Nelson TB

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996  n   Part XVII Infectious Diseases
During the last decade of the 20th century the number of new 
cases of tuberculosis increased worldwide. Currently, 95% of 
tuberculosis cases occur in developing countries where HIV/AIDS 
epidemics have had the greatest impact and where resources are 
often unavailable for proper identification and treatment of these 
diseases (Figs. 207-1 and 207-2). In many industrialized coun-
Chapter 207
Tuberculosis 
(Mycobacterium tuberculosis)
Jeffrey R. Starke
Figure 207-1  Trajectories of tuberculosis epidemic for 9 epidemiologically different 
regions of the world. Points mark trends in estimated incidence rates, derived from case 
notifications for 1990-2003. Groupings of countries based on WHO regions. High HIV = 
incidence >4% in adults aged 15-49 yr in 2003; low HIV = <4%. Established market 
economies = all 30 OECD (Organization for Economic Co-operation and Development) 
countries, except Mexico, Slovakia, and Turkey, plus Singapore. Countries in each region 
are listed in full elsewhere. (From Dye C: Global epidemiology of tuberculosis, Lancet 
367:938–940, 2006.)
Yr
World
Africa (high HIV)
Africa (low HIV)
South East Asia
Western Pacific
Eastern Mediterranean
Eastern Europe
Latin America
Central Europe
Established market economies
400
600
200
0
1990 1995 2000 2005
N
ew
 c
as
es
/1
00
,0
00
 p
er
 y
r
tries, most cases of tuberculosis occur in foreign-born popula-
tions (Figs. 207-3 and 207-4). The World Health Organization 
(WHO) estimates that >8 million new cases of tuberculosis occur 
and that approximately 2 million people die of tuberculosis 
worldwide each year. Almost 1.3 million cases and 450,000 
deaths occur in children each year. More than 30% of the world’s 
population is infected with Mycobacterium tuberculosis. If 
present trends continue, 10 million new cases are expected to 
occur annually by 2010, with Africa having more cases than any 
other region of the world (see Fig. 207-1). In the USA, after a 
resurgence in the late 1980s, the total number of cases of tuber-
culosis began to decrease in 1992, but tuberculosis continues to 
be a public health concern (see Fig. 207-3).
ETIOLOGY
There are 5 closely related mycobacteria in the M. tuberculosis 
complex: M. tuberculosis, M. bovis, M. africanum, M. microti, 
and M. canetti. M. tuberculosis is the most important cause of 
tuberculosis disease in humans. The tubercle bacilli are non–
spore-forming, nonmotile, pleomorphic, weakly gram-positive 
curved rods 2-4 µm long. They can appear beaded or clumped in 
stained clinical specimens or culture media. They are obligate 
aerobes that grow in synthetic media containing glycerol as the 
carbon source and ammonium salts as the nitrogen source 
(Loewenstein-Jensen culture media). These mycobacteria grow 
best at 37-41°C, produce niacin, and lack pigmentation. A lipid-
rich cell wall accounts for resistance to the bactericidal actions 
of antibody and complement. A hallmark of all mycobacteria is 
acid fastness—the capacity to form stable mycolate complexes 
with arylmethane dyes such as crystal violet, carbolfuchsin, aura-
mine, and rhodamine. Once stained, they resist decoloration with 
ethanol and hydrochloric or other acids.
Mycobacteria grow slowly, with a generation time of 12-24 hr. 
Isolation from clinical specimens on solid synthetic media usually 
takes 3-6 wk, and drug susceptibility testing requires an addi-
tional 4 wk. Growth can be detected in 1-3 wk in selective liquid 
medium using radiolabeled nutrients (e.g., the BACTEC radio-
metric system), and drug susceptibilities can be determined in an 
additional 3-5 days. Once mycobacterial growth is detected, the 
species of mycobacteria present can be determined within hours 
using high-pressure liquid chromatography analysis (based on 
the fact that each species has a unique fingerprint of mycolic 
acids) or DNA probes. The presence of M. tuberculosis in clinical 
specimens sometimes can be detected directly within hours using 
nucleic acid amplification (NAA) tests (including polymerase 
chain reaction) that employ a DNA probe complementary to 
mycobacterial DNA or RNA. Data from children are limited, but 
the sensitivity of some NAA techniques is similar to that for 
culture for pulmonary tuberculosis and is better than culture for 
extrapulmonary disease. Restriction fragment length polymor-
phism (RFLP) profiling of mycobacteria is a helpful tool to study 
the epidemiology of tuberculosis.
