Identification and Management of

Tuberculosis
ANTHONY F. JERANT, M.D., University of California, Davis, School of
Medicine, Davis, California
MICHELLE BANNON, P.A.-C, M.P.H., and STEPHEN RITTENHOUSE, CPT,
MC, USA, Eisenhower Army Medical Center, Fort Gordon, Georgia
Am Fam Physician. 2000 May 1;61(9):2667-2678.
See related patient information handout on tuberculosis, written by the authors
of this article.
Related Editorial
Although the resurgence of tuberculosis in the early 1990s has largely been
controlled, the risk of contracting this disease remains high in homeless
persons, recent immigrants and persons infected with the human
immunodeficiency virus (HIV). Purified protein derivative testing should be
targeted at these groups and at persons with known or suspected exposure to
active tuberculosis. Most patients with latent tuberculosis are treated with
isoniazid administered daily for nine months. In patients with active
tuberculosis, the initial regimen should include four drugs for at least two
months, with subsequent therapy determined by mycobacterial sensitivities
and clinical response. To avoid harmful drug interactions, regimens that do
not contain rifampin may be employed in HIV-infected patients who are
taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors.
To maximize compliance and minimize the emergence of mycobacterial drug
resistance, family physicians should consider using directly observed therapy
in all patients with tuberculosis.
During the early years of the past century, one of every five persons in the United
States developed active tuberculosis. The disease was the leading killer of that
time, the captain of all men of death. 1 After 1953, the incidence of tuberculosis
declined by almost 75 percent, to a low of 9.3 cases per 100,000 general population
in 1985.1
Beginning in 1986, an unexpected resurgence of tuberculosis occurred in the
United States, with the incidence of the disease rising to 10.5 cases per 100,000
population by 1992.1 Contributing factors included the human immunodeficiency
virus (HIV) epidemic, the immigration of large numbers of persons from countries

in which tuberculosis is highly prevalent, the rise of multidrug-resistant

mycobacterial organisms and the decline of local tuberculosis control programs.
Subsequent to renewed emphasis on public health control measures, the overall
incidence of tuberculosis declined to an all-time low of 7.4 cases 100,000 general
population in 1997.2 Yet a number of groups continue to experience rising rates of
tuberculosis infection (Table 1).3,4 Since 1992, for example, the incidence of
tuberculosis has risen 6 percent in foreign-born persons living in the United
States.2 Most cases are imported from the countries of origin, 5 some of which have
multidrug-resistant tuberculosis rates in excess of 20 percent because of years of
selection pressure from suboptimal antimicrobial regimens. 6
TABLE 1 Groups at High Risk for Tuberculosis

View Table
The decline in the overall incidence of tuberculosis in the United States is
encouraging, but further reductions may not be feasible unless global efforts are
made to eradicate this disease in potential reservoir groups. By keeping current on
risk factors, diagnostic tests and drug therapy, family physicians can effectively
contribute to the ongoing efforts to control tuberculosis.

Screening for Tuberculosis

The American Thoracic Society (ATS) and the Centers for Disease Control and
Prevention (CDC) recently issued updated recommendations for targeted
tuberculin testing and the treatment of latent tuberculosis infection. 3 According to
these recommendations, tuberculin testing generally should be performed only in
persons who belong to at least one of the high-risk groups noted in Table
1.3,4 Routine screening of other persons, including children not belonging to highrisk groups, is discouraged because it wastes resources and generates many falsepositive tests.3,7
Screening should be performed using the Mantoux test (intracutaneous tuberculin
test). A tuberculin syringe with a 26- or 27-gauge needle should be used to
introduce 0.1 mL (5 units) of purified protein derivative (PPD) tuberculin
intracutaneously, raising a wheal 6 to 10 mm in diameter. After 48 to 72 hours, the
test should be read by personnel who have been adequately trained in its
interpretation.8
The interpretation of Mantoux tests by inadequately trained personnel has been
shown to produce false-negative reading rates of up to 30 percent. 9 Test
interpretation varies with the tuberculosis risk and health status of the individual
patient (Table 2).3,10 Even when properly placed and interpreted, the Mantoux test
may be associated with false-positive or false-negative results (Tables 3 and 4).4,11

TABLE 2 Interpretation of the PPD Tuberculin Skin Test

View Table
TABLE 3 Causes of False-Negative Results for PPD Tuberculin Skin Tests

View Table
TABLE 4 Causes of False-Positive Results for PPD Tuberculin Skin Tests

