Tuberculosis: Pathophysiology, Clinical Features, and Diagnosis

Tuberculosis is often underrecognized; the author describes how to obtain a definitive diagnosis of tuberculosis.Tuberculosis has recently reemerged as a major health concern. Each year, approximately 2 million persons worldwide die of tuberculosis and 9 million become infected.1 In the United States, approximately 14000 cases of tuberculosis were reported in 2006, a 3.2% decline from the previous year; however, 20 states and the District of Columbia had higher rates.2 The prevalence of tuberculosis is continuing to increase because of the increased number of patients infected with human immunodeficiency virus, bacterial resistance to medications, increased international travel and immigration from countries with high prevalence, and the growing numbers of the homeless and drug abusers.3 With 2 billion persons, a third of the world population,1 estimated to be infected with mycobacteria, all nurses, regardless of area of care, need to understand the pathophysiology, clinical features, and procedures for diagnosis of tuberculosis. The vulnerability of hospitalized patients to tuberculosis is often underrecognized because the infection is habitually considered a disease of the community. Most hospitalized patients are in a suboptimal immune state, particularly in intensive care units, making exposure to tuberculosis even more serious than in the community. By understanding the causative organism, pathophysiology, transmission, and diagnostics of tuberculosis and the clinical manifestations in patients, critical care nurses will be better prepared to recognize infection, prevent transmission, and treat this increasingly common disease.Tuberculosis is an infection caused by the rod-shaped, non–spore-forming, aerobic bacterium Mycobacterium tuberculosis.4 Mycobacteria typically measure 0.5 μm by 3 μm, are classified as acid-fast bacilli, and have a unique cell wall structure crucial to their survival. The well-developed cell wall contains a considerable amount of a fatty acid, mycolic acid, covalently attached to the underlying peptidoglycan-bound polysaccharide arabinogalactan, providing an extraordinary lipid barrier. This barrier is responsible for many of the medically challenging physiological characteristics of tuberculosis, including resistance to antibiotics and host defense mechanisms. The composition and quantity of the cell wall components affect the bacteria’s virulence and growth rate.5 The peptidoglycan polymer confers cell wall rigidity and is just external to the bacterial cell membrane, another contributor to the permeability barrier of mycobacteria. Another important component of the cell wall is lipoarabinomannan, a carbohydrate structural antigen on the outside of the organism that is immunogenic and facilitates the survival of mycobacteria within macrophages.5,6 The cell wall is key to the survival of mycobacteria, and a more complete understanding of the biosynthetic pathways and gene functions and the development of antibiotics to prevent formation of the cell wall are areas of great interest.6Mycobacterium tuberculosis is spread by small airborne droplets, called droplet nuclei, generated by the coughing, sneezing, talking, or singing of a person with pulmonary or laryngeal tuberculosis. These minuscule droplets can remain airborne for minutes to hours after expectoration.5 The number of bacilli in the droplets, the virulence of the bacilli, exposure of the bacilli to UV light, degree of ventilation, and occasions for aerosolization all influence transmission.7 Introduction of M tuberculosis into the lungs leads to infection of the respiratory system; however, the organisms can spread to other organs, such as the lymphatics, pleura, bones/joints, or meninges, and cause extrapulmonary tuberculosis.Once inhaled, the infectious droplets settle throughout the airways. The majority of the bacilli are trapped in the upper parts of the airways where the mucus-secreting goblet cells exist. The mucus produced catches foreign substances, and the cilia on the surface of the cells constantly beat the mucus and its entrapped particles upward for removal.8 This system provides the body with an initial physical defense that prevents infection in most persons exposed to tuberculosis.9Bacteria in droplets that bypass the mucociliary system and reach the alveoli are quickly surrounded and engulfed by alveolar macrophages,7,8 the most abundant immune effector cells present in alveolar spaces.10 These macrophages, the next line of host defense, are part of the innate immune system and provide an opportunity for the body to destroy the invading mycobacteria and prevent infection.11 Macrophages are readily available phagocytic cells that combat many pathogens without requiring previous exposure to the pathogens. Several mechanisms and macrophage receptors are involved in uptake of the mycobacteria.11 The mycobacterial lipoarabinomannan is a key ligand for a macrophage receptor.12 The complement system also plays a role in the phagocytosis of the bacteria.13 The complement protein C3 binds to the cell wall and enhances recognition of the mycobacteria by macrophages. Opsonization by C3 is rapid, even in the air spaces of a host with no previous exposure to M tuberculosis.14 The subsequent phagocytosis by macrophages initiates a cascade of events that results in either successful control of the infection, followed by latent