EPIDEMIOLOGY
Latent tuberculosis infection (LTBI) occurs after the inhalation 
of infective droplet nuclei containing M. tuberculosis. A reactive 
tuberculin skin test (TST) and the absence of clinical and 
radiographic manifestations are the hallmark of this stage. The 
word tuberculosis refers to disease that occurs when signs and 
symptoms or radiographic changes become apparent. Untreated 
infants with LTBI have up to a 40% likelihood of developing 
tuberculosis, with the risk for progression decreasing gradually 
Chapter 207 Tuberculosis (Mycobacterium tuberculosis)   n   997
Figure 207-2  Distribution of tuberculosis in the 
world in 2003. (From Dye C: Global epidemiology 
of tuberculosis, Lancet 367:938–940, 2006.)
No estimate
0-24
25-49
50-99
100-299
�300
Estimated incidence rate
per 100,000, all forms of
tuberculosis
Figure 207-3  Case rates of tuberculosis (TB), by age—USA, 1993-2008. (From the 
Centers for Disease Control and Prevention: Reported Tuberculosis in the United States, 
2008. Atlanta, U.S. Department of Health and Human Services, September 2009.)
Age group (years)
*Updated as of May 20, 2009.
TB case rates* by age group
USA, 1993-2008
0
5
10
15
20
1993 1996 20021999 2005
�15 15-24 45-6425-44 �65
2008
C
as
es
 p
er
 1
00
,0
00
Figure 207-4  Number of tuberculosis (TB) cases in U.S.-born and foreign-born 
persons—USA, 1993-2008. (From the Centers for Disease Control and Prevention: 
Reported Tuberculosis in the United States, 2008. Atlanta, U.S. Department of Health 
and Human Services, September 2009.)
*Updated as of May 20, 2009.
Number of TB cases in
U.S.-born vs. foreign-born persons
USA, 1993-2008*
0
5,000
10,000
15,000
20,000
1993 1996 20021999 2005
U.S.-born Foreign-born
2008
N
o.
 o
f c
as
es
continues to grow owing to several factors, including the impact 
of HIV epidemics, population migration patterns, increasing 
poverty, social upheaval and crowded living conditions in devel-
oping countries and in inner city populations in developed coun-
tries, inadequate health coverage and poor access to health 
services, and inefficient tuberculosis control programs.
Tuberculosis case rates decreased steadily in the USA during 
the 1st half of the 20th century, long before the advent of anti-
tuberculosis drugs, as a result of improved living conditions and, 
likely, genetic selection favoring persons resistant to developing 
disease. A resurgence of tuberculosis in the late 1980s was associ-
ated primarily with the HIV epidemic and transmission of the 
organism in congregate settings, adding to increased immigration 
and poor tuberculosis control (see Fig. 207-3). Since 1992, the 
number of reported cases of tuberculosis has decreased each year, 
reaching a record low of 12,904 cases (rate of 4.2/100,000 popu-
lation) in the year 2008. Of these, 786 (6.1%) cases occurred in 
children <15 yr of age (rate 1.3/100,000 population). The decline 
in overall incidence was mostly due to a substantial decrease in 
cases in persons born in the USA. About 59% of all cases were 
among foreign-born persons. The total number of cases among 
foreign-born persons increased 5% between 1992 and 2005 (see 
Fig. 207-4). In all age groups, the proportion of reported cases 
was strikingly higher in foreign-born and nonwhite persons, even 
though the number of cases among foreign-born children <15 yr 
of age has declined. In white populations in the USA, tuberculosis 
rates are highest among the elderly who acquired the infection 
decadesago. In contrast, among nonwhite populations, tubercu-
losis is most common in young adults and children <5 yr of age. 
The age range of 5-14 yr is often called the “favored age,” 
because in all human populations this group has the lowest rate 
of tuberculosis disease. Among adults two thirds of cases occur 
in men, but in children there is no significant difference in sex 
distribution.
In the USA, most children are infected with M. tuberculosis 
in their home by someone close to them, but outbreaks of child-
hood tuberculosis also occur in elementary and high schools, 
nursery schools, daycare centers and homes, churches, school 
buses, and sports teams. HIV-infected adults with tuberculosis 
can transmit M. tuberculosis to children, and children with HIV 
infection are at increased risk for developing tuberculosis after 
infection. Specific groups are at high risk for acquiring tuber-
through childhood to adult lifetime rates of 5-10%. The greatest 
risk for progression occurs in the first 2 yr after infection.
