The diagnosis of tuberculosis

The Diagnosis of Tuberculosis Philip A. LoBue, MD, and Antonino Catanzaro, MD urrently “the only effective measure for tuberculosis control is the identi$cation and treatment of patients with active disease or dormant infection to interrupt the chain of transmission” concluded a recent conference report on control of tuberculosis in the United States.’ This statement underscores the importance of rapid and accurate diagnosis of tuberculosis, including the ability to correctly distinguish between active disease and latent infection. The consequences of the failure to diagnose even a single case of tuberculosis in a timely manner can be disastrous. This is illustrated by an outbreak of disease in a small community in Maine.2 In a town that had reported no cases of tuberculosis in the previous 3 years, 2 1 new cases of active disease occurred over the next 3 years. All resulted from a single source patient in whom the disease went unrecognized for 8 months despite multiple visits to physicians during that time. Of 11.5 social contacts of the source patient, 61 (53%) had a positive skin test reaction in an area where prior screening indicated that the rate of positive skin tests was less that 1%. On the other hand, the difficulty in distinguishing between active versus inactive disease often leads to overtreatment. In a study of patients suspected of having pulmonary tuberculosis who had negative acid-fast bacillus (AFB) smears, treatment was begun for a presumptive diagnosis based on radiographic abnormalities.3 In the end 66 (only 16 of whom were culture proven) of 139 (48%) patients were determined to have active tuberculosis. Significant adverse reactions to therapy occurred in 8.3% of patients whose tuberculosis was inactive. In addition, such overtreatment uses limited public health resources in terms of both money and manpower, especially when directly observed therapy (DOT) is used. Correct diagnosis of tuberculosis can be difficult, even for physicians experienced in the field. Given our current knowledge and understanding of this disease, a three-step approach to diagnosis is recommended. First, it is necessary to be familiar with the epidemiologic aspects of the disease to identify patients who are at high risk of both primary infection and DM,

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TABLE1. Risk

factors

for tuberculosis

Socioeconomic

Blologlc

Contact

HIV

Household

Poor

Malnutrition

Source

Foreign-born

Immunosuppressive drugs (e.g. steroids)

High-risk occupation (e.g.,health care worker)

Diabetes

Long

Elderly/nursing

Malignancy

Poor ventilation

Racial/ethnic

Correctional

minority

home facility

Homeless

Chronic

renal

contact case

duration

highly

infectious

of exposure

failure

Silicosis

progressionto active disease.Second,one must be able to recognizeclinical syndromes and radiographic abnormalities compatible with pulmonary and/orextrapulmonarytuberculosis.Today one must be particularly cognizant of atypical clinical and radiographic presentationsof the diseaseand the types of patients (e.g., those with AIDS) who are likely to present in such a fashion. Finally, one must make judicious use of the currently available laboratorytestsso that a diagnosiscanbe arrived at in the most rapid, least invasive,and most cost-efficient manner. Epidemiologic

Considerations

The salient featuresof the epidemiology of tuberculosis with regard to diagnosisaresummarizedbriefly, andthe readeris referredto the chapter by McDermott and Glassrothin Part I of this article for a detailed review of this topic. In diagnosingtuberculosis,one must begin with evaluation of epidemiologic factors that may place the patient at increasedrisk of infection or progressionto active disease.These factors can be divided into the following categories:socioeconomic,biologic, and exposure-related (Table 1). Socioeconomic factors associatedwith an increasedlikelihood of developing tuberculosis include racial/ethnic minority status,low income, and homelessness.4-6 Becausemany countries have a much higher case rate than the United States,foreign birth (especially recent immigration from a third-world country) is a major risk factor for tuberculosis.7Persons in certain occupationshave also been associatedwith an increased risk of tuberculosis,including healthcareworkers,prison guards,migrant farm workers, and miners with silicosis.8-13Two other populations that deservespecial mention with regardto tuberculosis are elderly residents of nursing homes andinmates of correctional facilities.‘4-17 186

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The most important biologic or host factor contributing to the resurgence of tuberculosis in the United States and throughout the world is disease caused by human immunodeficiency virus (HIV).r8 There are two features of tuberculosis in HIV-infected patients of which the clinician must be especially cognizant. Extrapulmonary disease is very common and is more likely to occur as the patient’s HIV infection progresses and the CD4 count falls.19 In addition, radiographic abnormalities tend to be typical (i.e., fibronodular cavitary disease) in early HIV infection but often are very atypical (including such findings as diffuse infiltrates, predominantly lower lobe infiltrates, massive adenopathy, or normal) in advanced disease.20 A number of other medical conditions have been associated, to varying degrees, with an increased likelihood of developing active tuberculosis in persons with latent infection. They are, in general, associated with immunosuppression due to malnutrition, immunosuppressive medications used to treat another disorder, or immunosuppressive effects of the underlying disease itself. These conditions include chronic peptic ulcer disease/postgastrectomy, intestinal bypass surgery associated with significant weight loss, malnutrition, diabetes mellitus, chronic renal failure/dialysis, steroids and other immunosuppressive drugs, and cancer.” There is also a much higher risk of developing tuberculosis associated with the occupational lung disease, silicosis.22 Since tuberculosis is an airborne infection spread from one person to another, known exposure to an active case is a significant risk factor for infection and subsequent progression to active disease.‘? The risk of transmission of tuberculosis from one person to another is dependent on infectiousness of the source case, duration of exposure, proximity of contact (e.g., household contacts are more likely to convert skin tests than nonhousehold contacts), and environmental factors (e.g., poor ventilation).2J It is therefore very important to question any person suspected of having tuberculosis about close contacts who currently have or in the past have had tuberculosis.As much information as possible about the circumstances of this contact, especially in regard to the aforementioned factors, should be obtained.

Clinical Evaluation History and Physical Examination Because tuberculosis is generally insidious in onset, symptoms may be minimal or completely absent until the disease is advanced. In the case of reactivation pulmonary tuberculosis, the symptoms include cough, fever, sweats or chills, anorexia, weight loss, and malaise.2s.26 Cough, which DM,

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may be dry or productive, is the most common symptom and the most sensitiveindicator of active disease.27Hemoptysis due to bronchiectasis, erosion of a calcified lymph node into a bronchus,a fungal ball superinfecting a cavity, or a Rassmussen’saneurysm(an exposeddilated blood vesselwithin a cavity) may occur.2oDyspneais more likely to occur from pleural involvement(effusion),but frank respiratoryfailure may occurwith extensiveparenchymal or miliary disease.28Chest pain, usually pleuritic in nature,resultsfrom involvement of the pleura or parenchymadirectly adjacentto the pleura.2oIn addition to being insensitive,thesesymptoms are also fairly nonspecific and may be seenwith other lung infections or malignant conditions.They cannotbe usedto differentiateactive tuberculosis from old inactive diseasewith any certainty, either. For example, a patient may have a chest radiograph with upper lobe fibronodular infiltrates from old, currently quiescenttuberculosisand a productive cough, fever,weight loss,andhemoptysisdueto residualbronchiectasiswith bacterial superinfection. As with pulmonary tuberculosis,patientswith extrapulmonarydisease often have some combination of systemic symptoms (e.g.,fever, sweats, weight loss) and localized symptoms that can be attributedto specific organinvolvement.For example,headacheandchangesin mental statusmay indicate meningeal involvement, localized back pain is seenwith spinal disease,increasing abdominal girth (ascites)and abdominal pain occur with peritoneal tuberculosis,etc. Such complaints areobviously not specific for tuberculosis and also occur with other infections or malignant conditions involving theseorgans. The physical examination is not particularly helpful in the diagnosisof tuberculosisbecausephysical signs, like symptoms, are both insensitive and nonspecific. In the early phasesof active disease,there are often no abnormalphysical findings. As tuberculosisbecomesadvanced,physical examination may revealsystemic findings suchas fever andcachexiaand findings of local organ involvement (e.g., rales, rhonchi, and bronchial breathsounds:pulmonarydisease;ascitesandabdominaltenderness:peritoneal disease;enlarged,tender lymph nodes:lymphadenitis; neck stiffness:meningeal involvement; etc.) Routine Laboratory Test Routine laboratorytests(completeblood count, serumchemistry) areusually normal exceptin patientswith advanceddisease.26 The most common hematologic abnormalitiesare anemiaandleukocytosis,which aregenerally mild.25,2g Hyponatremia, resulting from the syndromeof inappropriateantidiuretichormone(SIADH) secretion,hasbeenreportedin approxi188

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mately 7% to 10% of cases of active tuberculosis.“‘).3’ Hypercalcemia is the other electrolyte abnormality that has been noted to occur in active tuberculosis.32 Clearly, these findings are all nonspecific and occur in many other pulmonary and systemic disorders. Serology The detection in the serum of microbial antigens or antibodies raised against such antigens is useful for diagnosing a number of infectious diseases. It is not surprising, therefore, that there is great interest in developing a serologic test for the diagnosis of tuberculosis. The first attempt to develop such a test dates back to 1898.3Y Since that time numerous investigators have tried with varying success to develop an assay that is both sensitive and specific. The description of the sensitive enzyme-linked immunosorbent assay (ELISA) in 1972 led to renewed hope for the possibility of rapid serodiagnosis of tuberculosis.. “J The subsequently published research in this area has been extensively reviewed.“6,37 Studies of ELISA using purified M.vcobacterium tuberculosis antigens (e.g., PPD, antigen 5,38K, 303 1 K, etc.) designed to detect antibodies that bind to these antigens found in patients’ serum have revealed a sensitivity ranging from 49% to 94% and a specificity of 79% to 100%.36.“7 Lacking a large, multicenter, controlled trial including patients with various, but clearly defined, stages of tuberculosis infection and active disease, none of these tests has gained acceptance in the United States. It has been suggested, however. that the time for such a trial has come.?’ There is also concern about how well such a test will perform in patients with AIDS as the limited data that exist in this population are not promising.-‘7,‘8 In the final analysis, serodiagnosis by ELBA may have the greatest utility in developing countries because it is relatively inexpensive and the higher prevalence of tuberculosis in those areas will increase its positive predictive value.‘8 An alternative approach to the search for antibodies is to attempt to detect tuberculosis antigens themselves in the serum or other body fluids. Although no test of this type has gained widespread acceptance, several small studies suggest this approach may have value in helping to diagnose extrapulmonary tuberculosis, especially meningitis (using cerebral spinal fluid).“” The Tuberculin

Skin Test

Tuberculin is made up of components of killedMycobacterium tuberculosis organisms from culture filtrate. When injected intracutaneously (Mantoux method) into persons previously sensitized to tuberculosis after priDM.

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mary infection, a delayed-typehypersensitivity response(manifestedby induration at the site of injection) occurs.This reactionis usually maximal at 48 to 72 hoursbut may not peak until later,especially in certainpopulations suchasthe elderly or personsof Indochineseorigin.39,4o In the United Statesthe favored preparationof tuberculin is purified protein derivative (PPD). PPD was first isolatedin 1932by Seibertand Mundy, who precipitated culture filtrate with trichloroacetic acid. A lot preparedin 1941by SeibertandGlenn, known asPPD-S, hassubsequentlybecomethe United Statesandinternational standardfor PPD. All PPD preparedin the United Statesis standardizedagainstPPD-S. The PPD test, while of great interest in patients being examined for tuberculosis,shouldnot be considereda diagnostic test. To begin with, it is not 100% sensitive or specific for the diagnosis of tuberculosisinfection. It certainly cannotdifferentiatebetweenlatent primary infection and active disease.In general,it is believedthat 10% to 25% of patients with active tuberculosisdo not reactto tuberculin injection, althoughtherehas been significant variability from study to study.41One group found that 96% of patients with tuberculosishad measurableinduration after tuberculin skin testing with an averagesize of 16to 17mm.42However,another investigatorreportedthat 20% of patientswith newly diagnosedtuberculosis confirmed by a positive sputum culture had a negativetuberculin skin test.43Certain subpopulations,suchasthosewith suppressedcellular immunity (including patientswith severe,widely disseminatedactive tuberculosisor HIV infection), may haveratesof false-negativetuberculin skin testsexceeding50%.41+4 For this reason,it must be rememberedthat when oneis interpreting PPD tests,a smaller degreeof induration (5 mm) is consideredindicative of infection in a number of high-risk groups.45 With time, the immune responseto PPD may wane.Therefore,especially in personsover the ageof 55, oneshould considerrepeatingthe tuberculin test in 1 to 2 weeks if thereis no significant initial reaction. Induration of adequatesize after this secondtest should be consideredas significant as whenit occursafteraninitial PPD. Suchareactionis known asthe“booster” phenomenon. False-positivesalso occur with tuberculin skin testing. Causesinclude errors in administering and interpreting the test, prior vaccination with bacille Calmette-Guerin(BCG), and prior infection with nontuberculous mycobacteria.41 The tuberculin skin testis usedto identify infectedpersons,not to diagnose active disease.Becauseprimary infection is a sine qua non for the developmentof illness dueto tuberculosis,onewould expectthat it would at least be a sensitive screeningtest for active tuberculosis.However, as 190

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previously discussed, this is not the case and a negative PPD reaction does not exclude a diagnosis of active tuberculosis. False-positives also occur for various reasons. Nevertheless, tuberculin skin testing should be performed on all patients with suspected active tuberculosis. A PPD response that is indicative of tuberculosis infection provides additional support for the diagnosis of active disease when other evidence (e.g., compatible clinical syndrome and/or radiographic findings, positive AFB smear, etc.) points in that direction. This supporting evidence can be critical in the evaluation of a case of tuberculosis because in the final analysis there is no single test that can be used to make or exclude the diagnosis of tuberculosis with 100% certainty.

Pulmonary Disease Radiographic

Imaging:

The Chest

Radiograph

Primary Tuberculosis. Primary tuberculosis refers to the initial pulmonary infection occurring in a patient as a result of inhalation of Mycobacterium tuberculosis containing droplets from an infectious source. Primary tuberculosis, in the past, has been thought of as a disease of children. In the United States, however, the incidence of primary tuberculosis in adults has been increasing and has been estimated to account for up to 34% of adult cases.46 The explanation for this finding is that, with the improved control of tuberculosis starting in the 195Os, more children reached adulthood without having come into contact with M. tuberculosis. As adults. this population is now susceptible and at risk of primary infection when exposed to a contagious case. 47This theory is supported by data from Philadelphia, where the rate of tuberculin skin test reactivity in teenagers decreased from 16.4% in 1948 to less than 1% in the early 1990~~~ In most cases of primary tuberculosis infection, the patient has no or minimal symptoms and the chest radiograph is normal. However, significant illness can develop in patients with marked radiographic abnormalities with progressive primary tuberculosis. There are five major radiographic manifestations of active primary pulmonary tuberculosis: parenchymal consolidation, atelectasis, lymphadenopathy, pleural effusion. and miliary disease (Fig. 1). 47 Parenchymal consolidation is usually unifocal, with multilobar disease occurring in up to 25% of cases.“8J9 It can occur in any lobe, and there is controversy regarding whether there is a predilection for specific lobes.“7 It has been reported that lower lobe involvement is more frequent in adults.12 These findings can be indistinguishable from those of bacterial lobar pneumonia. Segmental or lobar atelectasis is most common in children under 2 years of age, but it also DM,

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FIG.