tuberculosis, or progression to active disease, called primary progressive tuberculosis.8 The outcome is essentially determined by the quality of the host defenses and the balance that occurs between host defenses and the invading mycobacteria.11,15After being ingested by macrophages, the mycobacteria continue to multiply slowly,8 with bacterial cell division occurring every 25 to 32 hours.4,7 Regardless of whether the infection becomes controlled or progresses, initial development involves production of proteolytic enzymes and cytokines by macrophages in an attempt to degrade the bacteria.11,12 Released cytokines attract T lymphocytes to the site, the cells that constitute cell-mediated immunity. Macrophages then present mycobacterial antigens on their surface to the T cells.11 This initial immune process continues for 2 to 12 weeks; the microorganisms continue to grow until they reach sufficient numbers to fully elicit the cell-mediated immune response, which can be detected by a skin test.4,8,11For persons with intact cell-mediated immunity, the next defensive step is formation of granulomas around the M tuberculosis organisms16 (Figure 1). These nodular-type lesions form from an accumulation of activated T lymphocytes and macrophages, which creates a micro-environment that limits replication and the spread of the mycobacteria.8,12 This environment destroys macrophages and produces early solid necrosis at the center of the lesion; however, the bacilli are able to adapt to survive.18 In fact, M tuberculosis organisms can change their phenotypic expression, such as protein regulation, to enhance survival.13 By 2 or 3 weeks, the necrotic environment resembles soft cheese, often referred to caseous necrosis, and is characterized by low oxygen levels, low pH, and limited nutrients. This condition restricts further growth and establishes latency. Lesions in persons with an adequate immune system generally undergo fibrosis and calcification, successfully controlling the infection so that the bacilli are contained in the dormant, healed lesions.18 Lesions in persons with less effective immune systems progress to primary progressive tuberculosis.4,8,13,18For less immunocompetent persons, granuloma formation is initiated yet ultimately is unsuccessful in containing the bacilli. The necrotic tissue undergoes liquefaction, and the fibrous wall loses structural integrity. The semiliquid necrotic material can then drain into a bronchus or nearby blood vessel, leaving an air-filled cavity at the original site. In patients infected with M tuberculosis, droplets can be coughed up from the bronchus and infect other persons. If discharge into a vessel occurs, occurrence of extrapulmonary tuberculosis is likely. Bacilli can also drain into the lymphatic system and collect in the tracheobronchial lymph nodes of the affected lung, where the organisms can form new caseous granulomas.18As the cellular processes occur, tuberculosis may develop differently in each patient, according to the status of the patient’s immune system. Stages include latency, primary disease, primary progressive disease, and extrapulmonary disease. Each stage has different clinical manifestations (Table 1).Mycobacterium tuberculosis organisms can be enclosed, as previously described, but are difficult to completely eliminate.15 Persons with latent tuberculosis have no signs or symptoms of the disease, do not feel sick, and are not infectious.19 However, viable bacilli can persist in the necrotic material for years or even a lifetime,9 and if the immune system later becomes compromised, as it does in many critically ill patients, the disease can be reactivated. Although coinfection with human immunodeficiency virus is the most notable cause for progression to active disease, other factors, such as uncontrolled diabetes mellitus, sepsis, renal failure, malnutrition, smoking, chemotherapy, organ transplantation, and long-term corticosteroid usage, that can trigger reactivation of a remote infection are more common in the critical care setting.8,19 Additionally, persons 65 years or older have a disproportionately higher rate of disease than any does other age group,20 often because of diminishing immunity and reactivation of disease.21Primary pulmonary tuberculosis is often asymptomatic, so that the results of diagnostic tests (Table 2) are the only evidence of the disease. Although primary disease essentially exists subclinically, some self-limiting findings might be noticed in an assessment. Associated paratracheal lymphadenopathy may occur because the bacilli spread from the lungs through the lymphatic system. If the primary lesion enlarges, pleural effusion is a distinguishing finding. This effusion develops because the bacilli infiltrate the pleural space from an adjacent area. The effusion may remain small and resolve spontaneously, or it may become large enough to induce symptoms such as fever, pleuritic chest pain, and dyspnea. Dyspnea is due to poor gas exchange in the areas of affected lung tissue. Dullness to percussion and a lack of breath sounds are physical findings indicative of a pleural effusion because excess fluid has entered the pleural space.7Active tuberculosis develops in only 5% to 10% of persons exposed to M tuberculosis. When a patient progresses to active tuberculosis, early signs and symptoms are often nonspecific. Manifestations often include progressive fatigue, malaise, weight loss, and a low-grade