The World Health Organization estimates that 30% of the 
world’s population (2 billion people) are infected with M. tuber-
culosis. Infection rates are highest in Africa, Asia, and Latin 
America (see Fig. 207-2). The global burden of tuberculosis 
998  n   Part XVII Infectious Diseases
Table 207-1  GROUPS AT HIGH RISK FOR ACQUIRING 
TUBERCULOSIS INFECTION AND DEVELOPING DISEASE  
IN COUNTRIES WITH LOW INCIDENCE
RISK FACTORS FOR TUBERCULOSIS INFECTION
Children exposed to high-risk adults
Foreign-born persons from high-prevalence countries
Homeless persons
Persons who inject drugs
Present and former residents or employees of correctional institutions, homeless 
shelters, and nursing homes
Health care workers caring for high-risk patients (if infection control is not 
adequate)
RISK FACTORS FOR PROGRESSION OF LATENT TUBERCULOSIS INFECTION  
TO TUBERCULOSIS DISEASE
Infants and children ≤4 yr of age, especially those <2 yr of age
Adolescents and young adults
Persons co-infected with HIV
Persons with skin test conversion in the past 1-2 yr
Persons who are immunocompromised, especially in cases of malignancy and 
solid organ transplantation, immunosuppressive medical treatments including 
anti–tumor necrosis factor therapies, diabetes mellitus, chronic renal failure, 
silicosis, and malnutrition
RISK FACTORS FOR DRUG-RESISTANT TUBERCULOSIS
Personal or contact history of treatment for tuberculosis
Contacts of patients with drug-resistant tuberculosis
Birth or residence in a country with a high rate of drug resistance
Poor response to standard therapy
Positive sputum smears (acid-fast bacilli) or culture ≥2 month after initiating 
appropriate therapy
culosis infection and progressing from LTBI to tuberculosis 
(Table 207-1).
The incidence of drug-resistant tuberculosis has increased dra-
matically throughout the world. In the USA, about 8% of M. 
tuberculosis isolates are resistant to at least isoniazid, whereas 
1% are resistant to both isoniazid and rifampin. Resistance to 
isoniazid remained relatively stable between 1992 and 2008, as 
did the proportion of cases that were multidrug resistant (about 
1%). In some countries, drug resistance rates range from 20% to 
50%. The major reasons for the development of drug resistance 
are the patient’s poor adherence to treatment and provision of 
inadequate drug regimens by the physician or national tubercu-
losis program.
TRANSMISSION
Transmission of M. tuberculosis is person to person, usually by 
airborne mucus droplet nuclei, particles 1-5 µm in diameter that 
contain M. tuberculosis. Transmission rarely occurs by direct 
contact with an infected discharge or a contaminated fomite. The 
chance of transmission increases when the patient has a positive 
acid-fast smear of sputum, an extensive upper lobe infiltrate or 
cavity, copious production of thin sputum, and severe and force-
ful cough. Environmental factors such as poor air circulation 
enhance transmission. Most adults no longer transmit the organ-
ism within several days to 2 weeks after beginning adequate 
chemotherapy, but some patients remain infectious for many 
weeks. Young children with tuberculosis rarely infect other chil-
dren or adults. Tubercle bacilli are sparse in the endobronchial 
secretions of children with pulmonary tuberculosis, and cough is 
often absent or lacks the tussive force required to suspend infec-
tious particles of the correct size. Children and adolescents with 
adult-type cavitary or endobronchial pulmonary tuberculosis can 
transmit the organism. Airborne transmission of M. bovis and 
M. africanum can also occur. M. bovis can penetrate the gastro-
intestinal (GI) mucosa or invade the lymphatic tissue of the 
oropharynx when large numbers of the organism are ingested. 
Human infection with M. bovis is rare in developed countries as 
a result of the pasteurization of milk and effective tuberculosis-
control programs for cattle. About 30% of culture-proven 
childhood tuberculosis cases in San Diego, California, since 
1990 were caused by M. bovis, likely acquired by children when 
visiting Mexico or another country with suboptimal veterinary 
tuberculosis-control programs.
PATHOGENESIS
The primary complex of tuberculosis includes local infection at 
the portal of entry and the regional lymph nodes that drain the 
area (Fig. 207-5). The lung is the portal of entry in >98% of 
cases. The tubercle bacilli multiply initially within alveoli and 
alveolar ducts. Most of the bacilli are killed, but some survive 
within nonactivated macrophages, which carry them through 
lymphatic vessels to the regional lymph nodes. When the primary 
infection is in the lung, the hilar lymph nodes usually are involved, 
although an upper lobe focus can drain into paratracheal nodes. 