1. Radiographic

manifestations

of primary

pulmonary

parenchymal infiltrate. B, Right middle lobe atelectasis. in an HIV-infected patient. D, Pleural effusion.

tuberculosis.

C, Hilar

and

A, Right mediastinal

lower

lobe

adenopathy

occurs in older children and adults.47 It results from endobronchial obstruction or extrinsic compression from lymphadenopathy, with the most common sites being the anterior segment of the upper lobe or the medial segment of the middle lobe. 51Enlargement of hilar or mediastinal lymph nodes occurs in up to 43% of adults and 96% of children with primary tuberculosis.47 It may be associated with parenchymal disease, or it may be the only radiographic abnormality. Pleural effusions are present in 6% to 7% of cases of primary tuberculosis. 46They are usually unilateral and free flowing. Although pleural effusion is often the only apparent abnor192

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TABLE

2. Radiographic

Primary

disease

Parenchymal infiltrates Atelectasis Lymphadenopathy Pleural effusion Miliary disease

findings:

Pulmonary

tuberculosis Reactivation

disease

Upper lobe predominance Cavitation Fibronodular disease Bronchiectasis Pleural thickening or scarring Hilar retraction Volume loss

mality in primary disease, computed tomography (CT) may reveal parenchymal disease or adenopathy, which is not seen on a plain chest film.5’ Miliary or disseminated tuberculosis makes up 1% to 7% of all forms of tuberculosis and may occur as a manifestation of primary tuberculosis.4647 The radiographic appearance is that of diffuse 1 to 3 mm nodules, which are usually, but not always, symmetrically distributed. In some cases, the nodules may not be easily detectable by plain film and a high-resolution CT scan (HRCT), which is more sensitive, may yield the diagnosis.‘? Persistent nodular or masslike opacities, known as tuberculomas, are generally thought to be residua of healed primary disease.5? A review of the literature has revealed that they are found in 7% to 9% cases of primary tuberculosis, usually are 3 cm or less in size and found in the upper lobes, often are multiple, may calcify. and generally remain stable in size over time.47 Reactivation or Postprimary Tuberculosis. Reactivation, also known aspostprimary tuberculosis, describes tuberculous disease that occurs after the primary infection has become latent. It is estimated that the overall lifetime risk for reactivation in persons with latent primary infection is ~O’%J.~” Unlike primary tuberculosis, reactivation tuberculosis is essentially a disease of adults. Although any of the radiographic abnormalities already described for primary disease may be seen with reactivation, there are several features that serve to distinguish these two entities (Table 2, Fig. 2). The first characteristic of reactivation tuberculosis is its predilection for the upper lobes. The most commonly involved segments are the apical and posterior upper lobe segments and the superior segment of the lower lobe.17 Whereas infiltrates in the anterior segment of the upper lobe or the basilar segments of the lower lobe are not unusual in combination with disease in the commonly involved areas listed previously, it is very rare to have isolated abnormalities in these segments. 49 The second abnormality associated with reactivation is cavitation, which occurs on average in about 50% of casesJi DM,

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FIG.

2.

loss,

and fibronodulor

Radiographic

manifestations

of reactivation

disease.

Upper

lobe

infiltrates,

volume

disease.

Cavities aremore frequently multiple than solitary andmay be thin walled or thick walled.46,49 Air fluid levels are present as much as 22% of the time.55In tuberculosisthere is generally some surrounding infiltrate, so that the appearanceof a single cavity without adjacentreaction should lead to considerationof alternativediagnoses.46 Over time, the opacitiesand/orinfiltrates in the upperlobe developinto more defined reticular and nodular lesions or what is often called “fibronodular” or “fibroproliferative” disease.47 As this processcontinues, hilar retraction and volume loss become evident. Unfortunately, this is sometimes read as old, inactive, or healed tuberculosis.Chest radiography, by itself, cannotbe usedto determineactivity of disease,and the use of such terminology can lead to misdiagnosisof active cases.49 Even stability of suchabnormalities for severalmonths or more doesnot exclude active tuberculosis.46 Bronchial stenosisand bronchiectasisare two other relatively common manifestationsof reactivationtuberculosis.Thesefindings areoften easier to seeon chestCT scansthan on plain films.47 Pleural involvement may also be seenwith postprimary tuberculosis.It is usually manifestedby pleuralthickening.Whenthis happensin the apex, it contributesto the abnormality referredto as “apical capping.“47Pleural effusions occur but are less common than in primary disease.One study found that 19% of tuberculosispleural effusions were associatedwith reactivation.56Air fluid levels in the pleural spaceindicate the presenceof a bronchopleuralfistula.57 194

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In immunocompetent hosts, hilar and mediastinal lymphadenopathy are rare and have been reported to occur in as few as 5% of cases of postprimary tuberculosis.49 Adenopathy is usually associated with extensive parenchyma1 disease. Miliary disease can also occur with reactivation but is thought to be more commonly associated with primary infection.46 Radiographic Changes of Tuberculosis in HIV-Infected Patients. The radiographic appearance of pulmonary tuberculosis in HIV-infected patients is often “atypical.” The chest radiograph in HIV-infected patients with active tuberculosis most commonly resembles that of primary disease (i.e., hilar and mediastinal adenopathy with or without noncavitating parenchymal infiltrates equally likely to occur in the upper or lower lobes).s8 In one study of Haitian patients with tuberculosis, 80% of HIV-seropositive persons had chest films compatible with primary tuberculosis compared with 30% of HIV-seronegative persons.s9 Another study found that cavities were present in 67% of patients without AIDS but in no patients withAIDS, whereas adenopathy was noted in 59% ofAIDS patients but in only 3% of non-AIDS patients. 58Chest radiographs have been reported to be normal in 12% to 14% of HIV-infected patients with active pulmonary tuberculosis confirmed by a positive sputum AFB smear or culture.‘8.60 Pleural effusions are seen in 7% to 12% of cases of active tuberculosis in HIV-positive patients, which is not significantly different from the rate seen in patients without HIV.58.s9 Findings on chest film consistent with miliary disease have been reported to occur in 6% to 19% of HIV-infected patients with tuberculosis.s8.6’ In tuberculosis associated with HIV infection, extrapulmonary involvement with or without pulmonary disease is much more common than in HIV-seronegative patients. Extrapulmonary tuberculosis is found in up to 70% of patients with a preexisting diagnosis ofAIDS or a diagnosis of AIDS shortly after the diagnosis of tuberculosis.6’ The occurrence of “atypical” presentations of tuberculosis in HIV-seropositive patients appears to be related to the degree of immunosuppression. This is illustrated by the finding that the frequency of extrapulmonary disease, mycobacteremia, and “atypical” radiographic findings increases with low CD4 counts (Fig. 3).6’.61 Radiographic Imaging: Computed Tomography (CT) and Magnetic Resonance Imaging (MN) of the Chest

CT scanning of the chest can be helpful in making the diagnosis of tuberculosis in some cases. It has been shown to be more sensitive than plain films for detecting cavities, intrathoracic lymphadenopathy, miliary disDM,

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195

A TYPICAL n=

18

B PLEURAL EFFUSION n = 32 C ATYPICAL INFILTRATE n = 51 D RETICULO - NODULAR n= 29

E ADENOPATHY n= 46

700

600

500

400

300

CD 4+T - Lymphocyte FIG. positive

3. CD4+

T-lymphocyte

patients.

zone infiltrate zone. Pattern

CD4+

T-cell

with or without A is associated

HIV infection.

Patients

may

counts numbers

associated

with

are shown

f

100

0

count (x lO’/L)

PTB radiographic

as mean

200

SD. Pattern

patterns

in 150

A is defined

HIV-

by upper

cavitation and pattern C by parenchymal infiltrate in mid or lower with early HIV disease, and patterns C, D, and E with advanced be included

in one

or more

categories

B to E.

ease, bronchiectasis, bronchial stenosis, and pleural disease.47,65High-resolution CT (HRCT) scanning is the preferred technique for detection of miliary disease and bronchiectasis. 47In patients withAIDS, one study found that low-density enlarged intrathoracic lymph nodes seen on CT scan were, in particular, associated with tuberculosis. 61It is obviously not necessary or cost-effective to perform CT scans on all patients suspected of having tuberculosis. In certain cases where there is significant clinical suspicion and plain film findings are minimal or ambiguous (as often occurs in patients with AIDS), CT scanning may provide useful diagnostic information because of its increased sensitivity. At present, MRI of the chest does not appear to have a role in the diagnosis of tuberculosis. 65The principal utility of chest MRI is to evaluate tumor invasion of the chest wall and vessels. CT scanning has better resolution, and MRI tissue characterization cannot differentiate tuberculosis from other infectious processes or tumors. Bacteriologic

Evaluation

If the diagnosis of pulmonary tuberculosis is suspected on the basis of clinical and radiographic evaluation, the next step should be examination of the sputum for mycobacteria. For patients with a productive cough, 196

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SEOUENTIAL

w > i&OP g30P w D 20Y f, !Cs a 4. Relationship

from

patients

with

Gross WM, Hawkins Med 1975;112:773-87.)

of number suspected

SPEGMENS

.H

1

FIG.

ADMISSION

2 NUMBER

of sputum

tuberculosis.

JE, et al. Laboratory

3 CF

0 ,--0 SPECIWXNS

specimens

collected

(Prepared, services

with for

to positive

permission,

mycobacterial

from disease.

cultures data

obtained

of Kubka Am

Gf:

Rev Respir

collection of an early morning freshly expectorated specimen is recommended.27*66 For patients unable to produce sputum, induction of sputum production should be attempted. This is done by having the patient inhale nebulized hypertonic (3%) saline for up to 15 minutes. Although this method has been shown to be useful in patients unable to produce sputum on their own, it is not known to have a better diagnostic yield than examination of spontaneously expectorated specimens. 67 Because the diagnostic yield of both AFB smear and culture increase with the obtaining of multiple samples, it has become standard practice to obtain at least three specimens, preferably on 3 consecutive days. There appears to be little, if any, increase in diagnostic yield if more than five specimens are collected (Fig. 4).68

ConventionalMethods: Direct Microscopy (AFB Smear) and Culture. Direct microscopic examination of sputum continues to play an important role in the diagnosis of tuberculosis because it is inexpensive, rapid, easy to perform, and has a reasonable but not outstanding diagnostic yield.69 Using culture as a gold standard, the sensitivity of the AFB smear ranges from 22% to 78%.66 These numbers are average values, which include specimens from different anatomic sites and patients at various stages of disease. For the initial diagnosis of pulmonary tuberculosis, the sensitivity of AFB smear compared with culture is believed to be somewhere in the middle of this range (about 50%).70 Obtaining multiple samples increases the sensitivity of the AFB smear. A review of the literature found that the sensitivity of a single sputum AFB smear was 30% to 40% but increased to 65% to 75% with multiple specimens.” Another key factor that affects DM.

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the diagnostic yield of direct microscopy is the extent of disease/organism burden of the patient. For example, one study demonstrated that the presence of cavitary disease resulted in a sensitivity for AFB smear almost twice that (57% vs. 32%) for noncavitary tuberculosis.72 Because direct microscopy cannot distinguish betweenMycobacterium tuberculosis and nontuberculous mycobacteria (e.g., Mycobacterium avium-intrucellulare), another concern is specificity. The prevalence of tuberculosis and nontuberculous mycobacteria in the population tested is the major variable, not any property of the test or the testers. Therefore the specificity of the AFB smear cannot be controlled by the microbiology laboratory. Before 1985 this was considered to be even more of a problem because of the decline in tuberculosis in the United States. According to Bayes’ theorem, with decreasing prevalence of a disease in the population the positive predictive value of a diagnostic test will decrease. Publication of data showing a poor positive predictive value (45%) for the AFB smear in diagnosing tuberculosis seemed to confirm this concern.73 More recently, however, several published studies have refuted these findings. They showed the AFB smear to continue to have excellent specificity (more than 99%) and positive predictive value (9 1.5% to 98%) for the diagnosis of tuberculosis.74%75 The positive predictive value of the AFB smear may not be this good if there is a high prevalence of nontuberculous mycobacterial infection and colonization in a population, especially among HIVinfected patients. The utility of the AFB smear has also been examined for HIV-infected patients. The lack of cavitary disease in this population raised the possibility that the sensitivity of the AFB smear might be lower for this group. In addition, the high incidence of infection with Mycobucterium uviumintrucellulure (MAC) resulted in concerns about lower specificity in these patients. Both of these issues have been addressed. Studies comparing the sensitivity of the AFB smear in HIV-infected patients (55% to 66%) and HIV-negative patients (55% to 79%) have demonstrated no significant difference between these two groups. 76-78Similarly, the positive predictive value of the AFB smear from expectorated sputum samples for the diagnosis of tuberculosis in a hospital with a very high incidence of HIV and MAC was found to be comparable (92%) to that found in earlier studies from the pre-AIDS era. 76One cautionary note from this study was that the positive predictive value of the AFB smear for induced sputa or bronchoscopy was significantly lower (70% to 71%) than that for expectorated sputa (92%). Mycobacterial culture is more sensitive and specific for the diagnosis of tuberculosis than theAFB smear. Determining its true sensitivity and speci198

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ficity is somewhat difficult. In the United States, a diagnosis of active tuberculosis may be reported to the Centers for Disease Control and Prevention (CDC) in the absence of a positive culture (see Culture-negative Tuberculosis). The “gold standard” against which culture is measured is usually the final judgment that a physician makes regarding the diagnosis of tuberculosis in an individual patient after reviewing all available data. These include clinical and radiographic evaluation, PPD testing, bacteriologic results, and response to antituberculosis therapy. This is clearly a subjective determination. Two physicians, even if they are both experts in the field, may disagree on a final diagnosis in any given case. Given these limitations, two studies have reported the sensitivity for sputum culture to be approximately 8 1% in pulmonary tuberculosis, with a significantly higher sensitivity of 96% for cavitary disease. “,” This sensitivity of 8 1% is consistent with more recent national data. In 1990, for example, only 86.7% of cases of active pulmonary tuberculosis reported to the CDC were culture proven. ‘” Mainly because of laboratory contamination, false-positives also occur with culture. Nevertheless, the specificity of culture has been reported to be as high as 98.5%.7’ The major limitation of mycobacterial culture is the delay in obtaining results. Using conventional methods in which mycobacteria are inoculated in egg-based (Lowenstein-Jensen) or agar-based (Middlebrook 7H 11) media and incubated, cultures may not grow for 3 to 8 weeks or more. In the late 1970s new culture methods were developed to shorten the delays inherent in culture. The most widely used system, BACTEC (Becton Dickinson, Sparks, Md.) employs a radiometric method that detects radiolabeled ‘CO2 produced when growing mycobacteria metabolize “C-labeled palmitic acid incorporated into the media.‘” Use of this system can decrease time to detection of positive cultures to 8 to 14 daysx” In terms of sensitivity, BACTEC is at least as good as conventional culture methods.66 Some recommend using BACTEC in conjunction with conventional media (L-J or M 7Hll) as this combination produces the highest yield foi detection of mycobacteria.‘” Adding to the inherent delay of culture for diagnosis is that, once mycobacterial growth is detected, further tests must be performed to identify M. tuberclrlosis and differentiate it from nontuberculous mycobacteria. Older methods were based on evaluation of growth characteristics, biochemical tests, pigment production, and colony morphology. With these tests, it can take weeks to make a definitive identification. Fortunately, they have been replaced by newer rapid methods. The NAP (p-nitro-a-acetylamino-Phydroxypropiophenone) test is usually used in conjunction with the BACTEC system. NAP specifically inhibits growth of M. tube~~lo.si,s DM,

