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Tuberculosis (TB),

a multisystemic disease with myriad presentations and manifestations, is the most common cause of infectious disease related mortality worldwide. The World Health Organization (WHO) has estimated that 2 billion people have latent TB and that globally, in 2009, the disease killed 1.7 million people.[1] New TB treatments are being developed,[2] and new TB vaccines are under investigation. (See Epidemiology and Treatment and Management, below.)[3] Although TB rates are decreasing in the United States, the disease is becoming more common in many parts of the world. In addition, the prevalence of drug-resistant TB is also increasing worldwide. Co-infection with the human immunodeficiency virus (HIV) has been an important factor in the emergence and spread of resistance. (See Treatment of Multidrug-Resistant TB, below.)[4] TB is an ancient disease. Signs of skeletal TB (Pott disease) were evident in Europe from Neolithic times (8000 BCE), in ancient Egypt (1000 BCE), and in the pre-Columbian New World. TB was recognized as a contagious disease by the time of Hippocrates (400 BCE), when it was termed "phthisis" (Greek from phthinein, to waste away). Mycobacterium tuberculosis, a tubercle bacillus, is the causative agent of TB. It belongs to a group of closely related organismsincluding M africanum, M bovis, and M microti in the M tuberculosis complex. Robert Koch discovered and isolated M tuberculosis in 1882. (See Etiology, below.) An image of the bacterium is seen below. Acid-fast bacillus smear showing characteristic cording in Mycobacterium tuberculosis. World incidence of TB increased with population density and urban development, so that by the Industrial Revolution in Europe (1750), it was responsible for more than 25% of adult deaths. Indeed, in the early 20th century, TB was the leading cause of death in the United States. (See Etiology and Epidemiology, below.) The US Centers for Disease Control and Prevention (CDC) has been recording detailed epidemiologic information on tuberculosis (TB) since 1953. The incidence of TB has been declining since the early 20th century because of various factors, including basic infection-control practices (isolation). Beginning in 1985, a resurgence of TB was noted. The increase was observed primarily in ethnic minorities and especially in persons infected with HIV. TB control programs were revamped and strengthened across the United States. (See Epidemiology.) As an AIDS (acquired immunodeficiency syndrome)-related opportunistic infection, TB is associated with HIV infections, with dual infections being frequently noted. Globally, coinfection with HIV is highest in South Africa, India, and Nigeria. Persons with AIDS are 20-40 times more likely than immunocompetent persons to develop active TB.[5] Correspondingly, TB is the leading cause of mortality among persons infected with HIV.[6] Worldwide, TB is most common in Africa, the West Pacific, and Eastern Europe. These regions are plagued with factors that contribute to the spread of TB, including the presence of limited resources, HIV infection, and multidrug-resistant (MDR) TB. Consequently, although international public health efforts have put a huge curb on the rate of increase in TB, these regions account for the continued increase in global TB. (See Epidemiology.) Drug-resistant TB MDR-TB is defined as resistance to the 2 most effective firstline drugs, isoniazid and rifampin.[6] Another type of resistant

TB, called extensively drug-resistant TB (XDR-TB), is resistant to isoniazid, rifampin, and second-line drugs used to treat MDR-TB. Mortality rates for patients with XDR-TB are similar to those of patients from the preantibiotic era. (Approximately 1 in 13 M tuberculosis isolates currently shows a form of drug resistance.)[6] Multiple factors contribute to the drug resistance of M tuberculosis, including incomplete and inadequate treatment or adherence to treatment, logistical issues, virulence of the organism, multidrug transporters, host genetic factors, and HIV infection. According to WHO, the prevalence of MDR-TB has been 1.1% in newly diagnosed patients; it is reportedly even higher in patients who have previously received anti-TB treatment (7%). MDR-TB and XDR-TB are becoming increasingly significant.[7] Genotype studies have shown that between 63% and 75% of XDR-TB cases progress through acquisition of resistance.[8] According to the US National TB Surveillance System (NTSS), between 1993 and 2006 a total of 49 cases (3% of evaluable MDR-TB cases) met the revised case definition for XDR-TB. The largest number of XDR-TB cases was found in New York City and California. The success rate of treatment with standard short-course chemotherapy (SCC) is less than 60% in patients with MDRTB, compared with a success rate of more than 85% in patients with drug-susceptible TB. (MDR-TB and XDR-TB not only produce fulminant and fatal disease among patients infected with HIV [time from TB exposure to death averages 2-7 mo] but are also highly infectious, with conversion rates of as much as 50% in exposed health care workers.) Global surveillance and treatment of TB As previously stated, multidrug resistance has arisen from poor compliance with TB therapies , resulting in difficulties in controlling the disease. Consequently, a threat of global pandemic occurred in the late 1980s and early 1990s. Reacting to these signals, the World Health Organization developed a plan to try to identify 70% of the world's cases of TB and to completely treat at least 85% of these cases by the year 2000. Out of these goals were born major TB surveillance programs and the concept of directly observed therapy (DOT), which requires a third party to witness compliance with pharmacotherapy. With worldwide efforts, global detection of smear-positive cases rose from 11% (1991) to 45% (2003), with 71-89% of those cases undergoing complete treatment. Approach to TB in the emergency department Despite the importance of early isolation of patients with active TB, a standardized triage protocol with acceptable sensitivities has yet to be developed.[9] Moran et al demonstrated that among patients with active TB in the emergency department (ED), TB was often unsuspected, and isolation measures were not used. [10] The difficulty in establishing such a protocol only highlights the importance of the emergency physicians role in the prompt identification and isolation of active TB. A large percentage of ED patients are at increased risk for having active TB, including homeless/shelter-dwelling patients, travelers from endemic areas, immunocompromised patients, health care workers, and incarcerated patients. Therefore, emergency physicians must consider the management and treatment of TB as a critical public health measure in the prevention of a new epidemic.[11] For high-risk cases, prehospital workers can assist in identifying household contacts who may also be infected or who may be at high risk of becoming infected.

Prehospital workers should be aware that any case of active TB in a young child indicates disease in 1 or more adults with close contact, usually within the same household. TB in a child is a sentinel event indicating recent transmission. Extrapulmonary involvement in TB Extrapulmonary involvement occurs in one fifth of all TB cases; 60% of patients with extrapulmonary manifestations of TB have no evidence of pulmonary infection on chest radiographs or sputum culture. Cutaneous TB The incidence of cutaneous TB appears low. In areas such as India or China, where TB prevalence is high, cutaneous manifestations of TB (overt infection or the presence of tuberculids) have been found in less than 0.1% of individuals seen in dermatology clinics. Ocular TB TB can affect any structure in the eye and typically presents as a granulomatous process. Keratitis, iridocyclitis, intermediate uveitis, retinitis, scleritis, and orbital abscess are within the spectrum of ocular disease. Choroidal tubercles and choroiditis are the most common ocular presentations of TB. Adnexal or orbital disease may be seen with preauricular lymphadenopathy. Because of the wide variability in the disease process, presenting complaints will vary. Most often, patients will complain of blurry vision that may or may not be associated with pain and red eye. In the rare case of orbital disease, proptosis, double vision, or extraocular muscle motility restriction may be the presenting complaint. Preseptal cellulitis in children with spontaneous draining fistula may also occur. In cases of both pulmonary and extrapulmonary TB, there may be ocular findings without ocular complaints. In patients with confirmed active pulmonary or active nonocular extrapulmonary TB, ocular incidence ranges from 1.4-5.74%. In HIV patients, the incidence of ocular TB may be higher, with a reported prevalence of from 2.8-11.4%. TB and the legal system Laws vary from state to state, but communicable-disease laws typically empower public health officials to investigate suspected cases of TB, including potential contacts of persons with TB. In addition, patients may be incarcerated for noncompliance with therapy. Pathophysiology Infection with M tuberculosis results most commonly from infected aerosol exposure through the lungs or mucous membranes. In immunocompetent individuals, this usually produces a latent/dormant infection; only about 5% of these individuals later show evidence of clinical disease. (See Etiology.) Alterations in the host immune system that lead to decreased immune effectiveness can allow M tuberculosis organisms to reactivate, with tubercular disease resulting from a combination of direct effects from the replicating infectious organism and from subsequent inappropriate host immune responses to tubercular antigens. Molecular typing of M tuberculosis isolates in the United States by restriction fragment-length polymorphism analysis suggests more than one third of new patient occurrences of TB result from person-to-person transmission, with the remainder resulting from reactivation of latent infection. Verhagen et al demonstrated that large clusters of TB are associated with an increased number of tuberculin skin testpositive contacts, even after adjusting for other risk factors for transmission.[12] The number of positive contacts was significantly lower for index cases with isoniazid-resistant TB compared with index cases with fully-susceptible TB. This suggests that some TB strains may be more transmissible than

other strains and that isoniazid resistance is associated with lower transmissibility. Uveitis caused by TB is the local inflammatory manifestation of a previously acquired primary systemic tubercular infection. There is some debate regarding molecular mimicry, as well as a nonspecific response to noninfectious tubercular antigens, which may produce active ocular inflammation in the absence of bacterial replication. Etiology M tuberculosis is a slow-growing, obligate aerobe and a facultative, intracellular parasite. The organism grows in parallel groups called cords (as seen in the image below). It retains many stains after decoloration with acid-alcohol, which is the basis of acid-fast stains. Acid-fast bacillus smear showing characteristic cording in Mycobacterium tuberculosis. Mycobacteria, such as M tuberculosis, are aerobic, non-sporeforming, nonmotile, facultative, intracellular, curved rods measuring 0.2-0.5 m by 2-4 m. Their cell walls contain mycolic, acid-rich, long-chain glycolipids and phospholipoglycans (mycocides) that protect mycobacteria from cell lysosomal attack and also retain red basic fuchsin dye after acid rinsing (acid-fast stain). Humans are the only known reservoir for M tuberculosis. The organism is spread primarily as an airborne aerosol from infected to noninfected individuals (although transdermal and GI transmission have been reported). These droplets are 1-5 m in diameter; a single cough can generate 3000 infective droplets, with as few as 10 bacilli needed to initiate infection. When inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. The organisms grow for 2-12 weeks, until they reach 1000-10,000 in number, which is sufficient to elicit a cellular immune response that can be detected by a reaction to the tuberculin skin test. Exposure to M tuberculosis can occur when common airspace is shared with an individual who is in the infectious stage of TB. Mycobacteria are highly antigenic, and they promote a vigorous, nonspecific immune response. Their antigenicity is due to multiple cell wall constituents, including glycoproteins, phospholipids, and wax D, which activate Langerhans cells, lymphocytes, and polymorphonuclear leukocytes. Because of the ability of M tuberculosis to survive and proliferate within mononuclear phagocytes, which ingest the bacterium, M tuberculosis is able to invade local lymph nodes and spread to extrapulmonary sites, such as the bone marrow, liver, spleen, kidneys, bones, and brain, usually via hematogenous routes. When a person is infected with M tuberculosis, the infection can take 1 of a variety of paths, most of which do not lead to actual TB. The infection may be cleared by the host immune system or suppressed into an inactive form called latent tuberculosis infection (LTBI), with resistant hosts controlling mycobacterial growth at distant foci before the development of active disease. Patients with LTBI cannot spread disease. Although mycobacteria are spread by blood throughout the body during initial infection, primary extrapulmonary disease is rare except in immunocompromised hosts. Infants, older persons, or otherwise immunosuppressed hosts are unable to control mycobacterial growth and develop disseminated (primary miliary) TB. Patients who become immunocompromised months to years after primary infection also can develop late, generalized disease. The lungs are the most common site for the development of TB; 85% of patients with TB present with pulmonary complaints. Extrapulmonary TB can occur as part of a primary or late generalized infection. An extrapulmonary location may also