The tissue reaction in the lung parenchyma and lymph nodes 
intensifies over the next 2-12 wk as the organisms grow in 
number and tissue hypersensitivity develops. The parenchymal 
portion of the primary complex often heals completely by fibrosis 
or calcification after undergoing caseous necrosis and encapsula-
tion (Fig. 207-6). Occasionally, this portion continues to enlarge, 
resulting in focal pneumonitis and pleuritis. If caseation is intense, 
the center of the lesion liquefies and empties into the associated 
bronchus, leaving a residual cavity.
The foci of infection in the regional lymph nodes develop some 
fibrosis and encapsulation, but healing is usually less complete 
than in the parenchymal lesion. Viable M. tuberculosis can persist 
for decades within these foci. In most cases of initial tuberculosis 
infection, the lymph nodes remain normal in size. However, hilar 
and paratracheal lymph nodes that enlarge significantly as part 
of the host inflammatory reaction can encroach on a regional 
bronchus (Figs. 207-7 and 207-8). Partial obstruction of the 
bronchus caused by external compression can cause hyperinfla-
tion in the distal lung segment. Complete obstruction results in 
atelectasis. Inflamed caseous nodes can attach to the bronchial 
wall and erode through it, causing endobronchial tuberculosis or 
a fistula tract. The caseum causes complete obstruction of the 
bronchus. The resulting lesion is a combination of pneumonitis 
and atelectasis and has been called a collapse-consolidation or 
segmental lesion (Fig. 207-9).
During the development of the primary complex (Ghon 
complex), which is the combination of a parenchymal pulmonary 
lesion and a corresponding lymph node site, tubercle bacilli are 
often carried to most tissues of the body through the blood and 
lymphatic vessels. Although seeding of the organs of the reticu-
loendothelial system is common, bacterial replication is more 
likely to occur in organs with conditions that favor their growth, 
such as the lung apices, brain, kidneys, and bones. Disseminated 
tuberculosis occurs if the number of circulating bacilli is large 
and the host’s cellular immune response is inadequate. More 
often the numberof bacilli is small, leading to clinically inappar-
ent metastatic foci in many organs. These remote foci usually 
become encapsulated, but they may be the origin of both extra-
pulmonary tuberculosis and reactivation tuberculosis in some 
persons.
The time between initial infection and clinically apparent 
disease is variable. Disseminated and meningeal tuberculosis are 
early manifestations, often occurring within 2-6 mo of acquisi-
tion. Significant lymph node or endobronchial tuberculosis 
usually appears within 3-9 mo. Lesions of the bones and joints 
take several years to develop, whereas renal lesions become 
evident decades after infection. Extrapulmonary manifestations 
develop in 25-35% of children with tuberculosis, compared with 
about 10% of immunocompetent adults with tuberculosis.
Pulmonary tuberculosis that occurs >1 yr after the primary 
infection is usually caused by endogenous regrowth of bacilli 
Chapter 207 Tuberculosis (Mycobacterium tuberculosis)   n   999
Figure 207-5  Overview of the immune response in tuberculosis. Control of Mycobacterium tuberculosis is mainly the result of productive teamwork 
between T-cell populations and macrophages (Mϕ). M. tuberculosis survives within macrophages and dendritic cells (DCs) inside the phagosomal 
compartment. Gene products of MHC class II are loaded with mycobacterial peptides that are presented to CD4 T cells. CD8 T-cell stimulation requires 
loading of MHC I molecules by mycobacterial peptides in the cytosol, either by egression of mycobacterial antigens into the cytosol or cross-priming, by 
which macrophages release apoptotic bodies carrying mycobacterial peptides. These vesicles are taken up by DCs and peptides presented. The CD4 
T-helper (Th) cells polarize into different subsets. DCs and macrophages express pattern recognition receptors (PRRs), which sense molecular patterns 
on pathogens. Th1 cells produce IL-2 for T-cell activation, interferon-γ (IFN-γ), or tumor necrosis factor (TNF) for macrophage activation. Th17 cells, 
which activate polymorphonuclear granulocytes (PNGs), contribute to the early formation of protective immunity in the lung after vaccination. Th2 cells 
and regulatory T cells (Treg) counter-regulate Th1-mediated protection via IL4, transforming growth factor β (TGF-β), or IL10. CD8 T cells produce IFN-γ 
and TNF, which activate macrophages. They also act as cytolytic T lymphocytes (CTL) by secreting perforin and granulysin, which lyse host cells and 
directly attack M. tuberculosis. These effector T cells (Teff) are succeeded by memory T cells TM). TM cells produce multiple cytokines, notably IL2, IFN-γ, 
and TNF. During active containment in solid granuloma, M. tuberculosis recesses into a dormant stage and is immune to attack. Exhaustion of T cells is 
mediated by interactions between T cells and DCs through members of the programmed death 1 system. Treg cells secrete IL10 and TGF-β, which 
suppress Th1. This process allows resuscitation of M. tuberculosis, which leads to granuloma caseation and active disease. B, B cell. (From Kaufman 
SHE, Hussey G, Lambert PH: New vaccines for tuberculosis. Lancet 375:2110–2118, 2010.)