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complex speciesbut not nontuberculousmycobacteria.The NAP test generally takes5 to 7 days and hasbeenfound to be up to 99% accurate.66,80 The fastestwidely availablemethod for identifying mycobacterial species usesnucleic acid probes.In this method chemiluminescentDNA probes, designedto hybridize with rRNA sequencesuniqueto the targetorganism, are usedto identify mycobacterial species.The one commercially available system, Gen-ProbeAccuprobe (Gen-Probe,Inc., SanDiego, Calif.), includes probesfor 44. tuberculosiscomplex, MAC, M. kunsasii, and M. gordonae.This identification system gives same-dayresults in cultured specimensand is nearly 100% sensitiveandspecific.66~80 One limitation of both the NAP and Gen-Probesystemsis that they cannotdifferentiate the individual speciesof the M. tuberculosis complex (e.g., M. tuberculosis vs.M. bovis). This may haveclinical significance,especiallyin areaswhere speciessuch as M. bovis are prevalent.BecauseM. bovis is inherently resistantto pyrazinamideandtherapymay haveto be altered,further identification testing should be performed in such situations. Another rapid identification method that has promise is high-performance liquid chromatography(HPLC) of mycolic acids. Mycolic acids areimportant componentsof cell walls of mycobacteriaandother microorganisms.When separatedby HPLC, mycolic acids of different mycobacterialspeciesproduceuniquepatternsthat canbe usedto identify them. Employing this technique,the specificity for identification of M. tuberculosis complex is 99.9%.*l As with NAP andAccuprobe,HPLC cannotdifferentiatebetweenthe individual speciesof theM. tuberculosis complex. Thesenewerculture andidentification techniqueshavehad a major impact on the diagnosisof tuberculosis.This is clearly illustrated in one study that comparedthe combination of BACTEC and DNA probesfor culture andidentification with conventionalmethods.@When BACTEC andDNA probeswere used,the median time from inoculation of culturesto identification wasreducedfrom 73 to 23 days.Despitethis significant improvement, eventhe newermethodscanhardly be called rapid when the median time for a positive diagnosis is more than 3 weeks.Obtaining a negative result takesevenlonger asmost laboratorieswill not give a final report of no growth until at least 8 weeks havepassed.For this reason,significant efforts have been made and will continue to be made to develop a truly rapid and accuratetest for the diagnosisof tuberculosis. Rapid Diagnostic Techniques:NucleicAcidAmplijkation. Recentadvancesin molecular biology haveofferednew opportunitiesfor the development of a rapid and accuratediagnostic test for tuberculosis.The successfuluseof DNA probesfor the identification of mycobacterial cultures raised the possibility that suchprobescould be usedto identify M. tuber200

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culosis in submitted specimens, such as sputum, directly and rapidly. This would avoid the delay of waiting for cultures to grow from inoculated specimens. There was a significant problem that had to be overcome first, though. The relatively small number of organisms initially present in a sputum sample possessed insufficient amounts of the targeted nucleic acid sequences for the DNA probes to detect. Fortunately, molecular biologists had developed techniques by which a single nucleic acid sequence could be copied, or amplified, a billion times or more in hours instead of weeks. Two such methods have been employed to effect a rapid diagnostic test for tuberculosis: transcription-mediated amplification and the polymerase chain reaction (PCR). Transcription-mediated amplification uses synthetic oligonucleotides, which are designed to hybridize with rRNA sequences unique to the M. tuberculosis complex. Once hybridized, these oligonucleotides serve as “primers” for reverse transcriptase, which then copies the ribosomal RNA into cDNA. Using a nucleic acid polymerase, the cDNA is copied (amplified) and the cycle is repeated until a billion or more copies are made. If the specific target nucleic acid sequence is not present in the specimen, the amplification process will not occur. Once the target rRNA has been sufficiently amplified, it can be detected by using nucleic acid probes similar to the method previously described for rapid identification of cultures. The Mycobacterium Tuberculosis Direct Test (MTD) (Gen-Probe, San Diego, Calif.) is a commercially available transcription-mediated amplification test for tuberculosis. It has been FDA approved for use on specimens that are AFB smear positive. The MTD test takes approximately 5 hours to run. Laboratory-based studies that have evaluated the MTD for the detection of the M. tuberculosis complex in respiratory specimens have found it to be sensitive and specific. Using culture as the “gold” standard, two studies found it to have a sensitivity of 96% and 98.4% and a specificity of 98% and 98.9%, respectively. 82,83A third investigation showed that the MTD was very specific (99%) but not as sensitive (71.4%) as reported in the other two articles.84 An evaluation of the clinical utility of the MTD has also been recently published (Fig. 5).85 One aspect of this investigation examined the ability of the MTD when used in conjunction with the AFB smear to establish or exclude the diagnosis of pulmonary tuberculosis. All respiratory specimens that were both smear and MTD positive came from patients who had a diagnosis of active pulmonary tuberculosis. Thus the MTD yielded the “correct” diagnosis 100% of the time when both smear and MTD were positive; 96.2% of specimens that were smear and MTD negative came DM,

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Smear

MTD

ATS

ATS

ATS

o,w

3

4

5+

(W

0

59

0

0

100

3

1

46.7

0 44

1 1

56.3 96.2

(+I (3 (+)

t-1

13 9

14 7

(4

t-1

660

32

Definition of abbreviations; Thoracic Society. ‘Total number +ATS Class

FIG. 5. Clinical A. Clinical pulmonary

MTD = amplified

of specimens,

5 not included

tuberculosis

direct

test;

ATS = American

844.

versus

final

of the Amplified

tuberculosis.

Mycobacterium

in final calculations.

utility of MTD

efficacy

MTD Correct

ATS

Am

J Respir

ATS classification.

Mycobacterium Crit

Care

Med

(From

Bradley

Tuberculosis

Direct

1996;153:

1606-l

SF: Reed SL, Cotanzaro Test for the diagnosis

of

0.)

from patients who did not have active tuberculosis. When both smear and MTD were in agreement, the MTD performed very well. In a small minority of specimens (5.7%) the MTD and smear were discordant. When this occurred, the ability of the MTD to provide the correct diagnosis was not nearly as good. When the MTD was positive and the smear was negative, the MTD yielded the correct diagnosis of active tuberculosis 46.7% of the time. When the MTD was negative and the smear was positive, the MTD gave the correct answer (i.e., the patient did not have active tuberculosis) 56.3% of the time. Like transcription-mediated amplification, PCR uses synthetic oligonucleotides, which are designed to hybridize only with DNA (instead of rRNA, which is the target for MTD) sequences unique to the A4. tuberculosis complex. Once hybridized, the oligonucleotides serve as primers for DNA polymerase, which then makes a copy of the M. tubercuZosis complex DNA. This process is repeated over and over so that the resulting “chain reaction” produces a billion or more copies of the desired DNA. If theM. tuberculosis complex DNA is not present in the specimen, the process will never begin because the primer will not hybridize. After the M. tuberculosis complex DNA has been amplified, it can be immediately detected by means of a DNA probe. The entire PCR assay can be completed in less than 6 hours.86A commercial kit called Amplicor (Roche, Branchburg, N.J.) is available. It has recently been approved for use by the Food and Drug Administration (FDA) on sputum AFB smear-positive specimens. PCR has been evaluated in a number of laboratory-based studies. These have used primarily respiratory specimens to determine its sensitivity and specificity with culture as the standard for comparison. Under these conditions, PCR performed well with a sensitivity of 83% to 95%.87-90In three 202

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of these studies PCR significantly outperformed the AFB smear, which had a sensitivity of 41% to 58%. In the remaining study, PCR and theAFB smear were equivalent, but the AFB smear had an unusually high sensitivity of 93%, which has not been previously reported (see Conventional Methods). For specimens that were smear negative, sensitivity decreased to 66% to 74% when compared with culture.x7,s9 Specificity of PCR ranged from 96% to 99%. PCR has also been examined for its clinical utility in diagnosing individual patients. Using a clinical diagnosis of tuberculosis based on smears, cultures, pathologic findings, and clinical presentation, one such investigation found PCR to be 100% sensitive. 91The problem was with specificity, which was only 70%. The false-positives occurred in patients with prior, treated TB, or asymptomatic infection. This highlights a potential limitation of nucleic amplification-based diagnostic tests. They may be so sensitive that they can detect DNA from nonviable (previously treated tuberculosis) or dormant (latent infection without active disease) organisms, resulting in false-p0sitives.A second study examining PCR’s clinical utility, however, found that it performed well in terms of both sensitivity and specificity.86 In this investigation a case of tuberculosis was defined as the presence of abnormalities on chest radiograph consistent with tuberculosis and either (1) a positive culture for M. tuberculosis from the respiratory tract or (2) a radiographic response to multidrug antituberculosis therapy within 3 months. Eleven patients in the study fit this definition. PCR correctly identified nine (81.8%) which was better than smear and culture, which identified three (27.3%) and seven (63.6%) respectively. PCR and culture were positive in all three smear-positive patients. In the eight smear-negative cases PCR identified six and culture identified four. In addition, PCR was positive in only one of 14 (7.1%) patients with clinically inactive tuberculosis and none of 37 patients with infection only. Some preliminary data suggest that PCR also has the potential to be applied to testing peripheral blood buffy coats to diagnosis pulmonary disease.‘)? PCR and MTD have been compared head to head. Using culture as the gold standard, the sensitivity (PCR--84.6%, MTD-84.6%) and specificity (PCR-98.7%, MTD-99.1%) were equal in respiratory specimensq3 In this particular study, they were not much better than the AFB smear, which had a sensitivity of 80.8% and a specificity of 99.1%. A second study looked at the ability of both PCR and MTD to identify patients with active pulmonary tuberculosis. 91 When three specimens were tested for each patient, all 52 patients with active tuberculosis in the study were correctly identified as such by both PCR and the MTD. DM,

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TABLE

3.

Sensitivity

and specificity

of diagnostic

tests

for pulmonary

tuberculosis:

Sputum

Sensltlvity 22% - 78% 81% - 86.7% 71% - 96%

AFB smear* AFB culture* * Direct amplification tests* (PCR and MTD) *Compared **Compared

to culture

Specificity 92% - 99% 98.5% 96% - 99%

as standard

to final clinical

diagnosis

as standard

The exactrole of the nucleic acid amplification testsin the diagnosisof tuberculosishasnot beendefined (Table3). Overall, the datasuggestthat PCR andMTD can detectabout50% to 75% ofAFB smear-negative,culture-positive casesof tuberculosis,making them more sensitivethan the AFB smear.95 Comparedwith culture, PCR andMTD havethe advantage of being very rapid. However,thereis concernthat they are likely to produce false-positive results in patients with old, inactive tuberculosis or asymptomatic infection. For several other reasons,they cannot replace culture, evenin circumstanceswhen they areessentially 100% diagnostic, as appearsto be the case when the smear and MTD are both positive. Cultures will still be neededfor drug-susceptibility testing. In addition, the MTD and PCR cannot differentiate betweenthe individual speciesof the M. tubercdosis complex. In certain casesthis may be important (e.g., M. bovis), becauseit may alter therapy.Finally, thereis the issueof cost. The PCR assaymay cost as much as $175.00to $225.00.6g Nevertheless,there appearto be situations in which thesetestsmay be useful. For example,supposefrom a clinical andradiographicstandpoint, it is thought that a patient probably has old, inactive tuberculosisor anotherdiseaseprocessandthat a diagnosisof active pulmonary tuberculosis is much less likely, but possible.Even if this patient hasthreenegative AFB smears,strongconsiderationstill would haveto be given to the institution of empiric therapyor theperformanceof invasivediagnosticprocedures.However,if PCR or MTD wereperformedand found to be negative on all threespecimens,this could allay concernsthat the patienthad active disease.One could feel more comfortable aboutwaiting for cultureresults without starting empiric therapy and thereforesavea substantialamount of money, especially when the costs of DOT and contact follow-up are included.A combination of threenegativesmearsand threenegativeamplification testsdoesnot absolutely excludeactive tuberculosis,however. In caseswhere the clinical suspicion of active tuberculosisis significant (e.g., when the patient is immunocompromised), strongconsiderationis 204

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given to empiric therapy,even in the face of negativesmears.If one or more of the PCR or MTD tests were positive in this case scenario,they would provide additional datain favor of starting empiric treatment. Consideranotherclinical scenarioin which a patienthad a positiveAFB smear andthe diagnosesof both tuberculosisand nontuberculousmycobacterial infection werebeing considered.If this specimenwere MTD- or PCR-positive also, this would be essentiallydiagnostic of active tuberculosis. If either of the nucleic acid amplification testswere negativein this situation, it would not excludetuberculosisand thereforewould not be as helpful. Under theseconditions, one would haveto correlateall clinical, radiographic, and bacteriologic datato arrive at a decision regardingthe initiation of therapy. It is clearly best, however, to err on the side of overtreatmentwhenthe situationis clinically ambiguousandtheAFB smear is positive. Invasive Diagnostic Needle Aspiration,

Procedures: and Surgery

Bronchoscopy,

Transthoracic

In certain instancesit may not be possible for a patient to producea sputum sample, even if the aerosolizedinduction method is used. In some caseswheresputum sampleshavebeenobtainedandthey areAFB smearnegative,it may not be acceptableto wait for the resultsof culture or responseto empiric therapy,both of which can take 2 to 3 months. This is particularly true when alternativediagnoses,suchas malignant diseaseor other infections (e.g.,fungal), are alsolikely possibilities. Under suchcircumstances,strong considerationshould be given to invasive diagnostic testing, such asbronchoscopy. A number of studieshaveevaluatedthe usefulnessof bronchoscopyin the diagnosis of tuberculosis. In one study of 56 patients suspectedof having tuberculosis who either had three negativeAFB smearsor were unableto producesputum, fiberoptic bronchoscopy(FOB) provided a diagnosisin 29 (52%).96The diagnoseswere mycobacterialinfections in 22 cases(39%) and other diseasesin 7 cases(13%). Transbronchialbiopsy hadthe highestyield for immediate microscopic diagnosis.Otherinvestigatorsexamined67 patientswith culture-proventuberculosis.97 FOB provided a diagnosis of tuberculosisin 11 of 67 patients who had negative sputum smearsand cultures.In addition, 7 of 21 patientswho were smearnegative,culture-positive by sputumtesting had positive AFB smearson bronchoscopy,yielding an immediate diagnosisin 33% of thesepatients. Another study showedthat, of 89 sputumAFB smear-negativepatientsin whom tuberculosiswas eventually diagnosed,67.4% were diagnosedby FOB, with 39 (44%) having a rapid diagnosis made by a positive AFB DM,