serve as a reactivation site; extrapulmonary reactivation may coexist with pulmonary reactivation. The most common sites of extrapulmonary disease are mediastinal, retroperitoneal, and cervical (scrofula) lymph nodes; vertebral bodies, adrenals, meninges, and the GI tract. That pathology of these lesions is similar to that in the lungs. (The most common site of tuberculous lymphadenitis (scrofula) is in the neck, along the sternocleidomastoid muscle. It is usually unilateral and causes little or no pain. Advanced cases of tuberculous lymphadenitis may suppurate and form a draining sinus.) Infected end organs typically have high, regional oxygen tension (as in the kidneys, bones, meninges, eyes, and choroids, and in the apices of the lungs). The principal cause of tissue destruction from M tuberculosis infection is related to the organism's ability to incite intense host immune reactions to antigenic cell wall proteins. Lesions in TB development The typical TB lesion is epithelioid granuloma with central caseation necrosis. The most common site of the primary lesion is within alveolar macrophages in subpleural regions of the lung. Bacilli proliferate locally and spread through the lymphatics to a hilar node, forming the Ghon complex. Early tubercles are spherical, 0.5- to 3-mm nodules with 3 or 4 cellular zones demonstrating (1) a central caseation necrosis, (2) an inner cellular zone of epithelioid macrophages and Langhans giant cells admixed with lymphocytes, (3) an outer cellular zone of lymphocytes, plasma cells, and immature macrophages, and (4) a rim of fibrosis (in healing lesions). Initial lesions may heal and the infection become latent before symptomatic disease occurs. Smaller tubercles may resolve completely. Fibrosis occurs when hydrolytic enzymes dissolve tubercles, and larger lesions are surrounded by a fibrous capsule. Such fibrocaseous nodules usually contain viable mycobacteria and are potential lifelong foci for reactivation or cavitation. Some nodules calcify or ossify and are seen easily on chest radiographs. Tissues within areas of caseation necrosis have high levels of fatty acids, low pH, and low oxygen tension, all of which inhibit growth of the tubercle bacillus. If the host is unable to arrest the initial infection, the patient develops progressive, primary TB with tuberculous pneumonia in the lower and middle lobes of the lung. Purulent exudates with large numbers of acid-fast bacilli can be found in sputum and tissue. Subserosal granulomas may rupture into the pleural or pericardial spaces and create serous inflammation and effusions. With the onset of host-immune response, lesions that develop around mycobacterial foci can be either proliferative or exudative. Both types of lesions develop in the same host, since infective dose and local immunity vary from site to site. Proliferative lesions develop where the bacillary load is small and host cellular-immune responses dominate. These tubercles are compact, with activated macrophages admixed, and are surrounded by proliferating lymphocytes, plasma cells, and an outer rim of fibrosis. Intracellular killing of mycobacteria is effective, and the bacillary load remains low. Exudative lesions predominate when large numbers of bacilli are present and host defenses are weak. These loose aggregates of immature macrophages, neutrophils, fibrin, and caseation necrosis are sites of mycobacterial growth. Without treatment, these lesions progress and infection spreads. Risk factors Four factors contribute to the likelihood of transmission, as follows: Number of organisms expelled

Concentration of organisms Length of exposure time to contaminated air Immune status of the exposed individual Infected patients living in crowded or closed environments pose a particular risk to noninfected persons. Approximately 20% of people in household contact develop infection (positive tuberculin skin test). Microepidemics have occurred in closed environments such as submarines and on transcontinental flights. Populations at high risk for acquiring the infection also include hospital employees, inner-city residents, nursing home residents, and prisoners. Increased risk of acquiring active disease occurs with HIV infection, intravenous (IV) drug abuse, alcoholism, diabetes mellitus (3-fold risk), silicosis, immunosuppressive therapy, cancer of the head and neck, hematologic malignancies, endstage renal disease, intestinal bypass surgery or gastrectomy, chronic malabsorption syndromes, and low body weight. The risk is also higher in infants younger than 5 years. Tumor necrosis factor-alpha (TNF-a) antagonists, used in the treatment of rheumatoid arthritis, psoriasis, and several other autoimmune disorders, have been associated with a significantly increased risk for TB.[13] Reports have included atypical presentations, extrapulmonary and disseminated disease, and deaths. Patients scheduled to begin therapy with a TNF- antagonist should be screened for latent TB and counseled regarding the risk of TB. Immunosuppressive therapy also includes chronic administration of systemic steroids (prednisone or its equivalent, given >15 mg/d for 4 wk or more) and/or inhaled steroids. Inhaled steroids, in the absence of systemic steroids, were associated with a relative risk of 1.5.[14] Smoking has been shown to be a risk factor for TB; smokers who develop TB should be encouraged to stop smoking to decrease the risk of relapse.[15] Obesity in elderly patients has been associated with a lower risk for pulmonary TB.[16] TB in children In children younger than 5 years, the potential for development of fatal miliary TB or meningeal TB is a significant concern. Osteoporosis, sclerosis, and bone involvement are more common in children with TB. The epiphyseal bones can be involved due to their high vascularity. Children do not commonly infect other children, because they rarely develop cough and sputum production is scant. However, cases of child-child and child-adult TB transmission are welldocumented. Go to Pediatric Tuberculosis for complete information on this topic. Epidemiology TB prevalence in the United States With the improvement of living conditions and the introduction of effective treatment (streptomycin) in the late 1940s, the number of patients in the United States reported to have tuberculosis (TB) underwent a steady decline (126,000 TB patients in 1944; 84,000 in 1953; 22,000 in 1984; 14,000 in 2004), despite explosive growth in the total population (140 million people in 1946, 185 million in 1960, 226 million in 1980). On a national level, the incidence of tuberculosis is at an all time low. In 2008, a total of 12,898 incident TB cases were reported in the United States, reflecting a 3.8% decline from 2007 to 4.2 cases per 100,000 population. [17] Demographics of TB in the United States Nearly half of all TB cases reported (49.2%) have been found to come from 7 states: California, Florida, Illinois, New York, New Jersey, Georgia, and Texas.

In 2007, almost 60% of cases of TB reportedly occurred among foreign-born persons. Approximately 52% of TB cases involving foreign-born individuals in 2007 were reported in persons from 4 countries: Mexico (24%), the Philippines (12.4%), India (8%), and Vietnam (7.4%). An estimated 10-15 million people in the United States have latent TB infection. International prevalence of TB and M tuberculosis infection Globally, more than 1 in 3 individuals is infected with tubercle bacillus. An estimated 9.27 million incident TB cases were reported internationally in 2007, an increase from 9.24 million in 2006. However, although the total number of cases increased, the number of cases per capita decreased from a global peak of 142 cases per 100,000 in 2004 to 139 cases per 100,000 in 2007. [1,
18]

Countries with the highest prevalence include Russia, India, Bangladesh, Pakistan, Indonesia, Philippines, Vietnam, Korea, China, Tibet, Hong Kong, Egypt, most sub-Saharan African countries, Brazil, Mexico, Bolivia, Peru, Colombia, Dominican Republic, Ecuador, Puerto Rico, El Salvador, Nicaragua, Haiti, Honduras, and areas undergoing civil war. The prevalence of TB in countries in Eastern Europe is intermediate. The prevalence of TB is lowest in Costa Rica, western and northern Europe, the United States, Canada, Israel, and most countries in the Caribbean. Africa, which is home to 13% of the world's population and 13 of the 15 countries with the highest TB incidence, shoulders over 25% of the annual global TB burden in terms of cases and deaths. Mortality in TB Internationally, TB a primary infectious cause of morbidity and mortality. As previously noted, WHO estimated that 1.7 million people worldwide died of TB in 2009.[1] In the United States, 2800 TB deaths are reported annually. Race prevalence As previously mentioned, in 2007 almost 60% of cases of TB reportedly occurred among foreign-born persons. This skewed distribution is most likely due to socioeconomic factors. Elevated rates of TB infection are seen in individuals immigrating from Mexico, the Philippines, India, Southeast Asia, Africa, the Caribbean, and Latin America. Based on 2007 CDC data, the frequency of TB in Hispanics, blacks, and Asians were 7.6, 8.5, and 23.5 times higher than in whites, respectively.[1] However, race is not clearly an independent risk factor, as foreign-born persons account for 77% of TB cases among Hispanics and 96% of TB cases among Asians, but only 29% of TB cases among blacks. Risk is best defined based on social, economic, and medical factors. Sex prevalence Despite the fact that TB rates have declined in both sexes in the United States, certain differences exist. TB rates in women decline with age, but in men, rates increase with age. In addition, men are more likely than women to have a positive tuberculin skin test result. The reason for these differences may be social, rather than biologic, in nature. The estimated sex prevalence for TB varies by source, from no sex prevalence to a male-to-female ratio in the United States of 2:1. Age predilection Higher rates of TB infection are seen in young, nonwhite adults (peak incidence, 25-40 y) than in white adults. In addition, white adults manifest the disease later (peak incidence, age 70 y) than do nonwhite persons.

In the United States, more than 60% of TB cases occur in persons aged 25-64 years; however, the age-specific risk is highest in persons older than age 65 years.[1] TB is uncommon in children aged 5-15 years. Prognosis Among published studies involving DOT treatment of tuberculosis (TB), the rate of recurrence ranges from 0-14%.[19] In countries with low TB rates, recurrences usually occur within 12 months of treatment completion and are due to relapse.[20] In countries with higher TB rates, most recurrences after appropriate treatment are probably due to reinfection rather than relapse.[21] Full resolution is generally expected with few complications in cases of non-MDR-TB and non-XDR-TB, when the drug regimen is completed. Poor prognostic markers include extrapulmonary involvement, an immunocompromised state, older age, and a history of previous treatment. Patient Education For patient education information, see the Bacterial and Viral Infections Center, as well as Tuberculosis. Additional information can be found through the following sources: CDC Division of Tuberculosis Elimination World Health Organization Tuberculosis Overview The following factors increase the likelihood that a patient will have tuberculosis (TB): HIV infection History of a positive purified protein derivative (PPD) test result History of prior TB treatment TB exposure Travel to or emigration from a TB endemic area Homelessness, shelter-dwelling, incarceration Classic features associated with active TB are as follows: Cough Weight loss/anorexia Fever Night sweats Hemoptysis Chest pain With regard to chest pain, a dull aching consistent with pericardial TB can lead to cardiac tamponade or constriction and presents similarly to congestive heart failure. Genitourinary symptoms are less common in patients with TB. In women, dysuria, hematuria, and frequent urination may be present. In men, painful scrotal mass, prostatitis, orchitis, and epididymitis may be present. Signs and symptoms of extrapulmonary TB may be nonspecific. They can include leukocytosis, anemia, and hyponatremia due to the release of ADH (antidiuretic hormone)-like hormone from affected lung tissue. Elderly individuals with TB may not display typical signs and symptoms of TB infection because they may not mount a good immune response. Active TB infection in this age group may manifest as nonresolving pneumonitis. Pulmonary tuberculosis (TB) Typical symptoms of pulmonary TB include a productive cough, fever, and weight loss. Patients with pulmonary TB occasionally present with hemoptysis or chest pain. Other systemic symptoms include anorexia, fatigue, and night sweats. Tuberculous meningitis Patients with tuberculous meningitis may present with a headache that is either intermittent or persistent for 2-3 weeks.

Subtle mental status changes may progress to coma over a period of days to weeks. Fever may be low-grade or absent. Go to Tuberculous Meningitis for complete information on this topic. Skeletal TB The most common site of skeletal TB involvement is the spine (Pott disease). Symptoms include back pain or stiffness. Lowerextremity paralysis occurs in up to half of patients with undiagnosed Pott disease. Tuberculous arthritis usually involves only 1 joint. Although any joint may be involved, the hips and knees are affected most commonly, followed by the ankle, elbow, wrist, and shoulder. Pain may precede radiographic changes by weeks to months. Genitourinary TB Reported symptoms of genitourinary TB include flank pain, dysuria, and frequency. In men, genital TB may manifest as epididymitis or a scrotal mass. In women, genital TB may mimic pelvic inflammatory disease. TB is the cause of approximately 10% of sterility cases in women worldwide and of approximately 1% in industrialized countries. Go to Tuberculosis of the Genitourinary System and Imaging of Genitourinary Tuberculosis for complete information on these topics. Gastrointestinal TB Any site along the gastrointestinal tract may become infected. Symptoms of gastrointestinal TB are referable to the site infected, including the following: nonhealing ulcers of the mouth or anus; difficulty swallowing (with esophageal disease); abdominal pain mimicking peptic ulcer disease (with stomach or duodenal infection); malabsorption (with infection of the small intestine); and pain, diarrhea, or hematochezia (with infection of the colon). Physical Examination Physical examination findings associated with TB depend on the organs involved. Patients with pulmonary TB have abnormal breath sounds, especially over the upper lobes or involved areas. Rales or bronchial breath signs may be noted, indicating lung consolidation. Signs of extrapulmonary TB differ according to the tissues involved. Signs may include confusion, coma, neurologic deficit, chorioretinitis, lymphadenopathy, and cutaneous lesions. Lymphadenopathy in TB takes occurs as painless swelling of 1 or more lymph nodes, usually bilaterally; typically, anterior or posterior cervical chain or supraclavicular may be present. The absence of any significant physical findings does not exclude active TB. In high-risk patients, classic symptoms are often absent, particularly in patients who are immunocompromised or elderly. Up to 20% of patients with active TB may deny symptoms. Therefore, sputum sampling is essential when chest radiography findings are consistent with TB. Approach Considerations Obtain the following laboratory tests: Sputum for acid fast smear and culture Complete blood count (CBC) Chemistries, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) Alkaline phosphatase Total bilirubin Uric acid Creatinine HIV serology in all patients with tuberculosis (TB) and unknown HIV status For congenital TB, the best diagnostic test is the examination of the placenta for pathology, histology, and culture.