View Table

Treatment of Latent Tuberculosis Infection

To avoid confusion among health care providers, the ATS-CDC recommendations
use treatment of latent tuberculosis infection rather than preventive therapy or
chemoprophylaxis in describing therapy for patients with tuberculosis infection
but no evidence of active disease.
Before initiating treatment of latent tuberculosis infection, physicians must ensure
that active disease is not present. Once active tuberculosis has been ruled out, the
decision to initiate treatment hinges on an analysis of risks and benefits. The chief
risk of isoniazid (INH), the treatment of first choice for most patients with latent
tuberculosis infection, is hepatotoxicity, but the drug can also cause anemia,
gastrointestinal tract symptoms and peripheral neuropathy.8
Although the risk of hepatotoxicity with isoniazid therapy is low in all age groups,
the risk does increase with age: from 0.3 percent in patients 20 to 24 years of age to
1.2 percent in patients 35 to 39 years of age to 2.3 to 3 percent in patients 50 years
of age and older. Alcohol consumption, chronic liver disease and concurrent use of
potentially hepatotoxic drugs such as acetaminophen (e.g., Tylenol) increase the
risk of isoniazid-associated hepatotoxicity in patients of any age. 12 Blacks,
Hispanics and postpartum women are also at increased risk of hepatotoxicity with
isoniazid treatment.8
Treatment of latent tuberculosis infection is usually indicated, regardless of age, in
patients who belong to one or more high-risk groups. 3 The ATS and CDC make no
firm recommendations regarding the treatment of patients at lower risk but suggest
that health care providers carefully weigh the benefits and risks of treatment,
particularly in patients more than 35 years of age. 3 Although treatment can safely
be deferred until after delivery in most pregnant women, those who belong to a
high-risk group or are likely to have been recently infected should be given
isoniazid as soon as active disease is excluded.
The usual dosage of isoniazid is 5 mg per kg per day to a maximum of 300 mg per
day. A nine-month regimen is now preferred over the previously suggested six-

month regimen.3 Randomized trials in HIV-negative patients have indicated that

nine months of treatment is more effective than six months, and that minimal
additional benefit is gained from extending therapy to 12 months. 13 A twice-weekly
dosing regimen is considered acceptable when compliance is in question, but
isoniazid should be administered only as directly observed therapy.
Despite the clear advantage of a nine-month isoniazid regimen, a six-month
regimen also provides protection and has been shown to be clearly superior to
placebo in HIV-negative and HIV-positive patients. 3Acknowledging the wide
variations in patient compliance and local health department resources, the new
ATS-CDC recommendations state that in some situations, treatment for six
months rather than nine months may provide a more favorable outcome from a
cost-effectiveness standpoint.3(p4)
The ATS-CDC panel and the American Academy of Pediatrics recommend the use
of a nine-month course of isoniazid in children. 3,14 To reduce the risk of drug-related
peripheral neuropathy with isoniazid therapy, pyridoxine (Hexa-Betalin), in a
dosage of 10 to 50 mg per day, may be coadministered in all children six years of
age and older. Pyridoxine administration should also be strongly considered in
patients who have conditions in which neuropathy is common (e.g., diabetes,
alcoholism and malnutrition), pregnant women and patients who are also taking
anticonvulsant drugs.
Monthly clinical assessments are mandatory in patients taking isoniazid for latent
tuberculosis infection. Compliance with these assessments can be facilitated by
dispensing only a one-month supply of medication at a time. Office mechanisms
for tracking patients and reminding them about follow-up visits should be
implemented.
At each monthly visit, patients should be evaluated for signs and symptoms of
hepatitis, anemia and neurotoxicity. Patients should be educated about worrisome
symptoms and instructed to stop taking isoniazid and seek medical attention
promptly if such symptoms occur.
Measurements of baseline serum aspartate aminotransferase, alanine
aminotransferase and bilirubin levels are recommended only in patients with
conditions that put them at risk for hepatotoxicity (e.g., HIV infection, alcoholism,
chronic liver disease, pregnancy or postpartum status). 3 Some physicians choose to
determine baseline liver enzyme levels in all patients to detect those with clinically
silent conditions (e.g., hepatitis C virus infection) that may predispose them to
isoniazid toxicity. Subsequent measurements are recommended only in patients
with elevated enzyme levels at baseline and in patients with predisposing
conditions for hepatotoxicity.