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smear from bronchial brushings or by histologic findings from transbronchial biopsy. 98An investigation that examined FOB with bronchoalveolarlavagefound this techniqueto be very sensitivefor the diagnosis of tuberculosis.99In patients with a diagnosis of tuberculosis, sputumwas smear-positivein 16of 47 (34%) andculture-positivein 24 of 47 (5l%), whereasbronchoalveolarlavage(BAL) was smear-positivein 34 of 50 (68%) andculture-positivein 46 of 50 (92%). FOB hasalso been evaluatedfor the diagnosisof tuberculosisin HIV-infected patients.The diagnosticyield was found to be similar to that for non-HIV-infected patients, with transbronchialbiopsy providing additional yield, especially for immediate diagnosis.loo~lolOn the basis of these studies and others, FOB clearly has a role in the diagnosis of tuberculosis,especially in patients with negativesputum smears.It will yield the diagnosis,often rapidly, in some casesthat otherwise would have been missed by sputum sampling. With FOB, one also has the ability to make other diagnoses suchascancer.The major problem with bronchoscopyis the needfor specialized equipment and trained personnel,making it costly. This is well illustrated by an investigation that comparedsputum induction to bronchoscopy.lo2Overall, the diagnostic yield of bronchoscopywas found to be no higher than that of sputum induction (Figs. 6 and 7) but it was approximately eight times more costly. It should also be noted that this study was performed in Canadaand the cost of bronchoscopyis much higher at most U.S. institutions. Transthoracicfine-needleaspiration(FNA) hasbeenusedprimarily for the diagnosisof cancer,but it also hasbeenused to make the diagnosisof tuberculosis.‘03Comparedwith FOB, little hasbeenwritten aboutthe efficacy of this procedurefor diagnosing tuberculosis.In one study, 10 patientswith negativeAFB smearsfrom sputumor bronchoscopicbrushings, in whom tuberculosis was ultimately diagnosed,underwentultrasoundguidedtransthoracicFNA (with aTru-Cut needlebiopsy if the initial AFB smearfrom aspirationwasnegative).lo4FNA/biopsy yielded the diagnosis of tuberculosisin 9 of the 10, with an immediate diagnosisby AFB smear or histologic study in 8. Becausethe numbersare small and the patients representa selectpopulation, it is difficult to draw a firm conclusion regarding the sensitivity of FNA. Nevertheless,it may have some utility in making a diagnosis in patients who areAFB smear-negativeby sputum and/orbronchoscopy. Rarely is a surgical procedurenecessaryfor diagnosisin a patient suspectedof having active tuberculosis.The most frequent way in which tuberculosis is diagnosedsurgically is when a patient undergoingthoracotomy or thoracoscopyfor removal of a lung nodule suspectedof being 206

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4-

P

of active

bronchoscopy

specificity,

i.e., diagnosis

and

and posltlve

only.

from sputum

InductIon.

Crit Care

Med

1995;

152: 1570.4.)

75 77 90 91

79 96

76 77 91 93

Negative Predictive Value

D. Comparison

to equal 100%

N, Menzies

were assumed

60 71 100 100

71 100

60 71 100 100

C, lnhaber

fol- cultures

Anderson

values

(From

predictive

predictive values of two diagnostic methods. in the diagnosis of tuberculosis. Am J Respir

by clinical/radiographic

obtained

TB; therefore,

with no specimen

IS excluded.

evidence

case and patients

FIG. 6. Comparison of sensitivity, sputum induction with fiber-optic

case,

the one unconfirmed

one unconfirmed

‘Excludes

Slncludes

the one X-ray diagnosed

as defmitwe

speciflclty

confirmed:

was taken

‘A positive

culture

97 97 100 100

12 19 70 74

‘Culture

97 100

97 97 100 100

Specificity*

22 a7

(n = 92*)

12 19 73 77

Sensitivity

Culture confirmed TB+ (n = 100) Bronchoscope smear induced sputum smear Bronchoscope culture Induced sputum culture Culture confirmed/adequate spec :imens Induced sputum smear Induced sputum culture All cases5 (n = 101) Bronchoscope smear Induced sputum smear Bronchoscope culture induced so&urn culture

Positive Predictive Value’

of

Bronchoscouv Capital costs Repairs Supplies Personnel Resp. tech. Cleaning/sterilization Transport of patient Nursing care Physician fee Total

22.53 19.78 11.33 18.25 10.44 3.90 5.37

Capital

6.49

Costs -

5.00

Supplies

(50 min) (40 min) (15 min) (15 min) 96.00 187.60

Induced sputum

Resp. Tech. Cleaning -

9.05 (25 min) 1.68 (5 min) -

Total

22.22

FIG. 7. Comparison of costs per procedure (Canadian dollars). (From Anderson C, lnhaber Menzies D. Comparison of sputum induction with fiber-optic bronchoscopy in the diagnosis tuberculosis. Am J Respir Crit Care Med 1995;152: 1570-4.)

N, of

malignant is subsequentlyfound to have a tuberculoma.lo5As tuberculosis, especially in patientswith AIDS, can presentas isolated mediastinal and/orhilar adenopathy,mediastinoscopymay beuseful in certaincases.lo5 Open-lungbiopsy by thoracotomy or thoracoscopyhasbeenshownto be useful for the diagnosis of diffuse parenchymallung diseases.lo6Openlung biopsy should be consideredin casesin which miliary pulmonary tuberculosis is considered a possibility and other procedures,such as transbronchialbiopsy, havefailed to provide a diagnosis. Smear-Negative 7iuberculosis, and Empiric Therapy

Culture-Negative

Tuberculosis,

Becausethe sputumAFB smearmay miss 50% or more of casesof active tuberculosis,for patientswho are suspectedof having active diseaseone must considerfurther diagnostictesting (asdescribedpreviously) or institution of empiric therapy in such patients with negative sputum smears. Although it has been shown that such proceduresas bronchoscopywill addto the diagnosticyield in combination with sputumsampling, they are very costly and cannot be routinely recommendedin all smear-negative suspects.Their greatestusefulnessis in patients in whom an alternative diagnosisis likely. Examplesof this include patientswithAIDS who areat risk of a numberof lung diseases(e.g.,Pneumocystiscarinii, fungal infection, lymphoma, etc.),which may be clinically andradiographicallyindistinguishable from tuberculosis,older patients(especially cigarettesmokers) who may havemass-like or nodular lesions that could also represent cancer,etc. In suchcircumstances,waiting up to 2 months for cultures to return or 2 to 3 months for evidence of radiographic improvement on empiric therapycould havedire consequences. 208

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It is reasonable to forego further invasive diagnostic tests in cases where the diagnosis is overwhelmingly likely to be tuberculosis and the question is whether the tuberculosis is clinically active or old, healed disease. An example of this would be a nonimmunocompromised patient with a reactive PPD and a chest radiograph that shows classic upper lobe fibronodular disease, who is otherwise at low risk of cancer. In such a patient who has negative AFB smears, there are two choices. The first is to await culture results. The second is to begin empiric therapy. Each has its disadvantages. In the first case there will be a delay in the start of therapy in some patients with active tuberculosis. In most cases this will not have a significant negative impact either on the well-being of the patient or on the community in terms of new cases resulting from the patient. However, in certain instances, especially if the patient is unreliable (e.g., homeless), there may be a significant delay between the time the cultures turn positive and the time the patient is located and started on therapy. During this period the patient may become progressively ill or infectious. The downside of beginning empiric therapy in all patients in this category is that many patients will be treated unnecessarily. This was demonstrated in a study in which smear-negative patients were started on therapy if their chest radiograph was thought to be consistent with tuberculosis.3 In the end only 48% of these patients were thought to have active tuberculosis, which means that 52% of those started on treatment did not require multidrug therapy. Although empiric therapy was found to be safe in that only 8.3% of patients had side effects that required alteration of their medications, such a policy, if instituted on wide scale, would be costly. In certain cases the new rapid nucleic amplification tests may turn out to be helpful in deciding whether or not to start empiric therapy. At this point, however, they must be used with caution as they are neither sensitive nor specific enough to serve as stand-alone tests for the diagnosis of tuberculosis. The rapid diagnostic tests must be used in conjunction with all other clinical and radiographic information. If one begins empiric therapy, it is imperative that the patient be reevaluated in 2 to 3 months, regardless of the culture results. Even if cultures are negative, a diagnosis of active tuberculosis can still be made on clinical and radiographic grounds. The combination of a positive PPD, a chest radiograph consistent with tuberculosis, and a clinical or radiographic response to multidrug therapy is considered sufficient to make a diagnosis of tuberculosis in the face of negative cultures.z0.70 In 1990, 14.3% of cases of active tuberculosis reported to the CDC were culture-negative and 9.4% were smear- and culture-negative. DM,

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209

100 90 80

60 E $ t P

0 Extrapulmonary

50

u Pulmonary

40 30 20 10 0 1978

1992 Year

FIG. from

8. Percent Cantwell,

of reported Snider, and

cases of extrapulmonary Cauthen4 and Hopewell.zo)

TB, 1978

versus

1992.

(Based

on data

Extrapulmonary Tuberculosis Although tuberculosis most commonly involves the lungs, it can produce disease in essentially every organ system. In fact, the incidence of extrapulmonary tuberculosis has been increasing in recent years and currently makes up about 20% of reported cases in the United States (Fig. 8). Much of this increase can be attributed to HIV infection, which is associated with a very high risk of development of extrapulmonary disease.19J07 Pleural and lymphatic disease make up the majority of cases, followed by bone and joint disease, genitourinary disease, miliary disease, meningitis, and peritonitis (Fig. 9). lo8 Other much less common areas of involvement include the pericardium, brain parenchyma, larynx, gastrointestinal tract, liver, pancreas, eyes, ears (otitis media), adrenal glands, pituitary, thyroid, and skin. This review concentrates on diagnostic evaluation of the more commonly affected sites: the pleura, lymph nodes, the central nervous system, bones and joints, the genitourinary system, the gastrointestinal system (including peritoneal disease), the pericardium, and miliary or disseminated disease. 210

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Distribution

of Extrapuimonaty 1990

Tuberculosis

Other 10% A

Peritoneal 3% Meningeal 6% A

Mliary 8%

Genitourinaty 9%

’

Bone and Joint

y

FIG. 9. Distribution of extropulmonary Extrapulmonary tuberculosis, excluding RR, editors.

Tuberculosis.

New

York:

1990. (Adapted from Thornton GE tuberculosis, the central nervous system. In: Rossman MD, MacGregor McGraw-Hill;

1995.)

In all cases of suspected extrapulmonary tuberculosis, an evaluation for pulmonary disease, including at minimum a chest radiograph, should also be performed. Pulmonary disease often occurs concurrently with extrapulmonary disease. Because it is frequently easier and less invasive to obtain specimens for microbiologic evaluation from the lungs than from many other organs, and because respiratory specimens usually have a higher diagnostic yield, it is important to look for pulmonary involvement. Even in the face of negative specimens from an extrapulmonary site, the confirmation of active pulmonary tuberculosis in the presence of a clinical or DM,

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211

radiographicpresentationconsistentwith tuberculousdiseaseat the suspectedextrapulmonary site is usually sufficient for diagnosis. One must always be aware,though, that the rule of Occam’s razor is occasionally violated and that a patient may have more than one concurrentdisease process.This is especially true in immunocompromised personssuch as thosewith AIDS andpatientswith transplants. Pleural Disease Pleural effusions are the second most common manifestation of extrapulmonary tuberculosis. Tuberculous effusions are usually unilateral, with bilateral effusionsbeing presentin fewer than 10% of cases.56Jog They generally occupy less than one half of a hemithorax but, rarely, can fill the entire hemithorax.iOgAssociated pulmonary infiltrates may be seen in up to 50% of patients.110The PPD has been reported to be nonreactivein up to 3 1% of cases,so that a negativePPD reaction does not exclude the diagnosis.iog The diagnosticwork-up of a suspectedtuberculouseffusion beginswith a thoracentesisto obtain pleural fluid for analysis.The fluid is nearly always an exudate,usually with a total protein of 5.0 gm/dl or greaterand rarely lessthan 3.0 gm/dl. 56~10g~110 Lactic dehydrogenasehasbeenreported to averagefrom 527 to 839.56~11g In the past it had beenthought that tuberculous pleural effusions were characterizedby a low glucose level, but more recentdata haveshown that a glucoselevel of greaterthan 50 or 60 is common.lw~*llAveragewhite blood cell countsrangefrom 2000to 4000 but can be much higher or lower.56~110~112 The predominantwhite blood cell found in the effusion varies with time. *13Very early, neutrophilsare most abundant,but over time thesearereplacedfirst by monocytesandthen by lymphocytes as the predominant cell type. At the time of diagnosis the percentageof lymphocytes usually exceeds65%.56,10gJ12 Eosinophils and mesothelial cells arerare or absentin tuberculouspleural effusions.l l l In addition to cellular and chemical analysis, pleural fluid should be stained and cultured for acid-fast bacilli. The diagnostic yield of AFB smearis unfortunately very low, ranging from 0 to 10%.56,112 The sensitivity of culture is better but still relatively low at 23% to 58%.56~10g~1*o~1*2 Consideration also should be given to obtaining a sputum specimen for AFB smear and culture. In one study the sputum smear was found to be positive in only 7% of all patients with tuberculous pleural effusion.l12 The yield of sputum culture is higher at 22% to 50%.*10,*12 A sputum culture is much more likely to be positive, not surprisingly, if pulmonary infiltrates are also presenton the chestradiograph.One group of investigatorsfound that in the absenceof infiltrates, sputum cultures were posi212