Mycobacterial blood cultures of the newborn may also be helpful. Treatment may be necessary until placental culture results are negative. If chest radiography findings suggest TB and sputum smear is positive for acid-fast bacilli, initiate treatment for TB. Ziehl-Neelsen staining of sputum is a simple 5-step process that takes approximately 10 minutes to accomplish. While highly specific for mycobacteria, this stain is relatively insensitive, and detection requires at least 10,000 bacilli per mL; most clinical laboratories currently use a more sensitive auramine-rhodamine fluorescent stain (auramine O). Routine culture uses a nonselective egg medium (LowensteinJensen or Middlebrook 7H10) and often requires more than 3-4 weeks to grow because of the 22-hour doubling time of M tuberculosis. Radiometric broth culture (BACTEC radiometric system) of clinical specimens significantly reduced the time (10-14 d) for mycobacterial recovery. Newer broth culture media and systems for isolation are available for use in clinical laboratories based on a fluorescent rather than a radioactive indicator. The indicator is inhibited by oxygen; as mycobacteria metabolize substrates in the tubes and use the oxygen, the tube begins to fluoresce.[22] Deoxyribonucleic acid (DNA) probes specific for mycobacterial ribosomal ribonucleic acid (RNA) identify species of clinically significant isolates after recovery. In tissue, polymerase chain reaction (PCR) amplification techniques can be used to detect M tuberculosis -specific DNA sequences and thus, small numbers of mycobacteria in clinical specimens.[23, 24] Extrapulmonary involvement occurs in one fifth of all TB cases, although 60% of patients with extrapulmonary manifestations of TB have no evidence of pulmonary infection on chest radiograph or sputum culture. Ocular TB can be especially difficult to identify, owing to its mimicry and its lack of accessible sampling; a high index of suspicion is required. The hallmark of extrapulmonary TB histopathology is the caseating granuloma, consisting of giant cells with central caseating necrosis. Rarely, if ever, are any TB bacilli seen. Altered mental status, neck stiffness, decreased level of consciousness, increased intracranial pressure, and cranial nerve involvement can indicate tuberculosis meningitis or tuberculoma. TB can directly seed the meninges and, if suspected, performing a lumbar puncture for evaluation of the cerebrospinal fluid is necessary. In addition, a tuberculoma can be substantiated based on an increase in intracranial pressure and computed tomography (CT) scanning/magnetic resonance imaging (MRI). If vertebral involvement (Pott disease) or brain involvement is suspected, it is important to consider that a delay in treatment could have severe repercussions for the patient (compression of the spinal cord and/or paraplegia); further evaluation is necessary with CT scanning or MRI. Tuberculin sensitivity Tuberculin sensitivity develops 2-10 weeks after infection and usually is lifelong. Multidrug-resistant TB Symptoms and radiographic findings do not differentiate MDRTB from fully susceptible TB. Suspect MDR-TB if the patient has a history of previous treatment for TB, was born in or lived in a country with a high prevalence of MDR-TB, has a known exposure to a MDR-TB case, or is clinically progressing despite standard TB therapy. Susceptibilities should be repeated if cultures remain positive after 2 months, even when initial susceptibilities did not reveal any resistance. Pregnancy Pregnancy provides an opportunity to screen for TB; all pregnant women can undergo tuberculin skin testing. If skin-

testing results are positive, chest radiography can be performed with lead shielding. Chest radiography should not be delayed during the first 3 months of pregnancy in patients with suggestive symptoms. TB in children Postnatal TB is contracted via the airborne route. The most common findings of postnatal TB include adenopathy and a lung infiltrate. However, the chest radiographic findings may be normal in infants with disseminated disease. Chest radiographs in children with TB may show only hilar lymphadenopathy or a patchy infiltrate. Most children with TB can be treated with isoniazid and rifampin for 6 months, along with pyrazinamide for the first 2 months if the culture from the source case is fully susceptible. Gastric aspirates or biopsies are not necessary if positive cultures have been obtained from the source case. Go to Pediatric Tuberculosis for complete information on this topic. Human immunodeficiency virus Individuals infected with HIV are at increased risk for TB, beginning within the first year of HIV infection.[25] Based on historical data, the initiation of antiretroviral therapy (ART) decreases the risk of developing TB in these patients.[26] In a study from Durban, South Africa, nearly 20% of patients starting ART had undiagnosed, culture-positive pulmonary TB. Neither cough nor acid-fast bacillus smear were sufficiently sensitive for screening. TB sputum cultures should be attempted before ART initiation in areas with a high prevalence of TB. [27] Patients with TB must be tested for HIV, and patients with HIV need periodic evaluation for TB with tuberculin skin testing and/or chest radiography. Patients with HIV and a positive tuberculin skin test result develop active TB at a rate of 3-16% per year. Patients with TB and HIV are more likely to have disseminated disease and less likely to have upper-lobe infiltrates or classic cavitary pulmonary disease. Patients with a CD4 count of less than 200/L may have mediastinal adenopathy with infiltrates. Cultures and Alternative Methodologies Patients suspected of having tuberculosis (TB) should submit sputum for smear and culture. Sputum should be collected in the early morning on 3 consecutive days. In hospitalized patients, sputum may be collected every 8 hours. However, the absence of a positive smear result does not exclude active TB infection. Approximately 35% of culture-positive specimens are associated with a negative smear result. In patients without spontaneous sputum production, sputum induction with hypertonic saline should be attempted. [28] Earlymorning gastric aspirate may also produce a good specimen, especially in children. Patients diagnosed with active TB should undergo sputum analysis for M tuberculosis weekly until sputum conversion is documented. Monitoring for toxicity includes baseline and periodic liver enzymes, CBC count, and serum creatinine. Another option is fiberoptic bronchoscopy with transbronchial biopsy and bronchial washings. Biopsy of bone marrow, liver, or blood cultures is occasionally necessary and may be helpful. Traditional mycobacterial cultures require weeks for growth and identification. Newer technologies, including ribosomal RNA probes and DNA PCR, allow identification within 24 hours. The DNA probes are approved for direct testing on smear-positive or smear-negative sputa. However, smear-positive specimens yielded higher sensitivity. Culture for acid-fast bacilli (AFB) is the most specific and allows direct identification and susceptibility of the causative organism; however, access to the organisms may require lymph node/sputum analysis, bronchoalveolar lavage, or aspirate of

cavity fluid or bone marrow. Unfortunately, obtaining the test results is slow (3-8 wk), and they have a very low positivity in some forms of disease. AFB stain is quick but requires a very high organism load for positivity. This is more useful in patients with pulmonary disease, but a delay in diagnosis can increase mortality, as other diagnostic testing may need to be considered. Blood cultures using mycobacteria-specific, radioisotopelabeled systems help to establish the diagnosis of active TB. Mycobacterial bacteremia (bacillemia) is detectable using blood cultures only if specialized systems are used. The bacilli have specific nutrient growth requirements not met by routine culture systems. Such blood cultures should be used for all patients with HIV who are suspected of having TB, because bacillemia is particularly prevalent in this population. If available, such cultures should be used for any patient highly suspected of having active TB. One study found an incidence of 88% mycobacterial infection (66% TB, 22% Mycobacterium avium complex [MAC]) detected by blood culture in stage IV HIV disease). Drug Susceptibility Testing Because conventional drug susceptibility tests for drug-resistant M tuberculosis take at least 3-8 weeks, Choi et al recommend direct DNA sequencing analysis as a rapid and useful method for detecting drug-resistant TB. In their clinical study of the use of direct DNA sequencing analysis for detecting drug-resistant TB, turnaround time of the direct DNA sequencing analysis was 3.8 +/- 1.8 days. A total of 113 sputum specimens from 111 patients in the study were tested for genes conferring resistance to isoniazid, rifampin, ethambutol, and pyrazinamide, and the results were compared with drug susceptibility tests. The sensitivity and specificity of the assay were 63.6% and 94.6% for isoniazid, 96.2 and 93.9% for rifampin, 69.2% and 97.5% for ethambutol, and 100% and 92.6% for pyrazinamide, respectively. [29] An automated molecular test that uses sputum samples for the detection of M tuberculosis and resistance to rifampin has been developed. In studies conducted in low-income countries, the sensitivity for TB was 98.3% (CI, 97-99%) using a single smear-positive sputum sample and 76.9% (CI, 72.4-80.8%) using a single smear-negative sputum sample. Sensitivity from smear-negative sputum samples increased to 90.2% when 3 samples were tested. The test correctly identified 94.4% (CI, 90.8-96.6%) of rifampin-resistant organisms and 98.3% (CI, 97.1-99%) of rifampin-sensitive organisms.[30, 31] Microscopic-observation drug susceptibility (MODS) and thinlayer agar (TLA) assays are inexpensive, rapid alternatives to conventional methods or molecular methods for TB drug susceptibility testing. WHO endorsed the MODS assay, as a direct or indirect test, for rapid screening of patients with suspected MDR-TB. The evidence is insufficient to recommend the use of the TLA assay for rapid screening, but this assay is a promising diagnostic technique. Further research is encouraged.[32] Chest Radiography Obtain a chest radiograph to evaluate for possible associated pulmonary findings (demonstrated in the images below). A traditional lateral and PA view should be ordered. In addition, an apical lordotic view may permit better visualization of the apices and increase the sensitivity of chest radiography for indolent or dormant disease. This radiograph shows a patient with typical radiographic findings of tuberculosis. Anteroposterior chest radiograph in a young ED patient presenting with cough and malaise. The radiograph shows a classic posterior segment right upper lobe

density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine, remotemedicine.org. Lateral chest radiograph of a patient with posterior segment right upper lobe density consistent with active tuberculosis. Image courtesy of Remote Medicine, remotemedicine.org. The chest film is also useful to screen for sarcoidosis, which closely imitates the clinical course of ocular TB. Radiologists look more decisively for signs of TB or sarcoid if the requesting physician simply asks to rule out sarcoid or TB. Chest radiographs may show a patchy or nodular infiltrate (as seen in the image below). TB may be found in any part of the lung, but upper-lobe involvement is most common. The lordotic view may better demonstrate apical abnormalities. Primary TB is more likely to mimic the appearance of routine community-acquired pneumonia on chest radiography, in contrast to reactivation TB. Studies have shown that either may be associated with pleural effusion or cavitation. Various patterns may be seen, as follows (these are further discussed below): Cavity formation - Indicates advanced infection and is associated with a high bacterial load Noncalcified round infiltrates - May be confused with lung carcinoma Homogeneously calcified nodules (usually 5-20 mm) Tuberculomas; represent old infection rather than active disease Miliary TB - Characterized by the appearance of numerous small, nodular lesions that resemble millet seeds on chest radiography (Go to Miliary Tuberculosis for complete information on this topic. Chest radiography (see the image below) consistent with TB indicates active disease in the symptomatic patient even in the absence of a diagnostic sputum smear. Similarly, normal chest radiographic findings in the symptomatic patient do not exclude TB, particularly in a patient who is immunosuppressed. In primary active TB, radiographic features of pulmonary tuberculosis are nonspecific, sometimes even normal. The chest radiograph typically shows a pneumonialike picture of an infiltrative process in the middle or lower lung regions, often associated with hilar adenopathy and/or atelectasis. In classic reactivation TB, pulmonary lesions are located in the posterior segment of the right upper lobe, apicoposterior segment of the left upper lobe, and apical segments of the lower lobes. Cavitation is most common; healing of tubercular regions results in the development of a scar with loss of lung parenchymal volume and calcification. In the presence of HIV or another immunosuppressive disease, lesions are often atypical. Up to 20% of patients who are HIV positive with active disease have normal chest radiographic findings. Old, healed TB presents differently, with dense pulmonary nodules found, with or without calcifications, in the hilar or upper lobes. Smaller nodules, with or without fibrotic scars, can be seen in the upper lobes. Nodules and fibrotic lesions are well demarcated, have sharp margins, and are dense. Persons with nodular or fibrotic scars with positive chest radiographic findings and positive PPD results should be treated as latent carriers. Calcified nodular lesions (granulomas) or apical pleural thickening has a lower risk of conversion. In disseminated/miliary tuberculosis, the chest radiograph commonly shows a miliary pattern, with 2-mm nodules that are histologically granulomas disseminated like millet seeds throughout the lung; however, chest radiographic patterns can