fever accompanied by chills and night sweats.22 Wasting, a classic feature of tuberculosis, is due to the lack of appetite and the altered metabolism associated with the inflammatory and immune responses. Wasting involves the loss of both fat and lean tissue; the decreased muscle mass contributes to the fatigue.23 Finger clubbing, a late sign of poor oxygenation, may occur; however, it does not indicate the extent of disease.24 A cough eventually develops in most patients. Although the cough may initially be nonproductive, it advances to a productive cough of purulent sputum. The sputum may also be streaked with blood. Hemoptysis can be due to destruction of a patent vessel located in the wall of the cavity, the rupture of a dilated vessel in a cavity, or the formation of an aspergilloma in an old cavity. The inflamed parenchyma may cause pleuritic chest pain. Extensive disease may lead to dyspnea or orthopnea because the increased interstitial volume leads to a decrease in lung diffusion capacity. Although many patients with active disease have few physical findings, rales may be detected over involved areas during inspiration, particularly after a cough. Hematologic studies might reveal anemia, which is the cause of the weakness and fatigue. Leukocytosis may also occur because of the large increase in the number of leukocytes, or white blood cells, in response to the infection.7Although the pulmonary system is the most common location for tuberculosis, extrapulmonary disease occurs in more than 20% of immunocompetent patients, and the risk for extrapulmonary disease increases with immunosuppression.20 The most serious location is the central nervous system, where infection may result in meningitis or space-occupying tuberculomas. If not treated, tubercular meningitis is fatal in most cases, making rapid detection of the mycobacteria essential.8 Headaches and change in mental status after possible exposure to tuberculosis or in high risk groups should prompt consideration of this disease as a differential diagnosis. Another fatal form of extrapulmonary tuberculosis is infection of the bloodstream by mycobacteria; this form of the disease is called disseminated or miliary tuberculosis. The bacilli can then spread throughout the body, leading to multiorgan involvement.25 Miliary tuberculosis progresses rapidly and can be difficult to diagnose because of its systemic and nonspecific signs and symptoms, such as fever, weight loss, and weakness.7 Lymphatic tuberculosis is the most common extrapulmonary tuberculosis, and cervical adenopathy occurs most often. Other possible locations include bones, joints, pleura, and genitourinary system.20Active tuberculosis may be considered as a possible diagnosis when findings on a chest radiograph of a patient being evaluated for respiratory symptoms are abnormal, as occurs in most patients with pulmonary tuberculosis. The radiographs may show the characteristic findings of infiltrates with cavitation in the upper and middle lobes of the lungs21 (Figure 2). However, specific groups of patients, such as the elderly and patients with advanced infection by human immunodeficiency virus, may not have these typical findings. Compared with other patients, both groups have the classic cavitation less often and may have lower-lobe infiltrates as a prominent finding.7,21 Although abnormal findings on a chest radiograph may suggest tuberculosis, they are not diagnostic for the disease.19Traditionally, the first laboratory test used to detect active tuberculosis in a patient with abnormal findings on chest radiographs is examination of a sputum smear for the presence of acid-fast bacilli (Table 2). Also, because the bacilli have entered the sputum, the patient is infectious to others. According to the Centers for Disease Control and Prevention,19 3 sputum specimens should be used for detection of pulmonary tuberculosis, with specimens collected in the morning on consecutive days. However, recently, investigators have the need for 3 that examination of 2 specimens is just as the sputum is on a and then with bacilli that are present will remain because they will not The test is not specific for tuberculosis, because other mycobacteria the but it does provide a to if respiratory should be more definitive is of sputum should be available within hours of the diagnosis of tuberculosis the of M tuberculosis in a of a diagnostic The most used from a patient with a and productive cough is sputum. most mycobacteria grow 3 to may be for growth on solid However, a in which is used to and cell wall mycolic provides of the disease in to 3 sputum were also used for but the of 2 as for also for are the of the is by sputum for the of 3 sputum for M tuberculosis may be when if respiratory can be A patient is considered to have when a is for the mycobacteria after a of have is the most important of response to not all patients with tuberculosis can be detected by of sputum a that can lead to or Additionally, many critically ill patients have the material from the lungs and or patients have sputum, of an of can be used to induce sputum for However, if sputum specimens are or the of for tuberculosis is high for M tuberculosis, are with or can provide sputum for In a is into the and fluid is in and then essentially a of cells and from the alveolar and from subsequent constitute patients with of lymph as by adenopathy of tuberculosis, have sputum for M tuberculosis, of specimens