Asymptomatic elevation of liver enzymes occurs in 10 to 20 percent of patients

who are treated with isoniazid. The drug should be discontinued only if
transaminase levels are more than three times higher than the upper limit of normal
in symptomatic patients or five times higher than the upper limit of normal in
asymptomatic patients.3
Not all patients will be able to comply with or tolerate a nine-month isoniazid
regimen. Acceptable treatment regimens for HIV-negative and HIV-positive
patients are summarized in Table 5.3 As in the new ATS-CDC document, ratings for
the strength of recommendations and the quality of evidence supporting each
recommendation, adapted from the U.S. Public Health Service, are included.
Twice-weekly dosing regimens should always be administered as directly observed
therapy. This approach should also be considered for daily short-course regimens.
TABLE 5 Regimens for the Treatment of Latent Tuberculosis Infection

View Table
Because rifampin (Rifadin) substantially decreases the blood concentrations of
protease inhibitors and nonnucleoside reverse transcriptase inhibitors, its use is
contraindicated in patients who are taking these medications. In such situations,
patients should be given rifabutin (Mycobutin), in a dosage of 5 mg per kg per day,
instead of rifampin.
Regimens for patients exposed to multidrug-resistant tuberculosis generally consist
of two drugs to which the infecting organism is likely to be susceptible.

Diagnosis of Active Tuberculosis

The identification and treatment of persons who have active tuberculosis remain
the first priority in controlling the spread of the disease. 15 Eliciting a history of
exposure is critical because patients with active tuberculosis may be minimally
symptomatic or asymptomatic until the disease is advanced.
Classic symptoms of pulmonary tuberculosis, particularly reactivation disease,
include cough, fever, sweats, chills, anorexia, weight loss and malaise. In a recent
decision analysis involving patients hospitalized because of suspected
tuberculosis,16 strong predictors of active disease included upper-zone disease on
the chest radiograph, fever, night sweats and weight loss, along with a CD4 count
of less than 200 cells per mm3 (0.2 109 per L) in HIV-infected patients.
Extrapulmonary tuberculosis may be associated with myriad symptoms, including
altered mental status (central nervous system involvement), back pain (spinal
disease) and abdominal pain (peritoneal disease). The most common types of
extrapulmonary tuberculosis, in descending order of frequency, are pleural,

lymphatic, bone and joint disease, genitourinary tract and miliary disease,
meningitis and peritonitis.
No single ancillary test is 100 percent accurate in making or excluding the
diagnosis of tuberculosis. Although a PPD test should always be performed, it may
be negative in 10 to 25 percent of patients with active disease. 17
When pulmonary tuberculosis is suspected, chest radiographs should be obtained.
In primary pulmonary tuberculosis, numerous abnormalities can be observed,
including atelectasis, parenchymal consolidation, lymphadenopathy, pleural
effusion and a miliary pattern. Any lung lobe may be affected, although lower-lobe
involvement may be somewhat more common. In contrast, reactivation
tuberculosis has a predilection for upper-lobe involvement, and cavitation occurs in
approximately 50 percent of patients.18 Atypical radiographic findings and
accompanying extrapulmonary disease are extremely common in HIV-infected
patients; the lower the CD4 count, the more likely such findings are. 19
Diagnostic testing for extrapulmonary tuberculosis varies, depending on the
suspected location of disease.20
Bacteriologic evaluation is generally required to confirm the diagnosis of
tuberculosis. In all patients with suspected active disease, three sputum samples for
mycobacterial acid-fast stain examination andMycobacterium tuberculosis cultures
should be collected on each of three consecutive days. Acid-fast smears are
especially useful in the early detection of active pulmonary tuberculosis because
they are usually complete within 24 hours.
The overall sensitivity of three acid-fast smears for identifying active tuberculosis
is about 70 percent.20 In HIV-infected patients, the specificity of acid-fast smears is
decreased because Mycobacterium avium-intracellulare, a frequent colonizer of the
respiratory tract in immunosuppressed patients, may also cause positive acid-fast
smears. In one study,21 the specificity of acid-fast smears in HIV-positive patients
was 52 percent, compared with the 99 percent or more specificity of these smears
in patients not infected with HIV.
Sputum cultures remain the gold standard for the diagnosis of tuberculosis.
Cultures are 81 percent sensitive and 98.5 percent specific for active
disease.22 Identification of M. tuberculosis by culture may require 10 to 14 days,
and antibiotic sensitivity reports may take 15 to 30 days. 15 These delays limit the
use of cultures in making early treatment decisions. 15
Recently developed rapid sputum tests, which amplify and detect M.
tuberculosis ribosomal RNA or DNA, may prove to be useful adjuncts in the early
stages of patient evaluation. Physicians may consider employing these tests when
clinical suspicion does not correlate with the acid-fast smear or culture results, or