vary and can include upper lobe infiltrates with or without cavitation. In pleural tuberculosis, the pleural space can be involved in 2 ways: a hypersensitivity response with pleuritic pain and fever, or an empyema that can be seen on chest radiograph with associated pleural effusions. CT Scanning and Technetium Scanning CT scanning CT scanning of the chest may help to better define abnormalities in patients with vague findings on chest radiography. If vertebral involvement (Pott disease) or brain involvement is suspected in a patient, it is important to consider that a delay in treatment could have severe repercussions for the patient (compression of the spinal cord and/or paraplegia); further evaluation is necessary with computed tomography (CT) scanning or magnetic resonance imaging (MRI). Technetium scanning Technetium-99m (99m Tc) methoxy isobutyl isonitrile singlephoton emission CT (SPECT) scanning for solitary pulmonary nodules yields a high predictive value for distinguishing TB from malignancy. Therefore, it has the potential to serve as a low-cost alternative when positron emission tomography (PET) scanning is not available, especially in endemic areas.[33] Tuberculin Skin Testing and IGRA The primary screening for TB infection (active or latent) is the tuberculin skin test with purified protein derivative (PPD). The mechanism of tuberculin skin testing is based on the fact that latent TB infection induces a strong cell-mediated immune response by measuring the delayed-type hypersensitivity response to intradermal inoculation of tuberculin PPD. The PPD test is given in an intradermal injection of 5 units of purified protein derivative, preferably with a 26-, 27-, or 30gauge needle. These delayed-type hypersensitivity tests should be read between 48 and 72 hours after administration. A negative response in immunologically intact individuals measures less than 5 mm. Population-based criteria for PPD positivity are as follows: For patients who are HIV positive, have abnormal chest radiographic findings, have significant immunosuppression, or have had recent contact with persons with active TB, the cutoff is 5 mm or more induration. For patients who are intravenous drug users, residents of nursing homes, prisoners, impoverished persons, or members of minority groups, the cutoff is 10 mm or more induration. For patients who are young and in good health, the cutoff is 15 mm or more induration. Reactions in patients who have received the bacilli CalmetteGurin (BCG) vaccine should be interpreted the same as above, regardless of BCG history, according to CDC guidelines. An in vitro blood test based on interferon-gamma release assay (IGRA) with antigens specific for M tuberculosis can also be used to screen for latent TB infection and offers certain advantages over tuberculin skin testing.[34, 35] Currently available tests include QuantiFERON-TB Gold In-Tube (QFT-GIT), an enzyme-linked immunosorbent assay or ELISA based on ESAT-6, CFP-10, and TB 7.7 antigens and T-SPOT.TB, an enzyme-linked immunospot (ELISpot) assay based on ESAT-6 and CFP-10 antigens. Both tests measure in vitro T-cell interferon (IFN)-gamma in response to antigens highly specific for M tuberculosis and absent from the BCG vaccine and M avium.[36] Overall, sensitivity and specificity of IGRA are comparable to those of tuberculin skin testing; however, unlike tuberculin skin testing, a second encounter for reading is unnecessary. Results

are reported as positive, negative, or indeterminate. Patients with an indeterminate result may have evidence of immunosuppression and may be nonreactive on skin testing. [37] Neither tuberculin skin testing nor IGRA testing is sufficiently sensitive to rule out TB infection.[38] Approximately 20% of patients with active TB, particularly those with advanced disease, may have normal PPD test results. Limited data exist on the sensitivity of TST and IGRA tests in some situations; caution is recommended on the interpretation of these tests in infants and patients with immunosuppressive conditions.[36] A systematic review of QuantiFERON-TB Gold (QFT-G)/Gold in-Tube (QFT-G-IT) and T-SPOT.TB by Chang and Leung concluded that QFT-G had the highest positive likelihood ratio (48.1) for latent TB infection and T-SPOT.TB had the best negative likelihood ratio (0.10). A negative T-SPOT.TB result in middle-aged and older patients makes active TB very unlikely.[39] Results from a study by Leung et al indicated that tuberculin skin testing was not predictive of the subsequent development of active TB.[40] The authors followed 308 males with increased risk of TB due to a diagnosis of silicosis. A positive TSPOT.TB finding was associated with a relative risk of 4.5 for subsequent TB in the group overall and a relative risk of 8.5 among the men who did not receive preventive treatment for latent TB. CFP-10 spot count was more predictive than the ESAT-6 spot count. In a separate study by Diel et al, all subjects who developed active tuberculosis within 4 years after exposure to a smearpositive index case had positive results using QuantiFERONTB Gold in-tube.[41] A systematic review of QuantiFERON-TB Gold (QFT-G)/Gold in-Tube (QFT-G-IT) and T-SPOT.TB by Chang and Leung concluded that, at a 90% certainty threshold, latent TB infection is best diagnosed with QFT-G/QFT-G-IT and best excluded with T-SPOT.TB. Neither test can diagnose TB disease, but TSPOT.TB can exclude it in middle-aged and older patients.[39] Advantages to IGRA compared with PPD include the following: One patient visit Ex vivo tests No booster effect Independent of BCG vaccination Disadvantages of IGRA include the following: High cost More laboratory resources required Complicated process of lymphocyte separation Lack of prospective studies ELISpot Testing of Other Fluids Jafari et al found that an M tuberculosis specific ELISpot assay can be used to differentiate TB cases with sputum smear negative for acid-fast bacteria (AFB) from latent TB infection. In a prospective study of 347 patients suspected of having active TB who were unable to produce sputum or who had AFB-negative sputum smears, ELISpot testing of bronchoalveolar lavage fluid displayed a sensitivity and specificity of 91% and 80%, respectively, for the diagnosis of active pulmonary TB.[42] Additional Rapid Tests Other rapid tests are also available, such as BACTEC-460 (Becton-Dickinson), ligase chain reaction; and luciferase reporter assay (within 48 h) (Franklin Lakes). These tests have been developed for rapid drug-susceptibilities testing, which can be available within 10 days. Drug resistance tests such as the FASTPlaque TB-RIF for rifampin resistance can be used after growth in semiautomated

liquid cultures such as BACTEC-460; rifampin resistance can be used as a surrogate marker for isoniazid resistance. Urinalysis Urinalysis and urine culture can be obtained for patients with genitourinary complaints. Patients are often asymptomatic; however, significant pyuria and/or hematuria with no routine bacterial organisms should prompt urine culture for acid-fast bacilli. HIV Testing All patients who are diagnosed with active tuberculosis (TB) and who are not known to be HIV positive should be considered for HIV testing. Approach Considerations Isolate patients with possible tuberculosis (TB) infection in a private room with negative pressure (air exhausted to outside or through a high-efficiency particulate air filter). Medical staff must wear high-efficiency disposable masks sufficient to filter the tubercle bacillus. Continue isolation until sputum smears are negative for 3 consecutive determinations (usually after approximately 2-4 wk of treatment). Unfortunately, these measures are neither possible nor practical in countries where TB is a public health problem. For initial empiric treatment of TB, start patients on a 4-drug regimen: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Once the TB isolate is known to be fully susceptible, ethambutol (or streptomycin, if it is used as a fourth drug) can be discontinued. Patients with TB who are receiving pyrazinamide should undergo baseline or periodic serum uric acid assessments, and patients with TB who are receiving long-term ethambutol therapy should undergo baseline and periodic visual acuity and red-green color perception testing. The latter can be performed with a standard test, such as the Ishihara test for color blindness. After 2 months of therapy (for a fully susceptible isolate), pyrazinamide can be stopped. Isoniazid plus rifampin are continued as daily or intermittent therapy for 4 more months. If isolated isoniazid resistance is documented, discontinue isoniazid and continue treatment with rifampin, pyrazinamide, and ethambutol for the entire 6 months. Therapy must be extended if the patient has cavitary disease and remains culturepositive after 2 months of treatment. DOT is recommended for all patients. Patients on the above regimens as DOT can be switched to 2- to 3-times per week dosing after an initial 2 weeks of daily dosing. Patients on twice-weekly dosing must not miss any doses. Prescribe daily therapy for patients on self-administered medication. The chest radiograph below was taken in a patient who had undergone TB treatment. This is a chest radiograph taken after therapy was administered to a patient with tuberculosis. Pregnancy Active TB should be treated, even in women in the first stage of pregnancy. Isoniazid, rifampin, and ethambutol may be used. In the United States, pyrazinamide is reserved for women with suspected MDR-TB. Elsewhere in the world, pyrazinamide is commonly used in pregnant women with TB. Preventive treatment is recommended during pregnancy, especially in the following situations: Pregnant women with a positive tuberculin skin test result who are HIV seropositive or who have behavioral risk factors for HIV infection but who decline HIV testing Pregnant women with a positive tuberculin skin test result who have been in close contact with a patient who is smear-positive for pulmonary TB

Pregnant women who have had a documented tuberculin skin test conversion in the past 2 years Pregnant women are at an increased risk for isoniazid-induced hepatotoxicity and should undergo monthly ALT monitoring while on treatment. This risk continues 2-3 months into the postpartum period. Pyridoxine should also be administered to pregnant women receiving isoniazid. Breastfeeding can be continued during preventive therapy. Many experts recommend supplemental pyridoxine for the breastfed infant. Lin et al have reported that women diagnosed with TB during pregnancy are at an increased risk of having babies who are of low birthweight and small for gestational age. However, preterm birth was not more common in women with TB. [43] Postnatal TB Many experts increase the treatment duration to 9 or 12 months because of the possible impaired immune system in children younger than 12 months. BCG vaccine is not recommended in infants in the United States but is commonly used around the world. Tuberculosis in children Isoniazid tablets may be crushed and added to food. Isoniazid liquid without sorbitol should be used to avoid osmotic diarrhea, causing decreased absorption. Rifampin capsules may be opened and the powder added to food. If rifampin is not tolerated, it may be taken in divided doses 20 minutes after light meals. Ethambutol is often avoided in young children because of difficulties monitoring visual acuity and color perception. However, studies show that ethambutol (15 mg/kg) is well tolerated and can prevent further resistance if the child is infected with a resistant strain. Go to Pediatric Tuberculosis for complete information on this topic. Human immunodeficiency virus Individuals infected with HIV are at an increased risk for TB, beginning within the first year of HIV infection.[25] Based on historical data, the initiation of antiretroviral therapy (ART) decreases the risk of developing TB in these patients.[26] Treatment regimens for active or latent TB in patients with HIV infection are similar to the treatment of individuals who are HIV negative, but dose adjustments may be necessary.[44, 45] The most significant differences involve the avoidance of rifampin in patients who are on protease inhibitors. Rifabutin may be used in place of rifampin in such patients. Patients with HIV and TB may develop a paradoxical response when starting antiretroviral therapy. This response has been attributed to a stronger immune response to M tuberculosis. Clinical findings include fever, worsening pulmonary infiltrates, and lymphadenopathy. However, in an open-label, randomized trial, Abdool Karim et al concluded that the initiation of antiretroviral therapy during TB therapy significantly improved survival. The investigators looked at results from 642 patients with a TB/HIV coinfection, to determine the optimal initiation of antiretroviral agents. In the study, the simultaneous initiation of antiretroviral therapy with TB therapy (429 patients) decreased the death rate over a sequential approach (213 patients), with a mortality rate of 5.4 deaths per 100 person-years (25 deaths) compared with 12.1 deaths per 100 person-years (27 deaths), respectively. The relative reduction was 56%. These results provide further impetus for the integration of TB and HIV services. [46] Swaminathan et al compared intermittent (3 times/wk) antitubular treatment regimens in patients with HIV infection and newly diagnosed TB. Patients received either a 6-month, 4drug regimen or a 9-month, 4-drug regimen. A significantly lower bacteriologic recurrence rate was observed in the 9-month