DM,

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tive in only 11% of cases whereas they were positive 89% of the time if infiltrates were observed. 110 Several relatively new tests may also be useful for the analysis of suspected tuberculous effusions. Adenosine deaminase (ADA) is an enzyme that is particularly abundant in activatedT-lymphocytes. High pleural fluid ADA activity has been associated with tuberculous pleuritis. In one study of 221 patients with pleural or peritoneal effusions, it was discovered that all subjects with an ADA level of 70 or higher had tuberculosis and that none of the tuberculosis patients had an ADA level below 40.“” Using a cutoff of 47 U/L for ADA activity, another investigation had similar results, reporting a sensitivity of 100% and a specificity of 95%.‘15 Despite the high sensitivity and specificity of ADA activity for the diagnosis of pleural effusion found in these studies and others, this test is not commonly used in the United States. There may be some reservations about its use because the studies cited were done in Spain where tuberculous pleurisy is much more common; therefore the positive predictive value of this test may be lower in the United States. High pleural fluid levels of interferon-y (IFN-y), another lymphocyte product, are also seen in tuberculosis pleuritis. One study of 80 patients with pleural effusions found that the mean EN-ylevel was greater than 90 in persons with tuberculous pleuritis compared with a mean of less than 2 for pleural effusions of all other causes.‘16 Another study, using an IFN-y level of 140 as a cutoff, revealed that this test had a sensitivity of 94.2% and a specificity of 91.8%.Ii5 Like the ADA activity level, this test is not frequently used in the United States. Nucleic acid amplification tests (PCR and MTD; see Pulmonary Disease: Rapid Diagnostic Techniques) have also been evaluated for the diagnosis of suspected tuberculous pleural effusions. In a study of 84 patients with pleural effusions, PCR correctly identified 43 of 53 (8 1% sensitivity) tuberculous effusions.“7 In 3 1 effusions due to other causes, there were 7 false-positives, resulting in a specificity of 78%. Another group examined 21 patients with tuberculous pleuritis confirmed by culture or pleural biopsy and 86 controls with nontuberculous effusions.“x PCR performed on pleural fluid was found to have a sensitivity of 8 1% and a specificity of 100%. This was superior to both pleural 1luidAFB smear (sensitivity, 14%) and culture (sensitivity, 52%). The MTD test has been reported to have a very low sensitivity (2O%j but good specificity (96.4%) when used to evaluate pleural fluid for tuberculosis.X’ Closed-needle pleural biopsy provides an excellent yield for the diagnosis of tuberculous pleuritis and should be considered if less invasive techniques are nondiagnostic. Pleural biopsy actually provides three fragDM,

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TABLE

4. Pleural

tuberculosis:

Diagnostic

tests

Characteristic Pleural fluid Protein LDH WBC count Differential AFB smear AFB culture ADA level I FN-y PCR MTD Pleural biopsy Histology AFB smear AFB culture

value

Sensitivity

~5.0 g/dl 527 - 839 2000 - 4000 >65% Lymphocytes

>70 >140

U/L U/L

0% - 10% 23% - 58% >95% 94.2% 81% - 84% 20% 69% - 97% 14% - 39% 40% - 85%

ments of tissue that can be used to diagnose tuberculosis: histology, AFB smear, and culture. The histologic findings of caseating or noncaseating granuloma on pleural biopsy, especially in persons with a positive PPD, are almost always diagnostic of tuberculosis.Although other diseases (e.g., coccidioidomycosis, sarcoidosis) can cause pleural granuloma, it is believed that more than 95% of granulomatous pleuritis is due to tuberculosis ‘11 The sensitivity of histologic examination alone is 69% to 97%.109~110~112~119 AFB smear alone has a sensitivity of 14% to 39%.‘09*“* Culture of the biopsy specimen has a sensitivity of 40% to 85%.109,110,“9 The sensitivity of histologic study and culture combined is as high as 95% when a final clinical diagnosis of pleural tuberculosis is used as the “gold’ standard.‘19 Because of the excellent yield of closed-needle pleural biopsy, a surgical procedure is rarely needed for the diagnosis of pleural tuberculosis. Nevertheless, there are instances in which this may be necessary. One scenario in which thoracotomy or thoracoscopy must be considered is the case of a patient with an exudative effusion that is likely to be either tuberculous or malignant and in whom all previous procedures, including closedneedle biopsy, have been nondiagnostic. The preferred technique is thoracoscopy, if available, because it is less morbid than thoracotomy and has an excellent diagnostic yield for both tuberculosis (93% to 94%) and cancer.‘06J20 Table 4 summarizes data on diagnostic tests for pleural tuberculosis. The diagnostic approach to patients with HIV infection suspected of 214

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having tuberculous pleuritis should be the same as that for non-HIV patients. The diagnostic yields of the individual tests that have been discussed may be different in these two groups, however. One group of investigators has examined this issue. 17’ They discovered that only 41% of HIV-infected patients with pleural tuberculosis had a positive PPD compared with 76% of non-HIV patients. The yields of pleural fluidAFB smears and cultures were equivalent in both groups. On pleural biopsy, however, AFB smears were more likely to be positive in HIV-infected patients (69% vs. 21%) but cultures were more likely to be positive in non-HIV patients (86% vs. 47%). Histologic findings from pleural biopsy were equivalent in both groups. Despite the fact that there was no statistical difference in the percentages of patients in both groups who had parenchymal infiltrates on chest radiograph, sputum cultures were more likely to be positive in the HIV-infected patients (53% vs. 23%). This suggests that sputum samples may be particularly useful in evaluating HIV-seropositive patients with suspected tuberculous pleuritis. Not surprisingly, the HIV-positive patients were also more likely to have positive cultures from other extrapulmonary sites (14% vs. 0% ). Lymphatic

Disease

(Extrathoracic)

The most common site of extrapulmonary tuberculosis is the lymphatic system. Intrathoracic adenopathy is usually seen in children as a manifestation of primary disease or in HIV-seropositive patients, as has already been discussed (see Pulmonary Disease). The cervical lymph nodes are the most common site of extrathoracic tuberculous lymphadenitis and are involved in about 70% of cases.lz’.‘?” The next most frequently involved lymph node groups are the inguinal and axillary.“’ In HIV-negative patients, tuberculin skin testing is positive in 74% to 100% of persons with lymph node tuberculosis.‘z’-‘zJ In the past, excisional lymph node biopsy was considered the preferred method for diagnosis. Even though this is more invasive, it was believed that any procedure that involved less than complete excision of the lymph node predisposed the patient to formation of chronic fistulous tracts.‘?’ More recent data have shown that percutaneous fine-needle aspiration is both safe and useful for the diagnosis of tuberculous lymphadenitis. In a series of more than 1300 FNAs for head and neck masses, 90 were done in persons given a final diagnosis of tuberculous lymphadenitis.“5 Cytologic study showed 69 of 90 with granulomatous changes or acid-fast bacilli on FNA, resulting in a sensitivity of 77% when histologic findings from surgical excision were used as the standard. With these criteria, the specilicity of FNA was 93%. Another study of 102 patients with peripheral lymDM,

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215

FIG.

10.

Lee KC,

Algorithm Tami

Laryngoscope

TA,

for diagnostic Lalwani

AK,

evaluation et al.

of suspected

Contemporary

tuberculosis

management

lymphadenitis. of cervical

(From

tuberculosis.

1992;102:60-4.)

phadenitisfound that FNA cytology had a sensitivity of 83% and the FNA culture had a sensitivity of 65%.lz2Again, histologic findings from surgical excisionservedasthe gold standardandweretherefore100%diagnostic. One group of investigatorscomparedsurgical excision with FNA in terms of pathology,AFB smear,and culture for the diagnosisof tuberculous lymphadenopathy.124Surgical excision was diagnostic in all casesby oneor more of theseparameters,with pathologic findings positive in 77%, smear positive in 37%, and culture positive in 93%. FNA had an overall sensitivity of 62%. The sensitivities for FNA cytology, smear,andculture were 55%, 34%, and 62%, respectively.On the basis of these data, the authorsproposedan algorithm for the diagnostic evaluationof suspected tuberculous lymphadenitis, which begins with FNA and proceeds to excisional biopsy if FNA is nondiagnostic(Fig. 10). In HIV-infected patients,the most common sitesof extrathoraciclymph nodeinvolvement arethe cervical and supraclavicularnodes,followed by the axillary nodes.126~127 In one seriesof 7 HIV-seropositivepersons,none 12’ Both FNA and excisional biopsy havebeenshown had a positive PPD. to have a high diagnostic yield in HIV-positive patients.In a study of 24 patients, excisional biopsy had an overall sensitivity of 92% by culture and histologic study.126FNA actually had a higher yield, being 100% sen216

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sitive by AFB smearor culture.Comparedwith specimensfrom HIV-negative patients with tuberculouslymphadenitis, specimensfrom HIV-positive patientswere much more likely to be smear-positive(HIV-positive = 77%, HIV-negative = 27%). In anotherseriesof 11 HIV-seropositivepersons with mycobacterial lymphadenitis, 8 underwentFNA and 3 underwent excisional biopsy.12’All procedureswere diagnosticby culture, with 7 specimensgrowing M. tuberculosis and 4 specimensgrowing M. avium complex (which can causelymphadenitisin normal or immunosuppressed hosts). Disease of the Central Nervous System (CNS) CNS tuberculosis,especially meningitis, can be an acutely life-threatening illness. Even in the eraof modem chemotherapy,the mortality ratefor this entity hasbeenreportedto be 21% for immunocompetentpersonsand 33% for those with HIV infection. 12*Untreatedtuberculousmeningitis is essentially always fatal, usually within 3 weeks of presentation.129 It is thereforevery important to diagnosethis diseasequickly so that appropriate therapycan be instituted. Patients with meningeal tuberculosis almost always have symptoms, with the most common complaints being fever, headache,mental status alteration, and nausea/vomiting.128~‘29 Meningeal signs are present on physical examination in about 70% of cases,with cranial nerve palsy or other focal neurologic findings seen in about 25% and 16% to 18% of patients, respectively.*28~129 Initially the PPD may be positive in 50% or fewer patients.129,130 Radiographicimaging of the CNS by CT scanor MRI may be helpful in diagnosingtuberculousmeningitis. CT scanningand MRI usually reveal thickened,isoattenuatingor hypoattenuatingbasalcisternson noncontrast images, with intense,homogeneousenhancementafter administration of contrast(or gadolinium for MRI). 131~132 Hydrocephalusand infarcts in the middle cerebralartery distribution are two other fairly common findings. One group of investigatorsreviewed22 studiesof tuberculousmeningitis, which included 260 patientswho underwentCT scanningand 47 patients who underwentMRI.133From the combined data of thesestudies,it was found that CT scanningand MRI revealedbasalenhancementin 62% and 73% of cases,respectively.The authorsimplied thatthis estimatesthe sensitivity of theseparticularfindings because,on the basisof autopsydata,basal inflammation occurs in nearly 100% of casesof meningealtuberculosis. Hydrocephaluswas detectedin 80% of patientsby both imaging methods. Infarcts wereseenmuch more frequentlywith MRI (65% vs. 28%). Examination of CSF is crucial for the diagnosisof tuberculousmeninDM,

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TABLE

5. Tuberculosis

CSF Opening pressure Protein Glucose WBC count Lymphocytosis ADA level CSF AFB smear AFB culture

meningitis

diagnostic

tests:

Characteristic

Lumbar value

(mean = 200) Elevated ~40 mg/dl 6 - 500 (mean = 200)

puncture Freauencv

80 - 550

710

U/L

62% - 100% 53% - 87% 95% 60% - 68% 60% - 100% Sensitivity 10% - 30% 45% - 70%

gitis (Table 5). Lumbar puncture opening pressure is usually elevated, averaging about 200 mm H,O and ranging from about 80 to 550 mm H,0.129 Chemical analysis of the CSF frequently reveals an elevated protein concentration and a low glucose level. High CSF protein concentrations are Glucose levels less than 40 mg/dl found in 62% to 100% of cases .128J30.134 are seen in 53% to 87% of patients but are likely to be higher in those with Therefore, alan elevated serum glucose level (e.g., diabetics). 113.128,129,134 though high protein and low glucose levels are the classic findings associated with meningeal tuberculosis, the absence of one or both does not exclude the diagnosis. Cellular analysis of the CSF almost always reveals a pleocytosis, although a CSF WBC count of less than 5/mm3 has been reported to occur in up to 11% of HIV-seropositive patients and 5% of HIV-seronegative patients.128 The average CSF WBC count is about 200, with one study reporting the distribution as follows: less than lOO-28%; 100 to 39951%. more than 400-21%.129 In terms of the WBC differential, a lymphocytosis is the most common finding, occurring in 60% to 68% of cases.128,12g~134 Neutrophils may be the predominant CSF cell type early in the disease. l l3 The sensitivity of the AFB smear from CSF is low and has been reported to be approximately 10% to 30%. 128~129~130~134 Performing serial lumbar punctures or subjecting the specimens to cytocentrifugation may increase the yield of theAFB smear. l l3 It is also not unusual for cultures to be negative. CSF cultures positive for M. tuberculosis are seen in only 45% to 70% of cases.130,135 Because of the lack of sensitivity and specificity of standard CSF chemical and cellular analysis and AFB smear, attempts have been made to develop other tests for the diagnosis of tuberculous meningitis.As with pleural fluid, ADA levels are often elevated in the CSF. An ADA level of greater 218

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than 10 is found in the CSF of 60% to 100% of patients with meningeal tuberculosis.128.136’137Because ADA levels may also be high in bacterial meningitis, this test is not specific enough by itself to be diagnostic of tuberculosis.‘37 Using such techniques as ELISA (see Diagnostic Approach: Clinical Evaluation, Serology), latex agglutination, and radioimmunoassay (RIA), attempts have been made to detect mycobacterial antigens and other mycobacterial products in the CSF. A review of this work reported that sensitivity of these tests varied from 53% to 94% and specificity ranged from 79% to 1OO%.134Using the same techniques, investigators have had success detecting antibodies in the CSF directed against mycobacterial antigens. ‘34 Although the search for mycobacterial products and antibodies directed against them shows some promise on the basis of these studies, such tests have not been validated by large independent trials and therefore are not recommended for routine use. The PCR assay has also been applied to the diagnosis of tuberculous meningitis. When performed on CSF, PCR has a reported sensitivity of 70% to 75%.138,139Some studies have also demonstrated excellent specificity of 94% to 100%.‘3x~‘40Others, however, have found a very high falsepositive rate of up to 62%. 14’Because of such conflicting data, a multicenter trial using a standardized assay, such as Amplicor or MTD, would be of great benefit in determining the role of direct amplification testing in the diagnosis of meningeal tuberculosis. In addition to meningitis, CNS tuberculosis may present as parenchyma1 brain or (rarely) spinal cord disease. Such disease is usually manifested by solitary or multiple round/ovoid lesions known as tuberculomas. On CT scan and MRI, the lesions may be of low or high density and often enhance (especially around the outer rim) with contrast (or gadolinium).‘31~132 With miliary disease, the lesions are small (1 to 2 mm), diffuse, and numerous. In the presence of a definitive diagnosis of tuberculosis at another site, a CT scan or MRI that shows such lesions is usually sufficient for diagnosis. Lacking such additional confirming evidence, further testing is often warranted. This is because it is frequently very difficult, if not impossible, to distinguish tuberculomas from other infectious lesions (e.g., toxoplasmosis, brain abscess, fungal infection) or intracranial neoplasms (primary or metastatic). In one series, 12 of 15 patients with tuberculomas (80%) were initially misdiagnosed as having intracranial malignant lesions on the basis of initial CT scan findings.‘42 Of 3 patients in whom tuberculomas were confidently diagnosed on the basis of radiographic appearance, 2 were subsequently found to have gliomas and 1 was found to have a fungal infection. Therefore in a patient with DM,