when the results could substantially change early treatment and patient
management decisions.23 In patients who cannot produce sputum, bronchoscopy
should be considered.
A high index of suspicion for active tuberculosis must be maintained in infants and
children, because symptoms of active disease may be minimal until dissemination
occurs. Respiratory smears and cultures are less likely to detect disease in children
than in adults. Early-morning gastric washings, obtained with instillation of 20 to
50 mL of chilled sterile water through a sterile stomach tube, are more likely to
yield a diagnosis than is bronchoscopy.24
An algorithm for the evaluation of patients with suspected tuberculosis infection or
active disease is presented in Figure 1.
Evaluation for Tuberculosis

FIGURE 1.
Algorithm for the evaluation of patients with suspected tuberculosis. (PPD = purified protein derivative; HIV = human
immunodeficiency virus)

View Large

Treatment of Active Tuberculosis

A four-drug regimen should be initiated in all adults with confirmed or suspected
active tuberculosis, and pyridoxine in a dosage of 50 mg per day should be

administered with regimens containing isoniazid to help prevent

neurotoxicity (Tables 6 and 7).25
TABLE 6 Treatment of Adults and Children with Active Tuberculosis: First-Line Medications

View Table
TABLE 7 Regimen Options for the Preferred Initial Treatment of Children and Adults

View Table
After two months of a four-drug regimen to which the initial isolates were
sensitive, patients continue treatment with isoniazid and rifampin alone if repeat
sputum cultures are negative and the patient has improved clinically. Patients
continue this dual regimen for another four months, at which time treatment may
be discontinued if sputum cultures remain negative.
Monthly evaluations by a physician, including sputum acid-fast smears and
cultures, should be performed throughout treatment.
HIV-INFECTED PATIENTS

The latest CDC recommendations for the treatment of active tuberculosis in HIVinfected patients include streptomycin-based regimens or regimens that substitute
rifabutin for rifampin. Use of these regimens does not necessitate the
discontinuation or avoidance of protease inhibitors and nonnucleoside reverse
transcriptase inhibitors. In addition, flexibility in the dosing and duration of
regimens is allowed based on clinical response(Table 8).26
TABLE 8 Regimens for HIV-Related Tuberculosis

View Table
PATIENTS WITH MULTIDRUG-RESISTANT TUBERCULOSIS

Inappropriate use of medications and the prescription of inadequate regimens has

created selection pressure that has favored the proliferation of M.
tuberculosis strains with drug-resistant mutations.27 When resistance to a single
standard drug is identified, an alternative chemotherapeutic regimen should be
employed (Table 9).25
TABLE 9 Selected Regimens for Single-Drug Resistance

View Table
Multidrug-resistant tuberculosis is defined as disease that is resistant to at least
isoniazid and rifampin.27Patients with multidrug-resistant tuberculosis should be

treated with a regimen that includes three or four drugs to which the tuberculosis
isolate is susceptible. Treatment is highly challenging because of the adverse
effects of second-line agents and the frequent need for prolonged therapeutic
courses (12 to 24 months).
In determining the most appropriate treatment regimen, consultation with an
infectious disease or pulmonary specialist is highly recommended. 25 Surgery may
be considered in patients with well-localized disease who have adequate
pulmonary reserves.28
CHILDREN AND PREGNANT WOMEN

Treatment regimens in children are generally similar to those in adults (Tables

6 and 7).25 Because of the difficulty in monitoring for ocular toxicity, streptomycin
should be substituted for ethambutol (Myambutol) in very young children.
In pregnant women, treatment of active tuberculosis in pregnancy should not be
delayed until after delivery. Women who become pregnant while on
antituberculous therapy should continue treatment. The regimen should generally
include isoniazid, rifampin and ethambutol plus pyridoxine. Use of pyrazinamide,
streptomycin, kanamycin (Kantrex), capreomycin (Capastat Sulfate), quinolones,
ethionamide (Trecator-Sc) and cycloserine (Seromycin) should generally be
avoided.25
Once the rare but serious complication of congenital tuberculosis is ruled out,
infants born to mothers with active tuberculosis should be given isoniazid for at
least three months as treatment for latent tuberculosis infection. 29
Lactating women who are being treated for tuberculosis may continue to breastfeed. They should feed their infant before taking their medication and use bottle
supplementation for the first feeding after dosing. To avoid high serum drug levels,
bottle-feeding is recommended in infants who are receiving isoniazid for latent
tuberculosis infection whose mothers are also taking this medication. 30

