to therapy.¹⁴

Extremely drug-resistant TB

This form of TB is resistant to the first-line drugs isoniazid and rifampin, along with the most effective second-line drugs (including at least one fluoroquinolone and one injectable medication).¹⁴ Treatment is limited and requires third-line drugs with greater adverse reactions, especially in patients coinfected with HIV.^4,18 Drug resistance beyond extremely drug-resistant TB is known as total drug-resistant TB, and points out the need for new drug regimens.

PREVENTION

All clinicians must take infection control measures to limit TB transmission and outbreaks. Patients with suspected active TB should be admitted to a negative-pressure ventilation isolation room until the diagnosis is definitive.²⁰ All healthcare providers should receive annual respirator training and fit testing for N-95/high-efficiency particulate respirator masks.^6,20 Healthcare providers should have their TB status screened annually.²⁰ Patients should wear a mask on leaving the isolation room and all nonurgent procedures should be delayed until patients are noninfectious. Limit visitors, and discourage children from visiting to limit transmission.

CONCLUSION

TB is a major public health concern worldwide, and remains the world's second most common cause of death from infectious disease after HIV/AIDS.⁵ With the emergence of drug-resistant strains and the increased incidence of HIV, clinicians must understand the pathology, clinical manifestations, diagnosis, and management of this disease. Early identification and treatment reduce transmission and prevent increases in patient morbidity and mortality.