Tuberculosis

Nelson Essentials
ETIOLOGY
The agent of human tuberculosis is M. tuberculosis. The tubercle
bacilli are pleomorphic, weakly gram-positive curved rods about 2
to 4 m long. A hallmark of all mycobacteria is acid fastness: the
capacity to form stable mycolate complexes with arylmethane
dyes. The term acid-fast bacilli is practically synonymous with
mycobacteria. Mycobacteria grow slowly. Isolation from clinical
specimens on solid synthetic media usually takes 3 to 6 weeks, and
drug-susceptibility testing requires an additional 4 weeks. Growth
can be detected in 1 to 3 weeks in selective liquid media using
radiolabeled nutrients and PCR technology that allow almost
immediate diagnosis in many laboratories.
EPIDEMIOLOGY
Susceptibility to infection with M. tuberculosis disease depends on
the likelihood of exposure to an individual with infectious
tuberculosis (primarily determined by the individual's environment)
and the ability of the person's immune system to control the initial
infection and keep it latent. An estimated 10 to 15 million persons
in the U.S. have latent tuberculosis infection. Without treatment,
tuberculosis disease develops in 5% to 10% of immunologically
normal adults with tuberculosis infection at some time during their
lives. An estimated 8 million new cases of tuberculosis occur each
year among adults, and 3 million deaths are attributed to the
disease annually. In developing countries, 1.3 million new cases of
the disease occur in children younger than 15 years of age, and
450,000 children die each year of tuberculosis. Most children with
tuberculosis infection and disease acquire M. tuberculosis from an
adult with tuberculosis.
Transmission of M. tuberculosis is from person to person, usually by
respiratory droplets that become airborne when the ill individual
coughs, sneezes, laughs, sighs, or breathes. Infected droplets dry
and become droplet nuclei, which may remain suspended in the air

for hours, long after the infectious person has left the
environment. Only particles less than 10 m in diameter can reach
the alveoli and establish infection.
Several patient-related factors have been associated with an
increased chance of transmission. Of these, a positive acid-fast
smear of the sputum is most closely correlated with infectivity.
Children with primary pulmonary tuberculosis disease rarely, if
ever, infect other children or adults. Tubercle bacilli are relatively
sparse in the endobronchial secretions of children with primary
pulmonary tuberculosis, and a significant cough is usually lacking.
When young children do cough, they rarely produce sputum, and
they lack the tussive force necessary to project and suspend
infectious particles of the correct size. Nevertheless, hospitalized
children with suspected pulmonary tuberculosis are kept in
respiratory isolation initially if their parents or adult visitors have
not been evaluated fully for tuberculosis. Most initially infectious
patients become noninfectious within 2 weeks of starting effective
treatment, and many become noninfectious within several days.
In North America, tuberculosis rates are highest in foreign-born
persons from high-prevalence countries, residents of prisons,
residents of nursing homes, homeless persons, users of illegal
drugs, persons who are poor and medically indigent, healthcare
workers, and children exposed to adults in high-risk groups. Among
U.S. urban dwellers with tuberculosis, persons with AIDS and racial
minorities are overrepresented. Most children are infected with M.
tuberculosis from household contacts, but outbreaks of childhood
tuberculosis centered in elementary and high schools, nursery
schools, family daycare homes, churches, school buses, and stores
still occur. A high-risk adult working in the area has been the source
of the outbreak in most cases.
CLINICAL MANIFESTATIONS
Tuberculosis infection describes the asymptomatic stage of
infection with M. tuberculosis, also termed latent tuberculosis.
The tuberculin skin test (TST) is positive, but the chest radiograph
is normal, and there are no signs or symptoms of illness.
Tuberculosis disease occurs when there are clinical signs and
symptoms or abnormal chest radiographs or extrapulmonary