Directly Observed Therapy

Compliance with tuberculosis treatment regimens is limited by their complexity
and duration, a lack of symptoms in some patients and medication side effects. In
1993, at least 20 percent of patients with pulmonary tuberculosis did not complete
therapy.31 Noncompliant patients are 10 times more likely than compliant patients
to transmit multidrug-resistant tuberculosis, to require prolonged treatment and to
experience disease progression or relapse; they are also more likely to die as a
result of their infection.32Noncompliance is more likely to be a factor in men,
homeless persons, drug addicts, alcoholics, HIV-infected patients, patients with

mental and physical disabilities, and patients who have previously failed
treatment.32-35
Predicting noncompliance in advance is notoriously unreliable. Thus, directly
observed therapy, in which patients are observed swallowing each dose of
medication, should be strongly considered in patients with latent tuberculosis
infection who are being treated with twice- or thrice-weekly regimens and in all
patients who are being treated for active tuberculosis.
When directly observed therapy is used, treatment completion rates range from 85
to 96.5 percent.33 In the first two years after directly observed therapy became more
widely used, there was a 21 percent decrease in all tuberculosis cases and a 39
percent decrease in multidrug-resistant tuberculosis cases. 32
Local public health departments offer directly observed therapy services at
minimal or no cost. Community health care providers are responsible for
identifying and referring appropriate candidates for these services.

Prevention of Nosocomial Transmission

To prevent nosocomial spread, patients with possible active tuberculosis must be
categorized and managed according to disease risk from the time of hospital
admission (Table 10).36 When active tuberculosis is suspected in patients who
present to clinics or emergency departments, the patients should be evaluated
rapidly to minimize the time spent in patient care areas. Precautions in the
ambulatory care setting include placing these patients in a designated isolation
room, having them wear a surgical mask and instructing them to cover their mouth
and nose with tissues when they cough or sneeze.
TABLE 10 Risk Categories and Recommendations for Preventing the Transmission of Tuberculosis
from Hospitalized Patients

View Table

Final Comment
Local public health departments are ultimately responsible for the control of
infectious diseases, but no single entity or organization holds sufficient authority
and community coverage to combat tuberculosis alone. Control of tuberculosis will
increasingly be influenced by health department outsourcing of programs and
emerging private sector initiatives such as managed care.
Studies indicate that many physicians demonstrate poor compliance with
recommended tuberculosis treatment guidelines. 37 To achieve a continuing decline
in the tuberculosis infection rate, family physicians must work expertly and

collaboratively as members of a well-integrated team. Several sources of additional

information on tuberculosis are provided in Table 11.
TABLE 11 Tuberculosis Resources for Health Care Providers

View Table
The Authors

ANTHONY F. JERANT, M.D., is assistant professor and associate residency

director in the Department of Family and Community Medicine at the University
of California, Davis, School of Medicine, Davis. Previously he was a member of
the family practice residency faculty at Eisenhower Army Medical Center, Fort
Gordon, Ga. Dr. Jerant received his medical degree from Saint Louis University
School of Medicine, St. Louis, Mo., and completed a family medicine residency at
Madigan Army Medical Center, Fort Lewis, Wash.
MICHELLE BANNON, P.A.-C, M.P.H., is a physician assistant in the Department
of Family and Community Medicine at Eisenhower Army Medical Center and a
clinical instructor in the Physician Assistant Program at the Medical College of
Georgia, Augusta. She completed her physician assistant training at Long Island
University, Brooklyn, N.Y., and received her master of public health degree from
the University of South Carolina, Columbia.
STEPHEN RITTENHOUSE, CPT, MC, USA, is a third-year resident in the
Department of Family and Community Medicine at Eisenhower Army Medical
Center. He received a doctor of osteopathy degree from the Philadelphia College of
Osteopathic Medicine.
Address correspondence to Anthony F. Jerant, M.D., Department of Family and
Community Medicine, University of California, Davis, School of Medicine, 4860 Y
St., Suite 2300, Davis, CA 95817. Reprints are not available from the authors.
The opinions and assertions contained herein are the private views of the authors
and are not to be construed as official or as reflecting the views of the Army
Medical Department or the Army Service at large.
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