group. Acquired rifampin resistance (ARR) was high, and neither mortality nor ARR was altered by lengthening TB treatment.[44] Meningitis Dexamethasone added to routine 4-drug therapy reduces complications. Prehospital regimen for TB-drug-related seizures A special regimen exists for patients with TB who are actively seizing or who have overdosed on antimycobacterial medication. In these patients, overdose with isoniazid should be suspected. Diazepam can be attempted to control seizure activity, but IV pyridoxine is the drug of choice, in a gram-forisoniazid-ingested-gram dose. If the ingested dose is unknown, 5 g of pyridoxine can be used empirically. For patients who are awake and alert, an oral dose of activated charcoal (1 g/kg) with sorbitol can be administered. Treatment of Multidrug-Resistant TB Once multidrug-resistant tuberculosis (MDR-TB) is suspected due to relevant history or epidemiologic information and after sputum is cultured with anti-TB drug sensitivity, treatment is implemented. Treatment must be started empirically prior to culture results; once results are known modification of therapy is necessary according to susceptibilities. (Costs are many times higher for the treatment of MDR-TB.) When initiating treatment, utilize at least 3-5 previously unused drugs in which there is in vitro susceptibility. The fluoroquinolone levofloxacin has been shown to be best suited long-term and should be included in the regimen. The complexity of MDR-TB treatment lies in the futility of using isoniazid and rifampin. Isoniazid has the strongest antibactericidal action and significantly contributes to making patients rapidly noninfectious; rifampin has unique antibacterial properties against dormant bacilli that are no longer in the active phase of replication. Never add a single new drug to a failing regimen. Administer at least 3 (preferably 4-5) of the following medications according to drug susceptibilities: aminoglycosides (ie, streptomycin, amikacin, capreomycin, kanamycin); fluoroquinolone (ie, levofloxacin, ciprofloxacin, ofloxacin); thioamides such as ethionamide or prothionamide; pyrazinamide; ethambutol; cycloserine; terizodone; or paraaminosalicylic acid. Consider rifabutin substitution for rifampin, as approximately 15% of rifampin-resistant strains are rifabutin sensitive. Do not use intermittent therapy. Surgery is recommended for patients with MDR-TB whose prognosis with medical treatment is poor. Surgery can be performed with a low mortality rate (< 3%), with prolonged periods of a chemotherapeutic regimen for more than 1 year after surgery. All patients should be closely observed for 2 years after completion of treatment, with a low threshold for referral to TB centers. Clusters of MDR-TB with 7-drug resistance have been reported and have a high infectivity rate. Successful MDR-TB treatment is more likely in association with such factors as a lower prior patient exposure to anti-TB drugs, a higher number of anti-TB drugs to which the infection is still susceptible, and a shorter time since the first TB diagnosis (indicating a less advanced disease). Continue treatment for MDR-TB for 18-24 months after sputum culture conversion. The drugs should be prescribed daily (no intermittent therapy), and the patient should always be on DOT. Weekend DOT may not be possible; therefore, giving selfadministered oral drugs on Saturdays and Sundays may be reasonable.

In a study by Diacon et al, TMC207 added to standard therapy for MDR-TB reduced the time to conversion to a negative sputum culture compared with placebo and increased the proportion of patients with conversion of sputum culture (48% vs 9%).[47] The diagnosis of XDR-TB is established with an isolate that is resistant to isoniazid, rifampin, at least 1 of the quinolones, and at least 1 injectable drug. Treatment options for XDR-TB are very limited, and XDR-TB carries a very high mortality rate. Surgical Resection Surgical resection of an infected lung may be considered to reduce the bacillary burden in patients with MDR-TB. Procedures include segmentectomy (rarely used), lobectomy, and pneumonectomy. Pleurectomies for thick pleural peel are rarely indicated. However, intraoperative infection of uninvolved lung tissue has been observed. Complications include the usual perioperative complications, recurrent disease, and bronchopleural fistulas. Complications Late complications of pulmonary TB include relapse, aspergilloma, bronchiectasis, broncholithiasis, fibrothorax, and possibly carcinoma. A copy of the chest radiograph at the time of completion of therapy should be provided to the patient to facilitate the diagnosis of late complications. The relapse rate following appropriate completed therapy is only 0-4% and occurs within the first 2 years after completion. Therefore, retreatment is usually unnecessary, especially after DOT. Aspergilloma is a fungus ball that develops in a residual lung abnormality (eg, pneumatocele, bulla, bleb, cyst). It may appear as a crescent sign on chest radiographs. Other superinfections may manifest with an air-fluid level (seen in the image below) and often contain mixed bacteria, including anaerobes. Pulmonary tuberculosis with air-fluid Level Hemoptysis is the most common late complication. Broncholithiasis is the result of spontaneous lymph node migration into the bronchial tree and may be associated with postobstructive pneumonia or esophageal perforation. Bronchiectasis may progress to chronic bronchitis; bleeding from submucosal bronchial veins is usually self-limited. Fibrothorax is the development of trapped lung due to pleural fibrosis and scarring. The risk of carcinoma is controversial but should be considered with newly developing clubbing. Complications of antibiotic therapy in TB can be severe. They include the following: Hepatitis Peripheral neuropathy Retrobulbar optic neuropathy Deterrence Patients with a clinically significant result on tuberculin skin testing or a positive IGRA result should receive a course of therapy once active infection and disease are ruled out. Guidelines published by the CDC in 2000 refer to this as treatment of latent tuberculosis (TB). The recommended regimens are listed below: Isoniazid daily for 9 months Isoniazid twice weekly for 9 months (administered as DOT) Isoniazid daily for 6 months (should not be used in patients with fibrotic lesions on chest radiography, patients with HIV, or children) Isoniazid twice weekly for 6 months (administered as DOT; should not be used in patients with fibrotic lesions on chest radiography, patients with HIV, or children)

Rifampin daily for 4 months Another regimen, rifampin plus pyrazinamide daily for 2 months, is no longer recommended, because of an increased risk for liver toxicity. Children should receive isoniazid for 9 months. In addition, children younger than age 5 years who have close contact with a person who has active TB should be started on isoniazid, even if the results on skin testing are negative; preventive therapy can be stopped if the results on repeat skin testing are negative 2-3 months after last contact with a culture-positive source case. Household contacts to patients with MDR-TB have a particularly high risk for tuberculosis, 7.8% within 4 years in a study from Lima, Peru.[48] Limited data are available on regimens for the treatment of patients exposed to MDR-TB. However, if treatment is initiated, at least 2 drugs should be given, and the index isolate should be susceptible to all drugs used Recommended regimens in patients with HIV infection include rifampin alone daily for 4 months or isoniazid, daily or twice weekly, for 9 months. Patients on antiretroviral therapy may need rifabutin instead of rifampin because of potential drug interactions. The 2-month combination of pyrazinamide plus rifampin is no longer recommended for patients with HIV. The BCG vaccine continues to be used throughout much of the world and provides protection mostly until early childhood. Immunity begins to wane as early as 3 months after administration.[49] As previously noted, use of the BCG vaccine is not recommended in infants in the United States. Outpatient Care On patient discharge, conduct monthly follow-up appointments with the patient for sputum mycobacterial culture and sensitivity. Because of the prolonged course of anti-TB therapy, inpatient care is excessively costly and impractical. Local county health departments are expert and funded in the care of TB infection. Consultations The public health sector should be notified and involved in cases of TB. Consultation with a primary care, pulmonology, internal medicine, or infectious disease specialist prior to initiating therapy is helpful, and it may be appropriate for this consultant to manage the antitubercular chemotherapy. Consult an expert on MDR-TB in cases of multidrug resistance. Medication Summary The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Treatment of tuberculosis has 3 basic therapeutic principles. First, any regimen must use multiple drugs to which M tuberculosis is susceptible. Second, the therapy must be taken regularly. Third, the therapy must continue for a period sufficient to resolve the illness. New cases are initially treated with 4 drugs: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin for 2 months; they are then treated with a continuation phase of 4 months with isoniazid and rifampin. Retreatment cases should initially receive at least 5 drugs, including isoniazid, rifampin, and at least 2 new drugs to which the patient has not been exposed. Antitubercular agents Class Summary The goals of tuberculosis (TB) treatment are to shorten the clinical course of TB, prevent complications, prevent the development of latency and/or subsequent recurrences, and decrease the likelihood of TB transmission. In patients with latent TB, the goal of therapy is to prevent progression of disease. View full drug information

Isoniazid This is the drug of choice for preventive therapy and the primary drug in combination therapy for active TB. In patients receiving treatment for active TB, pyridoxine 25-50 mg PO qd should be coadministered to prevent peripheral neuropathy.. Rifampin (Rifadin) Rifampin is used in combination with at least 1 other antituberculous drug. It inhibits DNA-dependent bacterial, but not mammalian, RNA polymerase. Cross-resistance may occur. In most susceptible cases, the patient undergoes 6 months of treatment. Treatment lasts for 9 months if the patient's sputum culture result is still positive after 2 months of therapy. Pyrazinamide This is a pyrazine analog of nicotinamide that is either bacteriostatic or bactericidal against M tuberculosis, depending on the concentration of drug attained at site of infection. Pyrazinamide's mechanism of action is unknown. Administer the drug for the initial 2 months of a 6-month or longer treatment regimen for drug-susceptible TB. Treat drugresistant TB with individualized regimens. Ethambutol (Myambutol) Ethambutol diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). It impairs cell metabolism by inhibiting the synthesis of 1 or more metabolites, which in turn, causes cell death. No cross-resistance has been demonstrated. Mycobacterial resistance is frequent with previous therapy. In such cases, use ethambutol in combination with second-line drugs that have not been previously administered. Administer every 24 hours until permanent bacteriologic conversion and maximal clinical improvement are observed. Absorption is not significantly altered by food. Streptomycin Streptomycin sulfate is used for the treatment of susceptible mycobacterial infections. Use this agent in combination with other antituberculous drugs (eg, isoniazid, ethambutol, rifampin). The total period of treatment for TB is a minimum of 6 months. However, streptomycin therapy is not commonly used for the duration of therapy. The drug is recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated. Levofloxacin (Levaquin) Levofloxacin, a second-line drug, is used in combination with rifampin and other antituberculous agents in TB treatment. Levofloxacin is useful in treating most cases of MDR-TB. Moxifloxacin (Avelox) Moxifloxacin inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Rifapentine (Priftin) This agent is used in once-weekly regimens along with isoniazid. Rifapentine should not be used in individuals with HIV or with positive cultures after 2 months of treatment. Ethionamide (Trecator) Ethionamide is a second-line drug that is bacteriostatic against M tuberculosis. It is recommended if treatment with first-line drugs (isoniazid, rifampin) is unsuccessful. Ethionamide can be used to treat any form of active TB. However, it should be used only with other effective antituberculous agents.