tuberculosis becomes apparent. The term tuberculosis usually

refers to the disease. The interval between latent tuberculosis and
the onset of disease may be several weeks or many decades in
adults. In young children, tuberculosis usually develops as an
immediate complication of the primary infection, and the
distinction between infection and disease may be less obvious.
Primary pulmonary tuberculosis in older infants and children is
usually an asymptomatic infection. Often the disease is manifested
by a positive TST with minimal abnormalities on the chest
radiograph, such as an infiltrate with hilar lymphadenopathy or
Ghon complex. Malaise, low-grade fever, erythema nodosum, or
symptoms resulting from lymph node enlargement may occur after
the development of delayed hypersensitivity.
Progressive primary disease is characterized by a primary
pneumonia that develops shortly after initial infection. Progression
of the primary complex to pulmonary disease or disseminated
miliary disease or progression of CNS granulomas to meningitis
occurs most commonly in the first year of life. Hilar
lymphadenopathy may compress the bronchi or trachea.
Tuberculous pleural effusion, which may accompany primary
infection, generally represents the immune response to the
organisms. Pleurocentesis reveals lymphocytes and an increased
protein level, but usually does not contain bacilli. A pleural biopsy
may be necessary to obtain tissue to confirm the diagnosis by
showing the expected granuloma formation and acid-fast
organisms.
Reactivation pulmonary tuberculosis, common in adolescents and
typical in adults with tuberculosis, usually is confined to apical
segments of upper lobes or superior segments of lower lobes. There
is usually little lymphadenopathy and no extrathoracic infection as
a result of established hypersensitivity. This is a manifestation of a
secondary expansion of infection at a site seeded years previously
during primary infection. Advanced disease is associated with
cavitation and endobronchial spread of bacilli. Symptoms include
fever, night sweats, malaise, and weight loss. A productive cough
and hemoptysis often herald cavitation and bronchial erosion.

Tuberculous pericarditis usually occurs when organisms from the

lung or pleura spread to the contiguous surfaces of the
pericardium. There is an accumulation of fluid with lymphocytic
infiltration in the pericardial space. Persistent inflammations may
result in a cellular immune response, with rupture of granulomas
into the pericardial space and the development of constrictive
pericarditis. In addition to antimycobacterial therapy, tuberculous
pericarditis is managed with corticosteroids to decrease
inflammation.
Lymphadenopathy is common in primary pulmonary disease. The
most common extrathoracic sites of lymphadenitis are the cervical,
supraclavicular, and submandibular areas (scrofula). Enlargement
may cause compression of adjacent structures. Miliary tuberculosis
refers to widespread hematogenous dissemination with infection of
multiple organs. The lesions are of roughly the same size as that of
a millet seed, from which the name miliary is derived. Miliary
tuberculosis is characterized by fever, general malaise, weight
loss, lymphadenopathy, night sweats, and hepatosplenomegaly.
Diffuse bilateral pneumonitis is common, and meningitis may be
present. The chest radiograph reveals bilateral miliary infiltrates,
showing overwhelming infection. The TST may be nonreactive as a
result of anergy. Liver or bone marrow biopsy is useful for the
diagnosis.
Tuberculous meningitis most commonly occurs in children younger
than 5 years old and often within 6 months of primary infection.
Tubercle bacilli that seed the meninges during the primary
infection replicate, triggering an inflammatory response. This
condition may have an insidious onset, initially characterized by
low-grade fever, headache, and subtle personality change.
Progression of the infection results in basilar meningitis with
impingement of the cranial nerves and is manifested by meningeal
irritation and eventually increased intracranial pressure,
deterioration of mental status, and coma. CT scans show
hydrocephalus, edema, periventricular lucencies, and infarctions.
CSF analysis reveals increased cell number (50 to 500/mm 3
leukocytes), which early in the course of disease may be either
lymphocytes or polymorphonuclear leukocytes. Glucose is low, and
protein is significantly elevated. Acid-fast bacilli are not detected