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CNS lesions andwithout a confirmed diagnosisof an illness likely to producesuchlesions (e.g.,tuberculosis,malignant tumor, fungal infection), a CT-guided open or stereotacticbiopsy should be consideredfor diagnosis.143 In one seriesof 15 patients in whom intracranial tuberculoma was diagnosedby histologic findings from brain biopsy, 12 (80%) hadpositive culturesfor-M. tuberculosisand4 hadpositiveAFB smears(27%).*@There were 2 (13%) major surgical complications, both of which requiredadditional surgery.Becauseof theserisks, somehaveadvocatedan initial empiric therapeutictrial, especially in populations in which the incidenceof intracranial tuberculoma is high, and have recommendedthat biopsy be reservedfor thosewho do not respond.145 Although CNS infection is more common in HIV-infected personsthan in HIV-seronegativepersons,its clinical presentationis similar. In one study of all casesof culture-proventuberculousin oneinstitution overa 5yearperiod, it was found that the incidence of meningealdiseasewas significantly higher in HIV-seropositive patients(10% vs. 2%).‘28When the authorslooked at clinical presentation,there were no significant differencesin the frequenciesof the signs and symptoms (e.g.,fever,headache, meningeal signs) attributable to tuberculousmeningitis betweenthe two groups.CSF fluid analysis,including protein, glucose,WBC, differential, andADA level, yielded similar findings in both groups.The AFB smear was no more sensitive in HIV-negativepatients (26%) than in HIV-positive patients (22%). Disease

of the Bone and Joints

The most frequent site of bone andjoint tuberculosisis the spine (Pott’s disease),which accountsfor 50% to 60% of cases.146 Within the spinethe lower thoracicandthoracolumbarregionsarethemost commonly involved, accounting for 48% to 67% of spinal lesions. Tuberculosis typically infects the vertebra(osteomyelitis) and the adjacentjoint space(arthritis), resulting in inflammation anddestruction.113 With time the infection may spreadto the adjacentsoft tissue,resulting in the formation of a paravertebra1abscess.Localized pain at the site of involvementis the most frequent presentingcomplaint, occurring in more than 90% of patients.‘47,*48 Systemic symptoms such as fever and weight loss are less common but are reportedto be presentin up to 24% to 58% of cases.147,148 With very advanceddisease,weaknessandevenparalysis may occur.The PPD is positive 77% to 100% of the time.146~147~149 Radiographic imaging is useful for assessingthe number of vertebral bodies affected, which segmentsof an individual vertebraare affected, and soft-tissueinvolvement including paraspinalabscessformation. Plain 220

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films will detect long-standing disease but may be normal in early disease. In one series of 24 patients with early spinal tuberculosis, plain films were normal in all cases.150Radionuclide bone scanning using technetium 99m and gallium 67 scanning have been advocated as potentially more sensitive techniques for detecting spinal involvement, but in one study they were found to be normal in 35% and 70%, respectively, of patients with tuberculous spondylitis.149 CT scanning provides earlier detection of bony abnormalities and can be used to localize the best site for biopsy.‘46,‘47 At present the best imaging modality is MRI. One study evaluated MRI in 24 patients suspected of having early spinal tuberculosis.‘50 In 11 of these patients this diagnosis was confirmed by biopsy and the remainder were given a clinical diagnosis of spinal tuberculosis based on a good response to antituberculosis chemotherapy. Plain bone radiographs were negative in all patients. Radionuclide bone scanning was more sensitive and detected abnormalities in 14 of the 16 cases tested (88%). MRI was the most sensitive, however, and revealed evidence of disease in 23 of 24 patients (96%). In addition, paraspinal abscesses were found in 22 patients by MRI, only 1 of which was suspected clinically. MRI also has another advantage: it is more specific than plain films or bone scans. With MRI, bacterial and tuberculous spondylitis show different patterns of findings. Using imaging criteria alone (Fig. 1 l), one group was able to correctly distinguish between bacterial and tuberculous spondylitis in 94% of cases.“’ In the same study, MRI was able to predict the presence of neurologic complications 93% of the time. The specificity of MRI patterns for the diagnosis of spinal tuberculosis does not eliminate the need for biopsy in all cases. Especially if there is no other easily accessible site of active disease, biopsy of the spine should be considered to confirm the diagnosis and obtain cultures for sensitivities. In the past the only method for histologically confirming the diagnosis of spinal tuberculosis was an open surgical procedure. More recently it was demonstrated that FNA could be used to make the diagnosis by cytology with confirmation from culture of the aspirated material.‘52 In a series of 116 patients who underwent FNA for osteolytic lesions, spinal tuberculosis was diagnosed in 38 on the basis of cytologic tindings.ls3 In the other 78 a definitive diagnosis of malignant tumor was made by FNA. Of the 38 patients with a cytologic diagnosis of tuberculosis, 34 (89%) had a positive culture for M. tuberculosis from the aspirate and in the other 4 AFB was identified in their sputum. In cases in which surgery is required for therapeutic reasons (e.g., significant spinal deformity with current or impending neurologic deficit), FNA is unnecessary because sufficient material for pathologic study, smear, and culture can be obtained at the time of DM,

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Lower lumbar spine

Lower

BS

TS

Body

Severely damaged, with evidence of osteomyelitis

Morphologically intact despite evidence of osteomyelitis

Vertebral

May be affected

Not affected

Posterior Elements

FIG. 11. Use of MRI to differentiate bacterial spondylitis (BS) from spinal infections: MR imaging. Radiology 1990;177: 101-7.)

thoracic spine

Area of Predilection

Type of infection

tuberculous

spondylitis

Severely damaged

Moderately reduced in size despite evidence of involvement

Disk Space

(TS). (From

Sharif

HS, Clark

Severely affected by extension of abscess, meningeal involvement, and/or bone fragments

Moderate extension caused by granulation tissue and/or edema

Epidural

DC, Aobed

Frequently affected by abscess collections

Frequent

Extremely infrequent

Associated Spinal Deformity

MY, et al. Granulomatous

Rarely affected by granulation tissue and/or edema

Parasplnal Soft Tissues

the operation. Material from the surgical specimen is usually diagnostic. One group reported that of 67 patients who underwent surgery for spinal tuberculosis and had specimens taken for analysis, culture was positive in 44 (66%) and in the other 23 cytologic findings revealed caseating granuloma with necrosis.“9 Outside of the spine, skeletal tuberculosis is most commonly found in the femur, ribs, and bones of the pelvis, shoulder, elbow, and wrist; disease of the fingers and skull is rare. ‘I3 On a radiograph, the bony lesions are generally osteolytic and may be confused with metastatic carcinoma. FNA of the involved bone is often diagnostic. Tuberculous arthritis excluding the spine usually occurs in weight-bearing joints. The distribution of joint involvement has been reported as follows: knees-24%, hip-20%, wrist-20%, ankle-12%, elbow-S%, and tarsal-metatarsal, shoulder, carpal-metacarpal, proximal interphalangealeach 4%.15’ In this series of 25 patients all disease was monoarticular, and the most frequent symptoms were joint pain and swelling of insidious onset. The PPD was positive in all cases. Radiographs of the involved joint revealed metaphyseal erosions in 19 patients (76%) joint space narrowing in 3 patients (12%), and no abnormalities in 3 patients (12%). For patients with suspected tuberculosis arthritis with a joint effusion, arthrocentesis should be performed. The effusion is usually characterized by high protein and low glucose levels and a WBC count of 10,000 to 20,000 with a neutrophi1 predominance. In the previously cited study, AFB smear was positive in 4 of 15 synovial fluid specimens (27%) and culture was positive in 15 of 18 specimens (83%). Cultures of synovial tissue were positive in 3 of 8 (37%) patients. Overall culture was positive for M. t&~ulosis from synovial fluid or tissue in 17 of 18 cases (94%). Synovial biopsy was the most sensitive test and revealed granuloma in 19 of 20 pathology specimens (95%). Skeletal tuberculosis is rare among HIV-infected patients. In a study of 199 HIV-seropositive persons with tuberculosis, only 4 (2%) had bone or joint disease. lz6The incidence was actually lower than that seen in a comparable group of HIV-seronegative patients with tuberculosis. Because little has been written about skeletal tuberculosis and HIV, it is not known whether there are any unique features. Genitourinary

Disease

Genitourinary tuberculosis, as the name implies, is tuberculosis of the urologic and reproductive systems. In the United States it is the fourth most frequent site of extrapulmonary disease. Tuberculosis has been reported to occur in the kidney, bladder, ureter, prostate, and the male or female reproductive organs (Table 6). DM,

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TABLE

6. Diagnosis

of genitourinary

tuberculosis

Recommended Urologic

Genital

Genital

test

Urine AFB culture Ultrasound-guided FNA *Histology *Culture

Sansltlvltv 80%

- 90%

86%

- 94% 44%

ma/e Specimen culture Biopsy of affected organ

11% ?

Menstrual blood culture Endometrial curettage *Histology *Culture Laparoscopy with biopsy or surgical excision

11%

female

60%

- 70% 34%

?

Urologic Disease. Most patientswith renal tuberculosishavesymptoms. In a seriesof 41 patients,themost common complaintsweredysuria(34%), hematuria(27%), andflank pain (1O%).156 Constitutional symptoms, such as fever and weight loss, were less frequent, occurring in 14% of cases. Twenty percentof personsin this study hadno symptoms.Tuberculin skin testsarepositive in 88% to 95% of patients.156,157 The evaluationof suspectedrenal tuberculosisbeginswith obtaining a urine specimenfor urinalysis, anAFB smear,and a mycobacterialculture. It hasbeenrecommendedthat threeto six early-morning urine samplesbe collected.‘13The yield of multiple daily samplesis thought to be comparable to 24-hoururine collection. The urinalysis is abnormalin up to 93% of cases,with the most common findings being isolated pyuria (46%), combined pyuria and hematuria (34%), and isolated hematuria ( 12%).156 These findings are obviously very nonspecific, although the finding of persistentpyuria in the face of negativebacterial cultures should alert the clinician to the possibility of urologic tuberculosis.Renalfunction is generally normal, andazotemiaattributableto tuberculosisonly occursin about 5% of casesor less.156J57 The sensitivity of urine cultures is high and has beenreportedto be 80% to 90%.156*157 Radiologic studiescan also be useful in the diagnosisof renal tuberculosis. Intravenouspyelograms (IVP) are abnormal in 63% to 93% of patients, with the most common abnormalities being renal calcification, calyceal dilation, parenchymal scarring, cavities, and filling defects.156,157 Ultrasonographyis probably more useful becauseit can also be used to guide biopsies. The abnormalities most frequently visualized via ultrasonographyarefocal renallesions5 to 15mm in size, which areechogenic 224

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or have an echogenic border. 158Focal bladder lesions may also be observed. Such findings can also be seen with bacterial infections and tumors, making them nonspecific, however. Ultrasound-guided fine-needle aspiration has been demonstrated to be useful in the diagnosis of renal tuberculosis. In one study, cytologic examination from FNA yielded granuloma in 15 of 16 patients (94%) with renal disease. 159FNA cultures were positive for AFB in 44%. The greatest value of this procedure was shown in 7 patients who consistently had negative urine cultures for AFB. FNA was able to make the diagnosis of tuberculosis in 6 (86%) of these cases. Genital Disease: Male. In male genital tuberculosis, the most frequently affected organs are the prostate (70% to lOO%), the epididymis (64% to 94%), and the seminal vesicles (32% to 62%).160 Tuberculous orchitis (testes) is less common and is usually associated with miliary disease. Involvement of multiple genital sites is typical. Epididymitis is the most common clinical presentation and is usually manifested by scrotal swelling (74% to 91%), with associated pain in the minority of cases (12% to 43%).‘“O With advanced disease, there may be abscess and fistula formation with purulent drainage. With prostatic disease, dysuria and urinary frequency may be noted. The prostate may be normal on digital rectal examination unless involvement is extensive, in which case it is often enlarged, firm, and nodular, mimicking cancer.16’ PPD has been reported to be positive in 88% to 100% of cases.156.1s7 If there is renal or prostatic involvement, urinalysis reveals pyuria in up to 70% of casesib However, if the disease is limited to the external genitals, pyuria and/or acid-fast bacilli will be detected on stain or culture of the urine in fewer than 30% of patients. I60 In tuberculous prostatitis, semen cultures have been used for diagnosis but have a low yield (1 1%).16? Radiologic studies, including IVP and scrotal ultrasonography, are often abnormal, but they are neither sensitive nor specific. The findings are generally consistent with an infectious process, but these tests cannot distinguish between chronic bacterial infections and tuberculosis.i6”,‘6” In almost all cases of male genital tuberculosis, biopsy material from the affected organ for histologic study and culture is required for diagnosis.‘56.‘60.‘64 Genital Disease: Female. In female genital tuberculosis, the most common sites of disease are the distal fallopian tubes (85%), the endometrium (70% to 75%), and the ovary (30% to 35%), with involvement of the vagina and vulva being rare. ‘I3 The most common presenting complaints are pelvic pain (32% to 45%), abnormal menstrual bleeding (11% to 41%), and infertility (13% to 47%).‘s6.‘h5.‘66 Systemic symptoms such as fever, weight loss, and anorexia are rare. Patients may be free of symptoms in up DM,

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to 11%of cases.‘@The resultsof physicalexamination,including bimanual examination, are often normal (36% to 43%) with detection of a pelvic massbeing the most common abnormality (24% to 45%).‘56,165 Tuberculin skin testing is usually positive.ls6 Urine collection for AFB cultures has beenrecommendedby somefor diagnosis of suspectedgenital tuberculosis in women, but such cultures havebeenreportedto be positive in only 0 to 3.5% of patientswith proven gynecologic tuberculosis.156~167 Culturesof menstrualblood may be useful a1so.113,166,168 Hysterosalpingographicandlaparoscopicfindings areabnormal in more than90% of cases,usually revealingobstructedfallopian tubes with nodularity and a “string sign.“165 Although suggestiveof tuberculosis, thesefindings arenot pathognomonicand may be seenwith tubal obstruction due to bacterial infection or endometriosis.‘65~168 A definitive diagnosis of female genital tuberculosis relies on obtaining tissue for histologic study andculture. In one study,endometrialcurettageyielded a diagnosisof granulomain 60% of patientswho underwentthis procedure for suspectedgenital tuberculosis.165In a seriesof 187women with gynecologic tuberculosis,130(70%) of the caseswerediagnosedby histologic study of material from endometrial curettage,of which 44 (34%) were culture-positive.166 In the remaining casesthe diagnosiswas madeby histologic study of material from fallopian tubes excised at surgery in 50 patients (27%), histologic study of cervical biopsy material in 1 patient (0.5%), andmenstrualblood or abscessculture in 11 patients(6%).166 It is also important to notethat anelevatedserumCA- 125level, which in association with a pelvic/adnexal mass is usually indicative of a malignant condition, hasalso beenreportedto occur with pelvic tuberculosis.169 Genitourinary Disease in HIV-Positive Patients. Genitourinaryinvolvement has beenreportedto be very common in HIV-seropositivepatients. In oneseriesgenitourinarydiseasewas seenin 37% of cases,with the vast majority of these (84%) being diagnosedby urine culture.126These patientsrarely (3%) hadsymptomsattributableto genitourinaryinvolvement; 40% had microscopic pyuria or hematuria.There were no casesof gynecologic tuberculosis and only 3 (1.5% of total and 4% of genitourinary tuberculosiscases)casesof male genital tuberculosis.Only 3 (1.5%) patients had isolated genitourinarytuberculosis. Abdominal Disease Abdominal tuberculosis refers to diseaseof the peritoneum, gastrointestinal tract, liver, biliary tract, and pancreas. The peritoneum, small bowel, and colon are the most frequent sites of infection. Involvement of the biliary tract and pancreasis quite rare. When hepatic disease 226