Amikacin Amikacin is a second-line drug that irreversibly binds to the 30S subunit of bacterial ribosomes. It blocks the recognition step in protein synthesis, causing growth inhibition. Use the patient's ideal body weight for dosage calculation. Cycloserine (Seromycin) Cycloserine, a second-line drug, inhibits cell wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in M tuberculosis. It is a structural analogue of D-alanine, which antagonizes the role of D-alanine in bacterial cell wall synthesis, inhibiting growth. Capreomycin (Capastat) Capreomycin is a second-line drug that is obtained from Streptomyces capreolus for coadministration with other antituberculous agents in pulmonary infections caused by capreomycin-susceptible strains of M tuberculosis. Capreomycin is used only when first-line agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli. Rifabutin (Mycobutin) This is an ansamycin antibiotic derived from rifamycin S. Rifabutin inhibits DNA-dependent RNA polymerase, preventing chain initiation. It is used for TB treatment in individuals on specific HIV medications, when rifampin is contraindicated (most protease inhibitors). Clofazimine (Lamprene) Clofazimine inhibits mycobacterial growth, binding preferentially to mycobacterial DNA. It has antimicrobial properties, but its mechanism of action is unknown. Always use this drug with other antituberculous agents. Para-aminosalicylic acid (Paser) This is a bacteriostatic agent that is useful against Mycobacterium tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. Administer aminosalicylate sodium with other antituberculous drugs.

PLEURAL EFFUSION
Background Approximately 1 million pleural effusions are diagnosed in the United States each year. The clinical importance of pleural effusions ranges from incidental manifestations of cardiopulmonary diseases to symptomatic inflammatory or malignant diseases, as shown in the image below, requiring urgent evaluation and treatment. Large, malignant, right-sided pleural effusion. Other eMedicine articles on pleural effusion include Pleural Effusion (from Emergency Medicine), Effusion, Pleural (from Radiology), Pleural Effusion (from Pediatrics), and Parapneumonic Pleural Effusions and Empyema Thoracis. Pathophysiology The normal pleural space contains approximately 1 mL of fluid, representing the balance between (1) hydrostatic and oncotic forces in the visceral and parietal pleural vessels and (2) extensive lymphatic drainage. Pleural effusions result from disruption of this balance. Epidemiology Frequency

United States The estimated incidence of pleural effusion is 1 million cases per year, with most effusions caused by congestive heart failure, malignancy, infections, and pulmonary emboli. International The estimated prevalence of pleural effusion is 320 cases per 100,000 people in industrialized countries, with a distribution of etiologies related to the prevalence of underlying diseases. History Dyspnea is the most common symptom associated with pleural effusion and is related more to distortion of the diaphragm and chest wall during respiration than to hypoxemia. In many patients, drainage of pleural fluid alleviates symptoms despite limited improvement in gas exchange. Underlying intrinsic lung or heart disease, obstructing endobronchial lesions, or diaphragmatic paralysis can also cause dyspnea, especially after coronary artery bypass surgery. Drainage of pleural fluid may partially relieve symptoms but, as importantly, may allow the underlying disease to be recognized on repeat chest radiographs. Less common symptoms from pleural effusions include mild nonproductive cough or chest pain. Other symptoms may suggest the etiology of the pleural effusion. For example, more severe cough or production of purulent or bloody sputum suggests an underlying pneumonia or endobronchial lesion. Constant chest wall pain may reflect chest wall invasion by bronchogenic carcinoma or malignant mesothelioma. Pleuritic chest pain suggests either pulmonary embolism or an inflammatory pleural process. Persistent systemic toxicity evidenced by fever, weight loss, and inanition suggests empyema. Physical Physical findings, which do not usually manifest until pleural effusions exceed 300 mL, include the following: Decreased breath sounds Dullness to percussion Decreased tactile fremitus Egophony (E-to-A change) Pleural friction rub Mediastinal shift away from the effusion: This is observed with effusions of greater than 1000 mL. Displacement of the trachea and mediastinum toward the side of the effusion is an important clue to obstruction of a lobar bronchus by an endobronchial lesion, which can be due to malignancy or, less commonly, a nonmalignant cause such as a foreign body. Causes Transudates are usually ultrafiltrates of plasma in the pleura due to imbalance in hydrostatic and oncotic forces in the chest. However, they can also be caused by the movement of fluid from peritoneal spaces or by iatrogenic infusion into the pleural space from misplaced or migrated central venous catheters or nasogastric feeding tubes. Transudates are caused by a small, defined group of etiologies, including the following: Congestive heart failure Cirrhosis (hepatic hydrothorax) Atelectasis (which may be due to malignancy or pulmonary embolism) Hypoalbuminemia Nephrotic syndrome Peritoneal dialysis Myxedema Constrictive pericarditis In contrast, exudates are produced by a variety of inflammatory conditions and often require more extensive evaluation and

treatment. Exudates arise from pleural or lung inflammation, from impaired lymphatic drainage of the pleural space, and from transdiaphragmatic movement of inflammatory fluid from the peritoneal space. The more common causes of exudates include the following: Parapneumonic causes Malignancy (carcinoma, lymphoma, mesothelioma) Pulmonary embolism Collagen-vascular conditions (rheumatoid arthritis, lupus) Tuberculous Asbestos exposure Pancreatitis Trauma Postcardiac injury syndrome Esophageal perforation Radiation pleuritis Drug use Chylothorax Meigs syndrome Sarcoidosis Yellow nail syndrome Laboratory Studies Thoracentesis should be performed for new and unexplained pleural effusions when sufficient fluid is present to allow a safe procedure. Observation of pleural effusion(s) is reasonable when benign etiologies are likely, such as in the setting of overt congestive heart failure, viral pleurisy, or recent thoracic or abdominal surgery. Laboratory testing helps distinguish pleural fluid transudates from exudates; however, certain types of exudative pleural effusions might be suspected simply by observing the gross characteristics of the fluid obtained during thoracentesis. Note the following: Frankly purulent fluid indicates an empyema. A putrid odor suggests an anaerobic empyema. A milky, opalescent fluid suggests a chylothorax, resulting most often from lymphatic obstruction by malignancy or thoracic duct injury by trauma or surgical procedures. Grossly bloody fluid may result from trauma, malignancy, postpericardiotomy syndrome, and asbestosrelated effusion, and this indicates the need for a spun hematocrit test of the sample. A pleural fluid hematocrit level of more than 50% of the peripheral hematocrit level defines a hemothorax, which often requires tube thoracostomy. Classification of transudates and exudates The initial diagnostic consideration is distinguishing transudates from exudates. Although a number of chemical tests have been proposed to differentiate pleural fluid transudates from exudates, the tests first proposed by Light et al have become the criterion standards.[1] The fluid is considered an exudate if any of the following apply: Ratio of pleural fluid to serum protein greater than 0.5 Ratio of pleural fluid to serum lactate dehydrogenase (LDH) greater than 0.6 Pleural fluid LDH greater than two thirds of the upper limits of normal serum value These criteria require simultaneous measurement of pleural fluid and serum protein and LDH. However, a meta-analysis of 1448 patients suggested that the following combined pleural fluid measurements might have sensitivity and specificity comparable to the criteria from Light et al for distinguishing transudates from exudates[2] :

Pleural fluid LDH value greater than 0.45 of the upper limit of normal serum values Pleural fluid cholesterol level greater than 45 mg/dL Pleural fluid protein level greater than 2.9 g/dL Clinical judgment is required when pleural fluid test results fall near the cutoff points. The criteria from Light et al and these alternative criteria identify nearly all exudates correctly, but they misclassify approximately 20-25% of transudates as exudates, usually in patients on long-term diuretic therapy for congestive heart failure because of the concentration of protein and LDH within the pleural space due to diuresis.[3] Using the criterion of serum minus pleural protein concentration level of less than 3.1 g/dL, rather than a serum/pleural fluid ratio of greater than 0.5, more correctly identifies exudates in these patients.[4] Although pleural fluid albumin is not typically measured, a gradient of serum albumin to pleural fluid albumin less than 1.2 g/dL also identifies an exudate in such patients.[5] In addition, studies suggest that pleural fluid levels of Nterminal pro-brain natriuretic peptide (NT-proBNP) are elevated in effusions due to congestive heart failure.[6] More recently, elevated pleural NT-proBNP was shown to out-perform pleural fluid BNP as a marker of heart failurerelated effusion.[7] Thus, at institutions where this test is available, high pleural levels of NT-proBNP (defined in different studies as >1300-4000 ng/L) may help to confirm heart failure as the cause of an otherwise idiopathic chronic effusion. Pleural fluid LDH Pleural fluid LDH levels greater than 1000 IU/L suggest empyema, malignant effusion, rheumatoid effusion, or pleural paragonimiasis. Pleural fluid LDH levels are also increased in effusions from Pneumocystis jirovecii pneumonia; the diagnosis is suggested by a pleural fluid/serum LDH ratio greater than 1, with a pleural fluid/serum protein ratio less than 0.5. Pleural fluid glucose and pH In addition to these tests, glucose and pleural fluid pH should be measured during the initial thoracentesis in most situations. A low pleural glucose concentration (30-50 mg/dL) suggests malignant effusion, tuberculous pleuritis, esophageal rupture, or lupus pleuritis, and a very low pleural glucose concentration (ie, < 30 mg/dL) further restricts diagnostic possibilities to rheumatoid pleurisy or empyema. Handle pleural fluid samples as carefully as arterial samples for pH measurements, with fluid collected in heparinized syringes and ideally transported on ice for measurement within 6 hours. However, studies have shown that when collected in heparinized syringes, pleural fluid pH does not change significantly even at room temperature over several hours. Consequently, if appropriately collected samples can be processed quickly, pH measurements should not be canceled simply because the sample was not transported on ice. Pleural fluid pH is highly correlated with pleural fluid glucose levels. Pleural fluid pH less than 7.30 with a normal arterial blood pH level is caused by the same diagnoses as listed above for low pleural fluid glucose. However, for parapneumonic effusions, a low pleural fluid pH level is more predictive of complicated effusions (that require drainage) than is a low pleural fluid glucose level. In parapneumonic effusions, pleural fluid pH less than 7.1-7.2 indicates the need for urgent drainage of the effusion, and pleural fluid pH more than 7.3 suggests that the effusion may be managed with systemic antibiotics alone. In malignant effusions, pleural fluid pH less than 7.3 has been associated in some reports with more extensive pleural

involvement, higher yield on cytology, decreased success of pleurodesis, and shorter survival times. Pleural fluid cell count differential If an exudate is suspected clinically or is confirmed by chemistry test results, send the pleural fluid for total and differential cell counts, Gram stain, culture, and cytology. Pleural fluid lymphocytosis, with lymphocyte values greater than 85% of the total nucleated cells, suggests tuberculosis (TB), lymphoma, sarcoidosis, chronic rheumatoid pleurisy, yellow nail syndrome, or chylothorax. Pleural lymphocyte values of 50-70% of the nucleated cells suggest malignancy. Pleural fluid eosinophilia (PFE), with eosinophil values greater than 10% of nucleated cells, is seen in approximately 10% of pleural effusions and is not correlated with peripheral blood eosinophilia. PFE is most often caused by air or blood in the pleural space. Blood in the pleural space causing PFE may be the result of pulmonary embolism with infarction or benign asbestos pleural effusion. PFE may be associated with other nonmalignant diseases, including parasitic disease (especially paragonimiasis), fungal infection (coccidioidomycosis, cryptococcosis, histoplasmosis), and a variety of medications. The presence of PFE does not exclude a malignant effusion, especially in patient populations with a high prevalence of malignancy. The presence of PFE makes tuberculous pleurisy unlikely and makes the progression of a parapneumonic effusion to an empyema unlikely. Mesothelial cells are found in variable numbers in most effusions, but their presence at greater than 5% of total nucleated cells makes a diagnosis of TB less likely. Markedly increased numbers of mesothelial cells, especially in bloody or eosinophilic effusions, suggests pulmonary embolism as the cause. Pleural fluid culture and cytology Culture of infected pleural fluid yields positive results in approximately 60% of cases, and even less often for anaerobic organisms. Diagnostic yields may be increased by directly culturing pleural fluid into anaerobic blood culture bottles. Note the following: Malignancy is suspected in patients with known cancer or with lymphocytic, exudative effusions, especially when bloody. Direct tumor involvement of the pleura is diagnosed most easily by performing pleural fluid cytology. Heparinize samples (1 mL of 1:1000 heparin per 50 mL of pleural fluid) if bloody, and refrigerate if samples will not be processed within 1 hour. The reported diagnostic yields of cytology vary from 60-90%, depending on the extent of pleural involvement and the type of primary malignancy. The sensitivity of cytology is not highly related to the volume of pleural fluid tested; sending more than 50-60 mL of pleural fluid for cytology does not increase the yield of direct cytospin analysis,[8, 9] and volumes of approximately 150 mL are sufficient when both cytospin and cell block preparations are analyzed.[9] Cytology findings are positive in 58% of effusions related to mesothelioma. Tumor markers, such as carcinoembryonic antigen, Leu-1, and mucin, are suggestive of malignant effusions (especially adenocarcinoma) when pleural fluid values are very high; however, because of low sensitivity, they are not helpful if values are normal or only modestly increased. Suspect TB pleuritis in patients with a history of exposure or a positive purified protein derivative (PPD) finding and in patients with lymphocytic exudative effusions, especially if less than 5% mesothelial cells are detected on differential blood cell counts.