frequently in the CSF by either routine or fluorescent staining

procedures. Although culture is the gold standard for diagnosis, PCR
for M. tuberculosis is useful to make this diagnosis. Treatment
regimens for tuberculous meningitis generally include four
antituberculous drugs and corticosteroids.
Skeletal tuberculosis with mycobacterial infection of the bone
results from either hematogenous seeding or direct extension from
a caseous lymph node. This is usually a chronic disease with an
insidious onset that may be mistaken for chronic osteomyelitis
caused by S. aureus. Radiographs reveal cortical destruction;
biopsy and culture are essential for proper diagnosis. Tuberculosis
of the spine, Pott disease, is the most common skeletal site,
followed by the hip and the fingers and toes (dactylitis).
Other forms of tuberculosis include abdominal tuberculosis that
occurs from swallowing infected material. This is a relatively
uncommon complication in developed nations, where dairy herds
are inspected for bovine tuberculosis. Tuberculous peritonitis is
associated with abdominal tuberculosis and presents as fever,
anorexia, ascites, and abdominal pain. Urogenital tuberculosis is a
late reactivation complication and is rare in children. Symptomatic
illness presents as dysuria, frequency, urgency, hematuria, and
"sterile" pyuria.
LABORATORY AND IMAGING STUDIES
Tuberculin Skin Test
The most important diagnostic tool for tuberculosis is the TST. The
TST response to tuberculin antigen is a manifestation of a T cellmediated delayed hypersensitivity. It is usually positive 2 to 6
weeks after onset of infection (occasionally 3 months) and at the
time of symptomatic illness. The Mantoux test, an intradermal
injection of 5 TU (tuberculin units) (intermediate test strength) of
Tween-stabilized purified tuberculous antigen (purified protein
derivative standard [PPD-S]) usually on the volar surface of the
forearm, is the standard for screening high-risk populations and for
diagnosis in all ill patients or contacts. False-negative responses
may occur early in the illness, with use of inactivated antigen (as a
result of poor storage practice or inadequate administration), or as

a result of immunosuppression (secondary to underlying illness,

AIDS, malnutrition, or overwhelming tuberculosis). Tests with
questionable results should be repeated after several weeks of
therapy and adequate nutrition.
The only TST that should be used in ordinary practice is the 5-TU
test (Mantoux test) that is interpreted based on the host status and
size of induration (Table 124-1). Only persons at high risk should be
offered a Mantoux test (Table 124-2). When persons at low risk are
given the TST, the positive predictive value of a positive test
decreases, and persons with active tuberculosis (mainly persons
with asymptomatic infection with atypical mycobacteria) are
subjected to unnecessary treatment.
Culture
The ultimate diagnostic confirmation relies on culture of the
organism, a process that usually is more successful when tissue is
used (pleural biopsy, pericardial membrane), rather than only the
pleural or pericardial fluid. Sputum is an excellent source for
diagnosis in adults, but is difficult to obtain in young children.
Therefore gastric fluid taken before or immediately on waking
containing swallowed sputum may yield positive results. Induced
sputum may be another method for young children. Large volumes
of fluid (CSF, pericardial fluid) yield a higher rate of recovery of
organisms, but slow growth of the mycobacteria makes culture less
helpful in very ill children. When the organism is grown, the drug
susceptibilities should be determined because of the increasing
incidence of resistant organisms. Antigen detection and DNA probes
have expedited diagnosis, especially in CNS disease.
Diagnostic Imaging

Because many cases of pulmonary tuberculosis in children are

clinically relatively silent, radiography is a cornerstone for the
diagnosis of disease. The initial parenchymal inflammation that
follows deposition of infected droplet nuclei in the alveoli of the
lung usually is not visible radiographically. A localized, nonspecific
infiltrate with an overlying pleural reaction may be seen, however.
This lesion usually resolves within 1 to 2 weeks. All lobar segments
of the lung are at equal risk of being the focus of the initial
infection. In 25% of cases, two or more lobes of the lungs are
involved, although disease usually occurs at only one site. Spread
of infection to regional lymph nodes occurs early.


Bacille Calmette-Gurin immunization is not a contraindication to TST.
Initial TST is at the time of diagnosis or circumstance, beginning at 3 months of age.
*Recommendations from the American Thoracic Society, Centers for Disease Control
and Prevention, Infectious Diseases Society of America, and the American Academy of
Pediatrics. Am J Respir Crit Care Med 61:S221-247, 2000.
TST, tuberculin skin test.