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occurs, it is usually associated (about 95% of the time) with miliary disease.“” Peritoneal Disease. Clinically, peritoneal tuberculosis is manifested by abdominal distention or swelling (53% to 94%), abdominal pain (50% to 65%), fever (50% to 79%), anorexia, and weight loss (38% to 66%).‘70-‘7’ Ascites is detectable on physical examination in 75% to 100% of cases.‘7’.‘71 Tuberculin skin testing may be negative 50% of the time or more.‘70-‘72 If ascites is present, as is usually the case, paracentesis is recommended as the initial diagnostic test. Ascitic fluid protein level is usually greater than 3 grn/dl but may be lower in alcoholics or other patients with underlying liver diseases. 170,17* For patients without underlying liver disease, the serum-to-ascites albumin gradient (SAAG) is essentially always less than 1.1 gm/dl in cases of tuberculous peritonitis.‘7’ In persons with concurrent tuberculous peritonitis and significant chronic liver disease (i.e., cirrhosis and portal hypertension), the SAAG is often but not always greater than 1.1 gm/dl. WBC count averages from about 1100 to 1700/mm3 but may be as low as 60/mm3 and as high as 5400/mm 3.‘70-‘72The WBC count differential usually reveals 80% or more lymphocytes, although tuberculous peritonitis associated with peritoneal dialysis may show a neutrophil predominance.‘72-‘74 AFB smear of ascitic fluid is almost always negative. In three studies with a combined total of 53 patients with tuberculous peritonitis, no AFB smears were positive.‘70.‘72.‘73 Ascitic fluid AFB culture is positive in 45% to 69% of cases. ‘70,‘72.‘73The yield has been reported to be as high as 83% if a large volume (11 or more) is concentrated by centrifugation and is cultured.17’ Analogous to their use in suspected tuberculous pleural effusions, measurements ofADA and IFN-)I in ascites have been advocated as diagnostic tests for peritoneal tuberculosis. In a series of 49 patients (19 with tuberculous ascites, 20 with cirrhotic ascites, 10 with malignant ascites), the mean ADA level was found to be 98.8 U/L in the tuberculous group compared to about 14 in the control groups. ‘76 Using a cutoff of more than 33 U/L for tuberculous ascites, this test had a sensitivity of 100% and a specificity of 96.6%. Another study of 30 patients with tuberculous peritonitis. 21 patients with malignant ascites, and 41 patients with cirrhosis yielded almost identical results.17’ The mean ADA level in the tuberculosis patients was 101.84 U/L compared with 13.49 U/L and 19.35 U/L in the control groups.A cutoff value of more than 30 U/L for tuberculous ascites provided a sensitivity of 93% and a specificity of 96%. This study also examined IFN-y levels in ascites in these patient groups. The mean IFN-y level in those with peritoneal tuberculosis was significantly higher (6.7) than in the controls (malignant = 3.1. cirrhotic = 3.08). Using a cutoff DM,

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value of more than 3.2 for tuberculosis,the sensitivity was 93% and the specificity was 98%. Thesestudiesdo not, however,addressthe ability of ADA andIFN-y to differentiatebetweentuberculosisandperitonitis caused by other infectious agents. Becausethe yield of AFB smearfrom ascitesis very poor and cultures take weeks to grow, further diagnostic evaluation is often necessaryin patientswith suspectedtuberculousperitonitis. In the past,blind percutaneousperitonealbiopsy specimenswereoften obtainedfor histologic study and culture.174 In the United Statesthis techniquehas beensupplantedby laparoscopy with biopsy. Tuberculous peritonitis has a characteristic laparoscopicappearancemanifestedby a thickened,erythematousperitoneum with diffuse multiple whitish yellow nodules that are uniform in size (2 to 5 mm).171~178 The typical nodular lesions areseenin 66% to 98% of cases.171*178-1so Although these findings usually indicate tuberculosis, malignant lesions can also have this appearance.171,180 Conversely,in certain casesof peritoneal tuberculosis,nodulesmay be absentand peritoneal thickening and erythema may be the only abnormalities visualized.171,178+179 For these reasons,biopsy, AFB staining, and culture are recommended.Histologic study andAFB culture of biopsy material have reported sensitivities of 79% to 100% and 37.5% to 73.8%, respectively.178-1s0 In some caseslaparoscopywill be nondiagnosticor not possible becauseof extensive,fibrous peritoneal adhesions.In these cases laparotomy with biopsy should be considered(Table7).171,174 Enteric Disease.Although tuberculosiscan affectany portion of the gastrointestinaltract from the mouth to the anus,the most commonly involved sitesarethe ileocecum,the colon,andthe small bowel (jejunum andileum). Thesethreesitesaccountfor 52% to 80% of enterictuberculosis.173~174~1s1~182 The most frequentpresentingsignsand symptomsareweight loss (66% to 83%), acuteor chronicabdominalpain (58% to 85%), anorexia(58%),nauseaandvomiting (25% to 50%), diarrhea(17% to 47%), andfever (35% to 72%).173,174,181 Rectalbleeding,melena,andconstipationhavealso beenreportedto occur.An abdominalmassmay be palpated(usually in the right lower quadrant)in up to 50% of cases.174Enteric tuberculosismay present asa smallbowel obstruction(20%)or (rarely)asa perforation(5% or less).174 The PPD testis positive in 50% to 80% of patients.181,182 The diagnosisof tuberculosisof the gastrointestinaltract is usually made by obtaining a positive culture from secretionsor by histologic study or positive culture from biopsy specimens.Radiologic studies may be suggestiveof the diagnosisbut arenot definitive. Barium studiesandabdominal CT scans often show irregular, thickened mucosa of the involved site.113,183Associated mesentericlymphadenopathyis also a common find228

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7. Diagnosis

TABLE

of peritoneal

tuberculosis Characteristic

Peritoneal fluid Protein No underlying liver disease Underlying liver disease SAAG * No underlying liver disease Underlying liver disease WBC count Differential ADA level I FN-y AFB smear AFB culture

value

Sensitivity

>3 gm/dl often ~3 gm/dl cl.1 gm/dl Often >l.l gm/dl 1000 2000 >80% lymphocytes >30 U/L >3.2 U/L

93% - 97% 93% Essentially 0% 45% 69%

Laparoscopy Appearance Biopsy Histology Culture *Serum

66% - 98% 79% - 100% 38% - 78%

to ascites

albumin

gradient

ing. These abnormalities can be seen with other intestinal infections or Crohn’s disease. Stool AFB smears and cultures may be useful in some cases. Their sensitivity has not been well documented but is believed to be 10w.l~” In most instances it is necessary to proceed to endoscopy with biopsy for diagnosis. In cases of severe bowel obstruction or perforation, diagnosis is made from tissue obtained at the time of surgery. For suspected tuberculosis of the colon and terminal ileum, colonoscopy is considered the most valuable diagnostic procedure. The colonoscopic appearance of enteric tuberculosis is characterized by nodularity and ulceration of the mucosa, which is seen in up to 80% of cases.‘84.‘R5 Strictures, deformity of the ileocecal valve, polyploidal lesions, fibrous bands, and lesions mimicking carcinoma may also be seen. The disease may be segmental or contiguous and may involve any portion of the colon. Biopsy is helpful, although often not definitive. In about 80% of cases it reveals abnormalities that are at least suggestive of tuberculosis, but in only about 45% is it truly diagnostic.1R4,185 Unfortunately, AFB smears and cultures from biopsy specimens are very rarely positive. In studies of 50 and 62 patients with a diagnosis of colonic tuberculosis who underwent colonoscopy with biopsy, AFB smear was negative in every patient.‘84,1xs Culture was positive for M. tuberculosis in 3 of 50 (6%) and none of 62 (0%) cases. Use of colonoscopic fine-needle aspiration may increase this DM,

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yield.is6PCR performed on biopsy tissue has also been used to confirm the diagnosisin casesin which theAFB stain andculture werenegative.lg7 Nevertheless,most diagnosesof colonic or ileocecaltuberculosisaremade in the absenceof confirmatory microbiologic specimens.The diagnosis usually is madein one of threeways: (1) definitive histologic findings, (2) compatible clinical, radiographic, or colonoscopic abnormalities in the presenceof documentedconcurrentpulmonary disease,or (3) compatible clinical, radiographic,or colonoscopicabnormalitieswith a goodresponse to a trial of empiric therapy(often documentedby improvement or resolution of colonic lesions on follow-up colonoscopy). Tuberculosis of the upper gastrointestinaltract is much less common thancolonic or small-bowel disease.The clinical presentationmay mimic that of peptic ulcer disease.Principles of diagnosisareessentiallythe same as for intestinal tuberculosis.Radiologic studies (e.g., barium swallow) often show abnormalitiesbut are nonspecific. Upper endoscopywith biopsy is probably the best diagnostic tool. In one seriesof 9 patientswith gastric or duodenal tuberculosis, upper gastrointestinalcontrast studies and upper endoscopy(EGD) were performed in 4 of 9 and 9 of 9 cases, respectively.‘88 Findings on uppergastrointestinalcontraststudiesincluded gastricoutlet obstruction,obstructiondistal to the duodenalbulb, narrowing of the pyloric canal, and stricturing of the first and secondparts of the duodenum.Endoscopicfindings included deformity in the pylorus (4/9) or duodenum(2/9), ulceration (5/9), andextrinsic mass(l/9). Biopsy was suggestiveof tuberculosis in only of 2 of 5 cases.For this reason,it is often necessaryto proceedto laparotomy with biopsy to confirm the diagnosis of tuberculosisand to definitively excludemalignant disease. Abdominal Diseasein HIV-Positive Patients. Abdominal diseaseis reported to occur in 14% of HIV-infected patients with extrapulmonarytuberculosis (only about 2.5% had peritoneal disease).126 Abdominal pain, tenderness,or asciteswas notedin 78% of thesepatients.Intra-abdominal lymphadenopathyis a common finding, especially in thosewith disseminateddisease.19 In one seriesof 17HIV-infected patientswho died of disseminatedtuberculosis,intra-abdominal tuberculous lymphadenitis was documentedin all 17 at autopsy.126In the same study it was found that intestinal perforation secondaryto tuberculosis also occurred more frequently in HIV-positive persons.It has also beenreportedthat stool AFB smearsarepositive in up to 40% of HIV-infected patientswith tuberculosis.19The majority of these patients usually also have positive sputum smearsand no other clinical signs of gastrointestinaldisease.It is therefore believed that thesepositive smearsactually representorganismsin swallowed sputa,not gastrointestinaltuberculosis. 230

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Pericardial Disease Tuberculous pericarditis is rare and makes up only about 1% of cases of extrapulmonary tuberculosis. ‘I3 Tuberculosis is the cause of 4% of cases of acute pericarditis and 7% of cases of pericardial tamponade.‘s9 There appears to be a predilection for this disease in African-American males.‘89.‘y0The most common symptoms are cough (38% to 94%), chest pain (57% to 76%), dyspnea (54% to 88%). orthopnea (53% to 66%), weight loss (23% to 85%), and night sweats (23% to 58%).‘89-‘y’ Fever is documented in a significant majority of cases (83% to 97%). Ascites. peripheral edema, and hemoptysis are reported to occur less commonly. Frequently reported physical examination findings include tachycardia (83% to 94%), pericardial friction rub (37% to 84%), hepatomegaly (63% to 65%), distant heart sounds (46% to 56%). pulsus paradoxus (23% to 7 1%) and distended neck veins (46% to 61%).‘89-‘y’ PPD is positive in 54% to 100% of patients.‘9”.‘yz The chest radiograph and electrocardiogram (ECG) are usually abnormal but nonspecific. Cardiomegaly and pleural effusions are seen on chest radiographs in 82% to 95% and 58% to 92% of cases, respectively.‘8y-‘“’ ECG commonly shows T-wave inversion, ST depression (up to 84% of cases), and low voltage, but ST elevation is rare (9%).‘89’90~‘91Findings on echocardiogram depend on the stage of disease.‘89 In the earliest stages, the echocardiogram may be normal. This is followed by the development of a pericardial effusion, often with evidence of adhesions and pericardial thickening. This may result in cardiac tamponade. Alternatively, with progressive pericardial fibrosis and thickening, constrictive pericarditis may be the result. In one series of 17 patients, 13 (76%) had moderate or large effusions on echocardiogram, and 4 (24%) of these had evidence of tamponade. I92The remaining 4 patients had findings consistent with constrictive pericarditis. As with chest radiography and ECG, the abnormalities seen on echocardiogram are not specific for tuberculosis and can be seen with other disease processes (e.g.. cancer) that cause pericarditis and pericardial effusions. Therefore, in the absence of documentation of active tuberculosis in another organ, additional testing is generally required for diagnosis. For patients with suspected tuberculous pericardial effusions. pericardiocentesis is a useful diagnostic tool. The pericardial fluid is most often serosanguineous in appearance but may be frankly hemorrhagic or even purulent. ‘I3 There is usually an increased WBC count with a predominance of lymphocytes and monocytes, but neutrophils may make up the majority of WBCs in the first 2 weeks.lx9 It is generally believed that the pericardial fluid AFB smear is almost always negative DM,