Because most tuberculous pleural effusions probably result from a hypersensitivity reaction to the Mycobacterium rather than from microbial invasion of the pleura, acid-fast bacillus stains of pleural fluid are rarely diagnostic (< 10% of cases), and pleural fluid cultures grow Mycobacterium tuberculosis in less than 65% of cases. In contrast, the combination of histology and culture of pleural tissue obtained by pleural biopsy increases the diagnostic yield to 90%. Adenosine deaminase (ADA) activity of greater than 43 U/mL in pleural fluid supports the diagnosis of TB pleuritis. However, the test has a sensitivity of only 78%; therefore, pleural ADA values less than 43-50 U/mL do not exclude the diagnosis of TB pleuritis.[10] Interferon-gamma concentrations in pleural fluid greater than 140 pg/mL also support the diagnosis of TB pleuritis, but this test is not routinely available. Additional tests Additional specialized tests are warranted when specific etiologies are suspected. Measure pleural fluid amylase levels if a pancreatic origin or ruptured esophagus is suspected, or if a unilateral left-sided pleural effusion remains undiagnosed after initial testing. Of note, increased pleural fluid amylase can also be seen with malignancy. An additional assay of amylase isoenzymes can help distinguish a pancreatic source (diagnosed by elevated pleural fluid pancreatic isoenzymes) from other etiologies. Measure triglyceride and cholesterol levels in milky pleural fluids when chylothorax or pseudochylothorax is suspected. Consider immunologic studies, including pleural fluid antinuclear antibody and rheumatoid factor, when collagenvascular diseases are suspected. Idiopathic exudative effusions Despite primary evaluation with repeated diagnostic thoracenteses, approximately 20% of exudative effusions remain undiagnosed. Clues to the diagnosis that may have been overlooked include (1) occupational exposure to asbestos 10-20 years earlier, which may suggest benign asbestos effusion; (2) medication exposure to nitrofurantoin, amiodarone, or medications associated with a drug-induced lupus syndrome; and (3) hepatic hydrothorax unrecognized in a patient with minimal or undetectable ascites. Chest CT scanning with contrast should be performed in all patients with an undiagnosed pleural effusion, if not previously performed, to detect thickened pleura or signs of invasion of underlying or adjacent structures. The 2 diagnostic imperatives in this situation are pulmonary embolism and tuberculous pleuritis. In both cases, the pleural effusion is a harbinger of potential future morbidity. In contrast, a short delay in diagnosing metastatic malignancy to the pleural space has less impact on future clinical outcomes. CT angiography should be ordered if pulmonary embolism is strongly suggested. Pleural biopsy should be considered, especially if TB or malignancy is suggested. Medical thoracoscopy with the patient under conscious sedation and local anesthesia has emerged as a diagnostic tool to directly visualize and take a biopsy specimen from the parietal pleura in cases of undiagnosed exudative effusions. As an alternative, closed-needle pleural biopsy is a blind technique that can be performed at the patient's bedside. Medical thoracoscopy has a higher diagnostic yield for malignancy; closed-needle pleural biopsy findings aid in diagnosis of only 7-12% of malignant effusions when cytology findings alone are negative. However, the yield of closed-needle pleural biopsy (histology plus culture) is as high as

thoracoscopy for TB pleuritis and is a useful alternative procedure for this diagnosis when available. In a randomized comparison of medical thoracoscopy with CT scanguided cutting-needle pleural biopsy (CT-CNPB), Metintas et al found no statistically significant difference in diagnostic sensitivity. The study included 124 patients with exudative pleural effusion who could not be diagnosed by cytologic analysis. These researchers recommend using CTANPB as the primary diagnostic procedure in patients with pleural thickening or lesions observed on CT scans, and using medical thoracoscopy in patients whose CT scans show only pleural fluid and in those who may have benign pleural pathologies other than TB.[11] Among patients with undiagnosed pleural effusions after the primary evaluation, those who meet all 6 of the following clinical parameters are predicted to have a benign course, and no further evaluation is necessary: Patients are clinically stable. Patients do not have weight loss. The results of the PPD test are negative and the pleural ADA value is less than 43 U/mL. The patient does not have a fever. The pleural fluid differential blood cell count has less than 95% lymphocytes. The effusion occupies less than 50% of the hemithorax. For other patients with undiagnosed exudative effusions, approximately 20% have a specific etiology determined, including malignancy. For such patients, weigh the benefits and risks of pursuing a diagnostic strategy that will involve using progressively more invasive procedures, given the low likelihood of finding a curable etiology. Note the following: Consider bronchoscopy only if a patient has parenchymal abnormalities or hemoptysis. Surgical approaches to the diagnosis of pleural effusions include thoracoscopy (pleuroscopy) and open thoracotomy, which reveal an etiology in 92% of effusions that remain undiagnosed after a medical evaluation. Where available, medical thoracoscopy may be both diagnostic and therapeutic; complete drainage of the effusion and talc sclerosis can be performed at the time of the procedure. Note that in most medical centers, surgical exploration using thoracoscopy or thoracotomy entails the risks of general anesthesia and is probably warranted only in patients who are symptomatic and anxious for a (potentially incurable) diagnosis. Imaging Studies Chest radiograph Effusions of more than 175 mL are usually apparent as blunting of the costophrenic angle on upright posteroanterior chest radiographs. On supine chest radiographs, which are commonly used in the intensive care setting, moderate-to-large pleural effusions may appear as a homogenous increase in density spread over the lower lung fields on a supine chest radiograph. Apparent elevation of the hemidiaphragm, lateral displacement of the dome of the diaphragm, or increased distance between the apparent left hemidiaphragm and the gastric air bubble suggests subpulmonic effusions. Note the image below. Chest radiograph showing left-sided pleural effusion. Lateral decubitus films more reliably detect smaller pleural effusions. Layering of an effusion on lateral decubitus films defines a freely flowing effusion and, if the layering fluid is 1 cm thick, indicates an effusion of greater than 200 mL that is amenable to thoracentesis. Failure of an effusion to layer on lateral decubitus films indicates loculated pleural fluid or some

other etiology causing the increased pleural density. Note the image below. Left lateral decubitus film showing freely layering pleural effusion. Ultrasonography and CT scanning A study by Gurung et al reviewed pleural fluid analysis, radiographic, sonographic, and echocardiographic findings in 41 consecutive patients with hepatic hydrothorax.[12] The study determined that hepatic hydrothorax virtually always presents with ascites that can be revealed by ultrasonography or CT scanning. Procedures Diagnostic thoracentesis Perform diagnostic thoracentesis if the etiology of the effusion is unclear or if the presumed cause of the effusion does not respond to therapy as expected. Pleural effusions do not require thoracentesis if they are too small to safely aspirate or, in clinically stable patients, if their presence can be explained by underlying congestive heart failure (especially bilateral effusions) or by recent thoracic or abdominal surgery. Relative contraindications to diagnostic thoracentesis include a small volume of fluid (< 1 cm thickness on a lateral decubitus film), bleeding diathesis or systemic anticoagulation, mechanical ventilation, and cutaneous disease over the proposed puncture site. Mechanical ventilation with positive end-expiratory pressure does not increase the risk of pneumothorax after thoracentesis, but it increases the likelihood of severe complications (tension pneumothorax or persistent bronchopleural fistula) if the lung is punctured. Complications of diagnostic thoracentesis include pain at the puncture site, cutaneous or internal bleeding, pneumothorax, empyema, and spleen/liver puncture. Pneumothorax complicates approximately 12-30% of thoracenteses but requires treatment with a chest tube in less than 5% of cases. Use of needles larger than 20 gauge increases the risk of a pneumothorax complicating the thoracentesis. In addition, significant chronic obstructive or fibrotic lung disease increases the risk of a symptomatic pneumothorax complicating the thoracentesis. In patients with large, freely flowing effusions and no relative contraindications to thoracentesis, diagnostic thoracentesis can usually be performed safely, with the puncture site initially chosen based on the chest radiograph and located at 1-2 rib interspaces below the level of dullness to percussion on physical examination. In other situations, ultrasound or chest CT imaging should be used to guide thoracentesis. After the site is disinfected with chlorhexidine (preferred) or povidone/iodine (no longer recommended) solution and sterile drapes are placed, anesthetize the skin, periosteum, and parietal pleura with 1% lidocaine through a 25-gauge needle. If pleural fluid is not obtained with the shorter 25-gauge needle, continue anesthetizing with a 1.5-inch, 22-gauge needle; for patients with larger amounts of subcutaneous tissue, a 3.5-inch, 22-gauge spinal needle with inner stylet removed can be used to anesthetize the deeper tissues and find the effusion. Confirm the correct location for thoracentesis by aspirating pleural fluid through the 25- or 22-gauge needle before introducing largerbore thoracentesis needles or catheters. If pleural fluid is not easily aspirated, stop the procedure and use ultrasound or chest CT imaging to guide thoracentesis. When possible, patients should sit upright for thoracentesis. Patients should not lean forward because this causes pleural fluid to move to the anterior costophrenic space and increases the risk of puncture of the liver or spleen. For debilitated and ventilated patients who cannot sit upright, obtain pleural fluid

by puncturing over the eighth rib at the mid-to-posterior axillary line. Such patients may require imaging to guide thoracentesis. Supplemental oxygen is often administered during thoracentesis, both to offset hypoxemia produced by changes in ventilation-perfusion relationships as fluid is removed and to facilitate reabsorption of pleural air if pneumothorax complicates the procedure. The frequency of complications from thoracentesis is lower when a more experienced clinician performs the procedure and when ultrasound guidance is used.[13] Consequently, a skilled and experienced clinician should perform thoracentesis in patients who have a higher risk of complications or relative contraindications for thoracentesis and for those patients who cannot sit upright. Postprocedure expiratory chest radiographs to exclude pneumothorax are not needed in asymptomatic patients after uncomplicated procedures (single needle pass without aspiration of air). However, postprocedure inspiratory chest radiographs are recommended to establish a new baseline for patients likely to have recurrent symptomatic effusions. Therapeutic thoracentesis Therapeutic thoracentesis to remove larger amounts of pleural fluid is used to alleviate dyspnea and to prevent ongoing inflammation and fibrosis in parapneumonic effusions. In addition to the precautions listed for diagnostic thoracentesis at the beginning of Procedures, note 3 additional considerations when performing therapeutic thoracentesis. First, to avoid producing a pneumothorax during the removal of large quantities of fluid, remove fluid during therapeutic thoracentesis with a catheter introduced into the pleural space rather than through a sharp needle. Various specially designed thoracentesis trays are available for introducing small catheters into the pleural space. Alternatively, newer systems using spring-loaded, blunt-tip needles that avoid lung puncture are also available. Second, monitor oxygenation closely during and after thoracentesis because arterial oxygen tension paradoxically might worsen after pleural fluid drainage due to shifts in perfusion and ventilation in the reexpanding lung. Consider use of empiric supplemental oxygen during the procedure. Third, only remove moderate amounts of pleural fluid to avoid reexpansion pulmonary edema and to avoid causing a pneumothorax. Note the following: Removal of 400-500 mL of pleural fluid is often sufficient to alleviate shortness of breath. The recommended limit is 1000-1500 mL in a single thoracentesis procedure. Larger amounts of pleural fluid can be removed if pleural pressure is monitored by pleural manometry and is maintained above -20 cm water.[14] However, this monitoring is rarely used by most proceduralists. The onset of chest pressure or pain during the removal of fluid indicates a lung that is not freely expanding, and the procedure should be stopped immediately to avoid reexpansion pulmonary edema.[14] In contrast, cough frequently occurs during removal of fluid, and this is not an indication to stop the procedure, unless the cough is causing the patient discomfort. The position of the mediastinum on the chest radiograph may predict whether a patient is likely to benefit from the procedure. A mediastinal shift away from the pleural effusion indicates a positive pleural pressure and compression of the underlying lung that can be relieved by thoracentesis. Note the image below. Massive right pleural effusion with shift of mediastinum towards left In contrast, a mediastinal shift towards the side of the effusion indicates lung entrapment by extensive pleural involvement or endobronchial obstruction that prevents