The hallmark of childhood pulmonary tuberculosis is the relatively

large size and importance of the hilar lymphadenitis compared with
the less significant size of the initial parenchymal focus, together
historically referred to as the Ghon complex (with or without

calcification of the lymph nodes). Hilar lymphadenopathy is

inevitably present with childhood tuberculosis, but it may not be
detected on a plain radiograph when calcification is not present.
Partial bronchial obstruction caused by external compression from
the enlarging nodes can cause air trapping, hyperinflation, and
lobar emphysema. Occasionally, children have a picture of lobar
pneumonia without impressive hilar lymphadenopathy. If the
infection is progressively destructive, liquefaction of the lung
parenchyma leads to formation of a thin-walled primary
tuberculous cavity. Adolescents with pulmonary tuberculosis may
develop segmental lesions with hilar lymphadenopathy or the apical
infiltrates, with or without cavitation, that are typical of adult
reactivation tuberculosis.
Radiographic studies aid greatly in the diagnosis of extrapulmonary
tuberculosis in children. Plain radiographs, CT, and MRI of the
tuberculous spine usually show collapse and destruction of the
vertebral body with narrowing of the involved disc spaces.
Radiographic findings in bone and joint tuberculosis range from
mild joint effusions and small lytic lesions to massive destruction of
the bone.
In tuberculosis of the CNS, CT or MRI of the brains of patients with
tuberculous meningitis may be normal during early stages of the
infection. As the disease progresses, basilar enhancement and
communicating hydrocephalus with signs of cerebral edema or early
focal ischemia are the most common findings. In children with
renal tuberculosis, IV pyelograms may reveal mass lesions, dilation
of the proximal ureters, multiple small filling defects, and
hydronephrosis if ureteral stricture is present.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of tuberculosis includes a multitude of
diagnoses because tuberculosis may affect any organ, and in early
disease the symptoms and signs may be nonspecific. In pulmonary
disease, tuberculosis may appear similar to pneumonia, malignancy,
and any systemic disease in which generalized lymphadenopathy
occurs. The diagnosis of tuberculosis should be suspected if the TST
is positive or if there is history of tuberculosis in a contact.
Otherwise, culture of respiratory secretions or of biopsied

pulmonary tissue may be required.

The differential diagnosis of tuberculous lymphadenopathy includes
infections caused by atypical mycobacteria, catscratch disease,
fungal infection, viral or bacterial disease, toxoplasmosis,
sarcoidosis, drug reactions, and malignancy. The diagnosis may be
confirmed by fine needle aspiration, but may necessitate excisional
biopsy accompanied by appropriate histologic and microbiologic
studies.
TREATMENT
The treatment of tuberculosis is affected by the presence of
naturally occurring drug-resistant organisms in large bacterial
populations, even before chemotherapy is initiated, and the fact
that mycobacteria replicate slowly and can remain dormant in the
body for prolonged periods. Although a population of bacilli as a
whole may be considered drug susceptible, a subpopulation of
drug-resistant organisms occurs at fairly predictable frequencies of
10-5 to 10-7, depending on the drug. Cavities may contain 10 9
tubercle bacilli with thousands of organisms resistant to any one
drug, but only rare organisms resistant to multiple drugs. The
chance that an organism is naturally resistant to two drugs is on the
order of 10-11 to 10-13. Because populations of this size rarely occur
in patients, organisms naturally resistant to two drugs are
essentially nonexistent.
For patients with large populations of bacilli, such as adults with
cavities or extensive infiltrates, at least two antituberculous drugs
must be given, but for patients with tuberculosis infection but no
disease, the bacterial population is small, and a single drug, such
as isoniazid, can be given. Therapy for latent infection is aimed at
eradicating the presumably small inoculum of organisms
sequestered within macrophages and suppressed by normal T cell
activity. To prevent reactivation of these latent bacilli, therapy
with a single agent (usually isoniazid for 9 months) is suggested.
Children with primary pulmonary tuberculosis and patients with
extrapulmonary tuberculosis have medium-sized populations in
which significant numbers of drug-resistant organisms may or may
not be present. In general, these patients are treated with at least
two drugs (Table 124-3).