collected by can be used to and diagnose the disease. With this specimens are collected by a through a patients are but and are used for diagnostic for detection of M tuberculosis include In these are used to and rapid detection of the tests have by the and is the which can be used to M tuberculosis from other mycobacteria on the of and provides results within Although the test can provide rapid of M tuberculosis in sputum specimens for acid-fast bacilli, it has including high low and low A for M tuberculosis in with a sputum smear for the organism tuberculosis, but in a patient with a sputum smear for the organism, the should be considered with clinical The results of these can not be on as the for or patients from a primary M tuberculosis infection and the infection becomes sputum specimens are for the and findings on chest radiographs are typically These patients also do not have signs or symptoms of infection, and they are not infectious to others. skin is the most common used to for latent M skin test is by of protein that contains to the is for but not (Figure Although the test is because the a skin cell-mediated immunity when in patients previously infected with mycobacteria, it is limited because it is not specific for the of mycobacteria. in the are in of mycobacteria. Also, the test is of limited in patients with active tuberculosis because of its low and can occur in patients are or because these patients an immune response to the and in 20% to of patients have active tuberculosis, because is a of 2 to between infection and the response for a skin can occur in patients have caused by mycobacteria other than M tuberculosis or have skin test the only test available to detect latent tuberculosis until an called by the and in in a new called and is to the which is no In both the cell-mediated to M tuberculosis is determined by blood with an antigen and then an to measure the amount of from white blood In the 2 specific in are used than a making this test more than its provides results in less than hours and can be used to detect both active and latent tuberculosis. The results of the test are to of the skin and the Centers for Disease Control and that the test be used in all in which the skin test have the of tuberculosis, being this disease is more important than Tuberculosis can be difficult to diagnose in of patients and spread of the disease. of extrapulmonary tuberculosis is generally even more difficult because this is often less to an important role in the clinical signs and symptoms of tuberculosis, a that in a for early recognition of the disease, leading to diagnosis and early to prevent diagnosis may be on clinical manifestations even without a for M are also in a to provide and patients and for discharge from the every of health care has in the of M The can a role in control because it is a of into the However, because of the nonspecific signs and symptoms and initial detection of tuberculosis is in a patient with tuberculosis can be into the or to the without any because of may also for tuberculosis, because the is on patients are to an intensive care where other patients are particularly to any patients are from the pulmonary and lack upper defenses that the lungs from tuberculosis have that nurses and other health care should that even hospitalized patients may have nurses a key role in tuberculosis, they should for prompt of patients with or M tuberculosis infection (Figure should be with the that be with tuberculosis should be in a and respiratory air should be readily available outside the for the The number of should be and should be from should be to their and with a tissue when or Additionally, they should a when leaving the and procedures should be until the infectious has should also be in a and respiratory should be used by the A should be used for In to the risk of or of M tuberculosis organisms into the a bacterial should be on the or on the of the care and to infection control should be a because is a infection and an to a patient with is an important feature all of to increase the risk for persons with low body mass are more at risk for tuberculosis than are with a high Additionally, patients at the of increase their weight by 5% during the first 2 of have less than do patients less than should of tuberculosis patients, that being is a risk for and Also, because often the of should be to lean should also patients to in physical to the loss of muscle mass and subsequent fatigue. for a and physical to a patient with tuberculosis to be an for to the of many nurses are also a key of for patients and during of from can to patients with tuberculosis of and and often with the can provide to patients and and to and can elicit to with can affect a patient’s to as as the patient’s and of the has reemerged as a major health and is the infectious disease the of this airborne disease, from the primary infection to primary progressive disease or latency, is the will critical care nurses be of the of the classic signs and symptoms for tuberculosis. different diagnostic tests can be used to a patient with tuberculosis, and the stage or progression of the disease the in critical care, each has an opportunity to to the control of tuberculosis by the signs and symptoms of the disease, risk specific to critical care patients, and the to should such a The more nurses tuberculosis, the more they can to its transmission, making early and increases in and due to this disease.