reexpansion of the lung when the pleural fluid is removed, or a trapped lung from encasement by chronic pleural thickening. Lung entrapment with malignant effusions is most common with mesothelioma or primary lung cancer. Attempts at therapeutic thoracentesis usually do not improve dyspnea in patients with lung entrapment, due to the inability of the lung to reexpand. In fact, attempts at drainage of fluid in these patients usually results in a hydropneumothorax visualized on postprocedure imaging studies. Note the image below. Lung entrapment with right hydropneumothorax and pleural drain in place Tube thoracostomy Although small, freely flowing parapneumonic effusions can be drained by therapeutic thoracentesis, most larger effusions and complicated parapneumonic effusions or empyemas require drainage by tube thoracostomy (see Treatment). Traditionally, large-bore chest tubes (20-36F) have been used to drain thick pleural fluid and to break up loculations in empyemas. However, such tubes are not always well tolerated by patients and are difficult to direct correctly into the pleural space. More recently, small-bore tubes (7-14F) inserted at the bedside or under radiographic guidance have been shown to provide adequate drainage, even when empyema is present. These tubes cause less discomfort and are more likely to be placed successfully within a pocket of pleural fluid. Using 20cm water suction and flushing the tube with normal saline every 6-8 hours may prevent occlusion of small-bore catheters. Insertion of additional pleural catheters, usually under radiographic guidance, or instilling fibrinolytics (eg, streptokinase, urokinase, or alteplase) through the pleural catheter can help drain multiloculated pleural effusions. Pleurodesis or pleural sclerosis Pleurodesis (also known as pleural sclerosis) involves instilling an irritant into the pleural space to cause inflammatory changes that result in bridging fibrosis between the visceral and parietal pleural surfaces, effectively obliterating the potential pleural space. Pleurodesis is most often used for recurrent malignant effusions, such as in patients with lung cancer or metastatic breast or ovarian cancer. Given the limited life expectancy of these patients, the goal of therapy is to palliate symptoms while minimizing patient discomfort, hospital length of stay, and overall costs. Patients with poor performance status (Karnofsky score < 70) and life expectancy of less than 3 months can be treated with repeated outpatient thoracentesis as needed to palliate symptoms. Unfortunately, pleural effusions can reaccumulate rapidly, and the risk of complications increases with repeated drainage. In addition, patients with lung entrapment from malignant effusions are not candidates for repeated thoracentesis, which does not provide relief of dyspnea in such patients, nor for pleurodesis, as the visceral and parietal pleural surfaces cannot stay apposed to allow the bridging fibrosis. The best treatment for effusions in such patients is the insertion of an indwelling tunneled catheter, which allows patients to remove pleural fluid as needed at home.[15] Various agents, including talc, doxycycline, bleomycin sulfate (Blenoxane), zinc sulfate, and quinacrine hydrochloride can sclerose the pleural space and effectively prevent recurrence of the malignant pleural effusion. Note the following: Talc is the most effective sclerosing agent and can be administered as slurry through chest tubes or pleural catheters. Although a systematic review suggested that direct insufflation of talc via thoracoscopy was more effective than talc slurry, both were equally effective in a 2005 prospective trial of malignant effusions.[16] Importantly, talc particles

tend to occlude the small drainage holes in small pleural catheters. Therefore, pleural catheters should be at least 1012F if intended for talc pleurodesis. Doxycycline and bleomycin are also effective in most patients and can be administered more easily through small-bore catheters, although they are somewhat less effective and substantially more expensive than talc. All sclerosing agents can produce fever, chest pain, and nausea. Talc rarely causes more serious adverse effects such as empyema and acute lung injury. The latter appears to be related to the particle size and amount of talc injected for pleurodesis. Injection of 50 mL of 1% lidocaine hydrochloride prior to instillation of the sclerosing agent might help alleviate pain. Additional analgesia might be required in some cases. Clamp chest tubes for approximately 2 hours after instillation of the sclerosing agent. A 2006 systematic review confirms that rotating the patient through different positions does not appear necessary to ensure distribution of soluble sclerosing agents throughout the pleural space. In addition, neither protracted drainage after instillation of sclerotics nor use of larger bore chest tubes increased the effectiveness of pleurodesis.[17] Pleural sclerosis is likely to be successful only if the pleural space is drained completely before pleurodesis and if the lung is fully reexpanded to appose the visceral and parietal pleura after sclerosis. Animal studies suggest that systemic corticosteroids can reduce inflammation during sclerosis and can cause pleurodesis failures. Medical Care Transudative effusions are usually managed by treating the underlying medical disorder. However, whether transudates or exudates, refractory large pleural effusions causing severe respiratory symptoms, even if the cause is understood and disease-specific treatment is available, can be drained to provide relief. The management of exudative effusions depends on the underlying etiology of the effusion. Pneumonia, malignancy, or TB causes most diagnosed exudative pleural effusions, with the remainder typically deemed idiopathic. Complicated parapneumonic effusions and empyemas should be drained to prevent development of fibrosing pleuritis. Malignant effusions are usually drained to palliate symptoms and may require pleurodesis to prevent recurrence. Medications cause only a small proportion of all pleural effusions and are associated with exudative pleural effusions. However, early recognition of these iatrogenic causes of pleural effusion avoids unnecessary additional diagnostic procedures and leads to definitive therapy, which is discontinuation of the medication. Implicated drugs include medications that cause drug-induced lupus syndrome (eg, procainamide, hydralazine, quinidine), nitrofurantoin, dantrolene, methysergide, procarbazine, and methotrexate. Of the common causes for exudative pleural effusions, parapneumonic effusions have the highest diagnostic priority. Even in the face of antibiotic therapy, infected pleural effusions can rapidly coagulate and organize to form fibrous peels that might require surgical decortication. Therefore, quickly assess pleural fluid characteristics predictive of a complicated course to identify parapneumonic effusions that require urgent tube drainage, which are observed more commonly in indolent anaerobic pneumonias than in typical community-acquired pneumonia. Note the following:

Indications for urgent drainage of parapneumonic effusions include (1) frankly purulent fluid, (2) pleural fluid pH less than 7.2, (3) loculated effusions, and (4) bacteria on Gram stain or culture. Patients with parapneumonic effusions who do not meet criteria for immediate tube drainage should improve clinically within 1 week with appropriate antibiotic treatment. Reassess patients with parapneumonic effusions who do not improve or who deteriorate clinically using chest CT imaging to evaluate the pleural space and direct further drainage attempts, if needed. Malignant pleural effusions usually signify incurable disease with considerable morbidity and a dismal mean survival of less than 1 year. For some patients, drainage of large malignant effusions relieves dyspnea caused by distortion of the diaphragm and chest wall produced by the effusion. Such effusions tend to recur, necessitating repeated thoracentesis, pleurodesis, or placement of indwelling tunneled catheters. Drainage systems using tunneled catheters (eg, PleurX, Denver Biomedicals, Denver, Colo; Aspira, Bard Access Systems, Salt Lake City, Utah) allow patients to drain their effusions as needed in the community. A meta-analysis and systemic review of 19 observational studies determined that pleural effusion drainage in patients on mechanical ventilation is safe and appears to improve oxygenation.[18] No data supported or refuted claims of beneficial effects on clinical outcomes such as duration of ventilation or length of stay. For patients with lung entrapment from malignant effusions, such indwelling tunneled catheter drainage systems are the preferred treatment and provide good palliation of symptoms. [19] In patients without lung entrapment, pleural sclerosis is another option to prevent recurrence of symptomatic effusions. Tuberculosis (TB) pleuritis typically is self-limited. However, because 65% of patients with primary TB pleuritis reactivate their disease within 5 years, empiric anti-TB treatment is usually begun pending culture results when sufficient clinical suspicion is present, such as an unexplained exudative or lymphocytic effusion in a patient with a positive PPD finding. Chylous effusions are usually managed by dietary and surgical modalities discussed below. However, studies suggest that somatostatin analogues also may help in reducing efflux of chyle into the pleural space. Surgical Care Surgical intervention is most often required for parapneumonic effusions that cannot be drained adequately by needle or smallbore catheters, and surgery might be required for diagnosis and sclerosis of exudative effusions. Note the following: Video-assisted thoracoscopy with the patient under local or general anesthesia allows direct visualization and biopsy of the pleura for diagnosis of exudative effusions. Pleural sclerosis by insufflating talc directly onto the pleural surface using video-assisted thoracoscopy is an alternative to using talc slurries. Decortication is usually needed for trapped lungs to remove a thick, inelastic pleural peel that restricts ventilation and produces progressive or refractory dyspnea. In patients with chronic, organizing parapneumonic pleural effusions, technically demanding operations might be required to drain loculated pleural fluid and to obliterate the pleural space. Surgically implanted pleuroperitoneal shunts are another treatment options for recurrent symptomatic effusions, most often in the setting of malignancy, but they are also used for management of chylous effusions. However, the shunts are prone to malfunction over time, are

poorly tolerated by patients, and can require surgical revision. In unusual cases, surgery might be required to close diaphragmatic defects (thereby preventing recurrent accumulation of pleural effusions in patients with ascites) and to ligate the thoracic duct to prevent reaccumulation of chylous effusions. Consultations A pulmonologist can be consulted for assistance with high-risk diagnostic thoracentesis, depending on the experience of the clinician. Drainage of complicated effusions usually requires consultation with a pulmonologist, interventional radiologist, or thoracic surgeon, depending on the location of the effusion and the clinical situation. Diet Restrictions of fat intake might help in the management of chylous effusions, although management remains controversial. Ongoing drainage of these effusions can rapidly deplete patients of fat and protein stores. Limiting oral fat intake might slow the accumulation of chylous effusions in some patients. Hyperalimentation or total parenteral nutrition can preserve nutritional stores and limit accumulation of the chylous effusion but probably should be restricted to patients in whom definitive therapy for the underlying cause of the chylous effusion is possible. Further Inpatient Care Monitoring pleural drainage Record the amount and quality of fluid drained and monitor for an air leak (bubbling through the water seal) each shift. Large air leaks (steady streams of air throughout the respiratory cycle) may be indications of loose connectors or of a drainage port on the catheter that has migrated out to the skin. Alternatively, they may indicate large bronchopleural fistulae. Consequently, dressings should be taken down and the position of the catheter inspected at the puncture site. Briefly clamping the catheter at the skin helps determine whether the air leak is originating from within the pleural cavity (in which case it stops when the tube is clamped) or from outside the chest (in which case the leak persists). Repeat the chest radiographs when drainage decreases to less than 100 mL/d to evaluate whether the effusion has been fully drained. If a large effusion persists radiographically, reevaluate the position of the chest catheter using chest CT scanning to ensure that the drainage ports are still positioned within the pleural collection. If the catheter is positioned appropriately, consider injecting lytics through the chest tube to break up clots that may be obstructing drainage. Alternatively, chest CT imaging may reveal lung entrapment/trapped lung, which is unlikely to respond to further drainage in the hospital. Prognosis Prognosis varies in accordance with the underlying etiology. Malignant effusions convey a very poor prognosis, with median survival of 4 months and mean survival less than 1 year. [20] Effusions from cancers that are more responsive to chemotherapy, such as lymphoma or breast cancer, are more likely to be associated with prolonged survival compared with those from lung cancer or mesothelioma. Parapneumonic effusions, when recognized and treated promptly, typically resolve without significant sequelae. However, untreated or inappropriately treated parapneumonic effusions may lead to constrictive fibrosis. Patient Education For excellent patient education resources, visit eMedicine's Lung and Airway Center.