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TABLE

8. Diagnosisof

pericardial

tuberculosis Character&k

Pericardial Appearance WBC ADA level AFB smear AFB culture

f/ uid

Pericardial

biopsy

Histologv

Serosanguinous Elevated 240 U/L

value

Sensitlvltv

93% O-42% 50% 65%

73% - 100%

in nonimmunosuppressedpersons.113One series, in which none of 11 pericardial fluid AFB smearsfrom patients with documentedpericardial tuberculosis were positive, lends support to this belief.‘92Another study of 12 patients, however, showed the yield of AFB smear to be substantially higher at 42%.193The yield of pericardial fluid AFB culture has beenconsistently reportedto be about 50% to 65%, which is better than AFB smearbut still less than desirable. The pericardial fluid ADA level has also been reported to be useful in differentiating tuberculous pericardial effusions from those of other causes.One study measuredADA levels in 14 patients with tuberculous pericarditis (9 later proven by biopsy,5 diagnosedon the basis of clinical suspicion) and comparedthem with levels found in patients with malignant pericardial effusions and acutepericarditis of other causes.194 The meanADA level in the tuberculosis patients was 101 and 100 in the biopsy-confirmed and clinically diagnosedgroups, respectively.The levels in the control groups were 22 (malignancy) and 17 (other causes).Using a cutoff ADA level of 40 for pericardial tuberculosis,the test had a sensitivity of 93% and a specificity of 97%. In a casereport, PCR has also beenusedon pericardial fluid to make the diagnosis of tuberculous pericarditis.195 Becauseof thepoorsensitivityof pericardialfluidAFB smearandthemarginal sensitivity anddelay of culture,a per&r-dial biopsy specimenis often neededfor thediagnosisof pericardialtuberculosis(Table8).The immediate diagnosticyield from this procedure,especiallyfrom histologicstudy,is good. In one seriesof 12 patients,histologic materialfrom biopsy or pericardiectomy was diagnosticin 10 (83%).190 The only casesin which characteristic pathologicfindings werenot seeninvolved2 patientswho underwentpericardiectomy9 monthsand5 yearsaftertreatment.In two otherstudiespericat-dialbiopsy and/orpositiveAFB smearwasdiagnosticin 3 of 3 (100%)and 8 of 11(73%) cases.191*192 In oneof thesestudies,culturefrom biopsymaterial wasreportedto bepositivein 7 of 7 (100%)patients.192 232

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In HIV-infected patients, per&r-dial tuberculosis is often manifested by large pericardial effusions and tamponade.126,‘96 In a series of 199 HIVseropositive persons with extrapulmonary tuberculosis, 3 (1.5%) had pericardial disease.126All 3 had pericardial tamponade and required a pericardial window for drainage. Two of 3 had cardiomegaly on chest radiograph. The third patient had bilateral pleural effusions. In a study of 14 patients with AIDS who had pericardial effusions, tuberculosis was believed to be the cause in 8 (57%).196 Seven (88%) had evidence of tamponade on clinical findings and/or echocardiogram. The diagnosis was made by a positive AFB smear from per&u-dial fluid in one case and in another from pericardial biopsy material. In another 6 patients there were no direct confirming data. In 4 of these cases the diagnosis was based on the fact that the patients had concurrent active pulmonary tuberculosis. The other 2 were believed to have tuberculous pericarditis on the basis of a clinical response to empiric multidrug therapy. In all 6 of the cases where there was no direct evidence of pericardial tuberculosis, the patients became afebrile, their presenting symptoms improved, and their pericardial effusions did not reaccumulate with multidrug tuberculosis therapy. Miliary

(Disseminated)

Disease

Milialy tuberculosis refers to widespread hematogenous dissemination of M. tuberculosis from a previously established focus.197 The disease takes its name from the characteristic radiographic appearance of diffuse multiple micronodular (1 to 2 mm) granulomatous lesions, which are about the size of millet seeds. Systemic or constitutional symptoms such as fever (84% to 96%), anorexia (78% to 91%), weight loss (66% to SS%), and night sweats (63% to 76%) are a hallmark of this entity.‘98-Z00 Symptoms attributable to local organ involvement, especially pulmonary, abdominal, CNS, and musculoskeletal complaints, also are noted with some frequency.‘99 Tuberculin skin testing has been reported to be positive in 28% to 72% of patients with miliary disease.‘97.198,200 Up to 68% of patients may be anergic.‘98 On routine laboratory tests, anemia is found in about 50% of the cases.‘99,200Most often the WBC and platelet counts are normal, but either may be high or low. ‘99.20n On chest radiographs the classic miliary pattern of diffuse, homogeneous micronodular (1 to 2 mm) or reticulonodular infiltrates is seen in 60% to 75% of cases.‘97-200Other findings may include pleural effusions, hilar or mediastinal adenopathy, cavitary disease, nodules of varying size, a reticular or interstitial pattern without nodules, pneumothorax, and fibronodular calcifications suggestive of prior tuberculosis.197-200 Chest radiographs are reported to be normal in 3% to 7% of patients.‘98,199 In cases DM,

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in which milky tuberculosisis suspectedbut the chestradiographis atypical (especially normal or a fine reticular pattern), high-resolution chest CT scanningmay be helpful. It hasbeendemonstratedthat this candetect a patternof diffuse micronodulesconsistentwith miliary infection in cases in which plain chest radiography was unable to do so.201,202 Cranial and abdominal CT scanningcan similarly be usedto detectmiliary tuberculosis in suspectedextrapulmonary sites of involvement (e.g., brain, liver, spleen). Confirmation of the diagnosisrelies on detectionof acid-fastbacilli by smear or culture from secretionsor biopsy tissue or characteristichistologic findings from biopsy material. In patients in whom pulmonary involvement is suspectedon the basis of an abnormal chest radiographor CT scan,it is worthwhile to obtain sputum samples.SputumAFB smears arepositive in 20% to 36% of patientswith miliary tuberculosis.197-200 Sputum cultures have a better yield of 54% to 76%.197-200 Urine AFB smears are also rarely positive (7% to 14%) and, as with sputum, urine cultures have a higher yield (23% to 59%).197-199 For a rapid diagnosis,however, more invasiveproceduresare usually required. Among the procedureswith the best yield for the diagnosisof milky tuberculosis arebronchoscopywith transbronchialbiopsy, bone marrow biopsy, liver biopsy, and lymph node biopsy. In an individual patient, the initial biopsy site shouldbe chosenon the basisof two factors.The first is the probability of involvement of that organasindicated by clinical, laboratory, and radiographic data. The secondis the relative morbidity and mortality ratesof the proceduresbeing considered. If enlargedsuperficial lymph nodesaredetectableon physical examination, a fine-needleaspirateis probably the test of choice. This procedure has a reasonablediagnosticyield and is minimally invasive. In the absenceof peripheral adenopathyand in the presenceof chest radiograph abnormalities, fiberoptic bronchoscopy with transbronchial biopsy is of great utility. In miliary tuberculosis,the sensitivity of AFB smearand culture from bronchial lavageand washingsis 9% to 27% and 54% to 55%, respectively.198~199 With transbronchialbiopsy,therateof smear positivity improves slightly (27% to 37%), althoughthe sensitivity of culture is essentially the same (37% to 52%) as for washings and brushings.198,199 One must rememberthat thesetestsaresomewhatcomplimentary,though. For example,an individual patient may havea negative AFB smearon lavagebut a positive smearon biopsy or vice versa.With the addition of transbronchialbiopsy, tissue for histologic study is obtained. This gives the highest rapid diagnostic yield, with granuloma being seen in 62% to 63% of cases.198~199 Finally, bronchoscopy with 234

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TABLE

9. Diagnosis

of miliary

Test or procedure Sputum

AFB AFB AFB AFB

Urine Bronchoscopy l BAL l

Transbronchial

Bone

marrow

Liver

biopsy

biopsy

biopsy

tuberculosis smear culture smear culture

AFB smear AFB culture AFB smear AFB culture Histology AFB smear AFB culture Histology AFB smear AFB culture Histology

Sensitivity 20% - 36% 54% _ 76% 7% - 14% 23% 59% 20% 54% 27% 37% 62% 7% 23% 31% 25% 23% 88%

36% 76% - 37% 52% - 63% - 14% 59% 100% 27% 50% - 100%

transbronchial biopsy is useful for diagnosing other diseases that produce diffuse abnormalities on chest radiographs that may be indistinguishable from miliary tuberculosis (e.g., Pneumocystis carinii pneumonia or lymphangitic spread of carcinoma). If bronchoscopy is nondiagnostic or unsafe (e.g., in a patient with respiratory compromise), bone marrow or liver biopsy should be considered (Table 9). Bone marrow biopsy is a safe procedure, with little associated morbidity. A number of series have shown bone marrow biopsy to have a high diagnostic yield, revealing granuloma in 71% to 100% of cases.197.199,203,204 One other study found the sensitivity of this procedure to be substantially lower, with granuloma being found in only 31% of patients with miliary tuberculosis. ‘99AFB are rarely seen in the biopsy specimen (0 to 25%).198,199,204 The yield of culture is also not very high (4% to 24%). ‘98~199.203 Granulomas are more likely to be seen in the bone marrow if leukopenia or thrombocytopenia is present.‘99 Although liver biopsy has greater associated morbidity and mortality, it also has a slightly better diagnostic yield. Granulomas are detected in 88% to 100% of patients.‘98’199,203The AFB smear and culture are positive in 25% to 27% and 23% to 50% of cases, respectively.‘98~‘99.z0’ Disseminated tuberculosis is very common in HIV-infected patients and has been reported to occur in up to 76% of HIV-seropositive patients with extrapulmonary tuberculosis. 126In a large series of HIV-infected persons, several unique features of HIV-associated miliary tuberculosis were noted.‘26 Only 32% of these patients had a miliary pattern on chest radioDM,

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graph.Tuberculin skin testing was positive in only 11%. Blood cultures, on the other hand,were frequently positive (28 of 50, or 56%) for Mycobacterium tuberculosis. In a control group of 8 HIV-seronegativepatients, blood cultures were not positive in any. Another study of disseminated tuberculosisin AIDS confirmed this finding, with blood cultures being positive in 59% of patients with AIDS with milky tuberculosis.205 The histologic findings from tissue biopsy in these patients have also been notedto be somewhatdifferent thanin non-HIV-infected patients.In HIVpositive patientsgranulomasaremore often poorly formed or absent.205 In addition,extensivenecrosisandnumerousAFB areoften observedin these tissue samples. Such findings are indicative of overwhelming infection, andthe short-termmortality in this group of patients is quite high. A Special Case: Pediatric Pulmonary Tuberculosis Tuberculosis is particularly diffkult to diagnosein infants and children. More than 50% of casesof pulmonary tuberculosisarediscoveredin children who are essentially free of symptoms and are being evaluatedbecauseof close contactwith an adult with tuberculosis.206 In thesechildren the tuberculin skin test is positive, and chest radiographsor physical examinationsshow abnormalitiessuggestiveof activepulmonary tuberculosis. Chest radiographsin infants and youngerchildren usually reveal parenchymal infiltrates, hilar and mediastinal adenopathy,pleural effusion, or atelectasis(i.e., changesconsistent with primary tuberculosis).207 In children, eventhose with pulmonary disease,bacteriologic confirmation occursin fewer than 40% of cases.208Culture confirmation is not consideredto be an absolutenecessityin pediatric pulmonary tuberculosis.The diagnosiscan be made on the basis of close contact with a sourcecase,a positivetuberculinskin test,andradiographicabnormalitiesconsistentwith tuberculosis.207 Drug-sensitivity results from the sourcecasecan be used to guide therapyin the child. In certain circumstances,however,it is recommendedthat specimensfor culture be obtained-e.g., failure to identify a sourcecase,a drug-resistantorganism in the sourcecase,or if the child hasextrapulmonarytuberculosisor is immunocompromised.207 It is generallynot possibleto obtain sputum samplesfrom infants andyounger children. For this reason,when culture samplesarerequired,early-moming aspirationof gastriccontentsis consideredthe initial sampling method of choice. It is believed that overnight respiratory secretionscontaining M. tuberculosis are swallowed and pool in the stomach.Culture of gastric aspiratesin children detectsM. tuberculosis in only 30% to 50% of cases, althoughthe yield may be ashigh as75% in infants.207,209,210 Gastric lavage and bronchoalveolarlavage (BAL) have beencomparedheadto headfor 236

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the diagnosisof pulmonary tuberculosis in children. Gastric lavage was found to be superior,althoughthe study size was small.*1°In a study of 20 children who underwentboth proceduresfor suspectedpulmonary tuberculosis, culture from gastric lavagewaspositive in 10(50%) while culture from BAL was positive in only 2 (10%). For cases of suspected extrapulmonary tuberculosis in children, diagnostic evaluation for individual organ sitesis essentiallythe sameas hasbeendescribedfor adults in the precedingsections. References 1. The American Thoracic Society. The American Lung Association conference on reestablishing control of tuberculosis in the United States. Am J Respir Crit Care Med 1996;154:251-2. 2. Allos BM, Gensheimer KF, Bloch AB, et al. Management of an outbreak of tuberculosis in a small community. Ann Intern Med 1996; 125: 114-7. 3. Gordin FM, Slutkin G, Schecter G, et al. Presumptive diagnosis and treatment of pulmonary tuberculosis based on radiographic findings. Am Rev Respir Dis 1989;139:1090-3. 4. Cantwell MF, Snider DE, Cauthen GM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994;272:535-9. 5. Brudney K, Dobkin J. Resurgent tuberculosis in New York City. Am Rev Respir Dis 1991;144:745-9. 6. Concato J, Rom WN. Endemic tuberculosis among homeless men in New York City. Arch Intern Med 1994;154:2069-73. 7. McKenna MT, McCray E. Onorato 1. The epidemiology of tuberculosis among foreign-born persons in the United States. N Engl J Med 1995;332: 107 l-6. 8. Sepkowitz K.Tuberculosis and the health-care worker: a historical perspective. Ann Intern Med 1994;120:71-9. 9. Menzies D, Fanning A, Yuan L, et al. Tuberculosis among health-care workers. N Engl J Med 1995;332:92-8. 10. Sugita M, Tsutsumi Y, Suchi M, et al. Pulmonary tuberculosis: an occupational hazard for pathologists and pathology technicians in Japan. Acta Path01 Jpn 1990;40: 116-27. 11. Catanzaro A. Nosocomial tuberculosis. Am Rev Respir Dis 1982;125:559-62. 12. Glaser JB, Greifinger RB. Correctional health care: a public health opportunity. Ann Intern Med 1993;118: 139-35. 13. Centers for Disease Control and Prevention. Prevention and control of tuberculosis in migrant farm workers. MMWR 1992:4l(RRlO):l-IS. 14. Stead WW, DuttAK. Tuberculosis in the elderly. Semin Respir Infect 1989;4: 189-97. 15. Stead WW. Tuberculosis among elderly persons: an outbreak in a nursing home. Ann Intern Med 1981;94:606-10. 16. Centers for Disease Control and Prevention. Prevention and control of tuberculosis in correctional institutions: recommendations of the Advisory Committee for the Elimination of Tuberculosis. MMWR 1989;38:3 13-20. 17. Braun MM, Truman BI, Maquire B, et al. Increasing incidence of tuberculosis in a prison inmate population, association with HIV infection. JAMA 1989;261:393-7. 18. Centers for Disease Control and Prevention. National plan to combat multi-drug resistant tuberculosis. MMWR 1992;41(RRll): 1-7 1. 19. Barnes PF, Le HQ, Davidson PT. Tuberculosis in patients with HIV infection. Med Clin North Am 1993:77: 1369-91. DM,

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