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Antibiotics
Isoniazid and rifampin are bactericidal for M. tuberculosis and are
effective against all populations of mycobacteria. Along with
pyrazinamide, they form the backbone of the antimicrobial
treatment of tuberculosis. Other drugs are used in special
circumstances, such as tuberculous meningitis and antibioticresistant tuberculosis. Ethambutol, ethionamide, streptomycin, and
cycloserine are bacteriostatic and are used with bactericidal
antituberculous agents to prevent emergence of resistance.
Treatment Duration

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Recommendations from the American Thoracic Society, Centers for Disease

Control and Prevention, and Infectious Diseases Society of America. Am J
Respir Crit Care Med 167:603-662, 2003.
DOT, directly observed therapy; TST, tuberculin skin test.

A 9-month regimen of isoniazid and rifampin cures more than 98%

of cases of drug-susceptible pulmonary tuberculosis in adults. After
daily administration for the first 1 to 2 months, both drugs can be
given daily or twice weekly for the remaining 7 to 8 months with
equivalent results and low rates of adverse reactions. The addition

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of pyrazinamide at the beginning of the regimen reduces the

duration of necessary treatment to 6 months. Therapy with
isoniazid, rifampin, pyrazinamide, and streptomycin during the
initial 2 months of treatment followed by isoniazid and rifampin in
the remaining 4 months routinely yields cure rates of more than
98% with relapse rates less than 4% in adults. In children with drugsusceptible pulmonary tuberculosis, a 9-month regimen of isoniazid
and rifampin is highly successful. Medications should be given daily
at first, but may be administered twice weekly during the final 7 to
8 months of treatment. The AAP has endorsed a regimen of 6
months of isoniazid and rifampin supplemented during the first 2
months by pyrazinamide as standard therapy for intrathoracic
tuberculosis in children (see Table 124-3). Noncompliance, or
nonadherence, is a major problem in tuberculosis control because
of the long-term nature of treatment and the sometimes difficult
social circumstances of the patients. As treatment regimens
become shorter, adherence assumes an even greater importance.
Improvement in compliance occurs with directly observed
therapy, which means that the healthcare worker is physically
present when the medications are administered.
COMPLICATIONS
Tuberculosis of the spine may result in angulation or gibbus
formation that requires surgical correction after the infection is
cured. With extrapulmonary tuberculosis, the major problem is
often delayed recognition of the cause of disease and delayed
initiation of treatment. Most childhood tuberculous meningitis
occurs in developing countries, where the prognosis is poor.
PROGNOSIS
In general, the prognosis of tuberculosis in infants, children, and
adolescents is excellent with early recognition and effective
chemotherapy. In most children with pulmonary tuberculosis, the
disease completely resolves, and ultimately radiographic findings
are normal. The prognosis for children with bone and joint
tuberculosis and tuberculous meningitis depends directly on the
stage of disease at the time antituberculous medications are
started.
PREVENTION

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Tuberculosis control programs involve case finding and treatment,

which interrupts secondary transmission of infection from close
contacts. Infected close contacts are identified by positive TST
reactions and can be started on appropriate treatment to prevent
transmission.
Prevention of transmission in healthcare settings involves
appropriate physical ventilation of the air around the source case.
Offices, clinics, and hospital rooms used by adults with possible
tuberculosis should have adequate ventilation, with air exhausted
to the outside (negative-pressure ventilation). Healthcare
providers should have annual TSTs.
Bacille Calmette-Gurin Vaccine
The only available vaccine against tuberculosis is the BCG. The
original vaccine organism was a strain of Mycobacterium bovis
attenuated by subculture every 3 weeks for 13 years. The preferred
route of administration is intradermal injection with a syringe and
needle because this is the only method that permits accurate
measurement of an individual dose. The official recommendation of
the World Health Organization is a single dose administered during
infancy. In the United Kingdom, a single dose is administered during
adolescence. In many countries, the first dose is given in infancy,
then one or more additional vaccinations are given during
childhood. In some countries, repeat vaccination is universal; in
others, it is based either on tuberculin negativity or on the absence
of a typical scar. Some studies showed a great deal of protection
from BCG, but others showed no efficacy at all. BCG vaccine is not
used frequently in the U.S. Many infants who receive BCG vaccine
never have a positive tuberculin reaction. When a reaction does
occur, the induration size is usually less than 10 mm, and the
reaction wanes after several years.

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