Cross-priming
M tuberculosis
M tuberculosis
PRR
PRR
CD8
CD8Direct presentation
PNGMHC I
MHC I
MHC II
MHC II
DC
DC
IL17
T
T
IFN�
M�
M�
M�
M�
M�
IFN�
IFN�
IL10
TGF�
IFN�
Th1Th17
CD4
CD4
IL2
IL4
B
Th2 Treg
Suppression
Active
disease
Caseous
granuloma
Latent
infection
Solid
granuloma
Protection
Protection
Exhaustion
TNF
CD4
Teff
CD8
Teff
CD8
CTLLysis
Lysis
CD8
TM
CD8
TM
Th1
TM
Figure 207-6  A and B, Posteroanterior and 
lateral chest radiograph images of an adolescent 
showing a 7-mm calcified granuloma in the left 
lower lobe (arrows). (From Lighter J, Rigaud M: 
Diagnosing childhood tuberculosis: traditional and 
innovative modalities, Curr Prob Pediatr Adolesc 
Health Care 39:55–88, 2009.)
A B
1000  n   Part XVII Infectious Diseases
Figure 207-7  A 14 yr old child with proven 
primary tuberculosis. Frontal (A) and lateral 
(B) views of the chest show hyperinflation, 
prominent left hilar lymphadenopathy, and alveolar 
consolidation involving the posterior segment of 
the left upper love as well as the superior segment 
of the left lower lobe. (From Hilton SVW, Edwards 
DK, editors: Practical pediatric radiology, ed 3, 
Philadelphia, 2003, Saunders, p 334.)
A B
Figure 207-8  An 8 yr old child with a history of cough. A single frontal view of the 
chest shows marked right hilar and paratracheal lymphadenopathy with alveolar disease 
involving the right middle and lower lung fields. This was also a case of primary 
tuberculosis. (From Hilton SVW, Edwards DK, editors: Practical pediatric radiology, ed 3, 
Philadelphia, 2003, Saunders, p 335.)
Figure 207-9  Right-sided hilar lymphadenopathy and collapse-consolidation lesions of 
primary tuberculosis in a 4 yr old child. persisting in partially encapsulated lesions. This reactivation 
tuberculosis is rare in children but is common among adolescents 
and young adults. The most common form is an infiltrate or 
cavity in the apex of the upper lobes, where oxygen tension and 
blood flow are great.
The risk for dissemination of M. tuberculosis is very high in 
HIV-infected persons. Reinfection also can occur in persons with 
advanced HIV or AIDS. In immunocompetent persons the 
response to the initial infection with M. tuberculosis usually 
provides protection against reinfection when a new exposure 
occurs. However, exogenous reinfection has been reported to 
occur in adults without immune compromise in highly endemic 
areas.
Pregnancy and the Newborn
Pulmonary and particularly extrapulmonary tuberculosis other 
than lymphadenitis in a pregnant woman is associated with 
increased risk for prematurity, fetal growth retardation, low 
birthweight, and perinatal mortality. Congenital tuberculosis is 
rare because the most common result of female genital tract 
tuberculosis is infertility. Congenital transmission usually occurs 
from a lesion in the placenta through the umbilical vein. Primary 
infection in the mother just before or during pregnancy is more 
likely to cause congenital infection than is reactivation of a previ-
ous infection. The tubercle bacilli first reach the fetal liver, where 
a primary focus with periportal lymph node involvement can 
occur. Organisms pass through the liver into the main fetal cir-
culation and infect many organs. The bacilli in the lung usually 
remain dormant until after birth, when oxygenation and pulmo-
nary circulation increase significantly. Congenital tuberculosis 
can also be caused by aspiration or ingestion of infected amniotic 
fluid. However, the most common route of infection for the 
neonate is postnatal airborne transmission from an adult with 
infectious pulmonary tuberculosis.
Immunity
Conditions that adversely affect cell-mediated immunity predis-
pose to progression from tuberculosis infection to disease. Rare 
Chapter 207 Tuberculosis (Mycobacterium tuberculosis)   n   1001
specific genetic defects associated with deficient cell-mediated 
immunity in response to mycobacteria include interleukin (IL)-12 
receptor B1 deficiency and complete and partial interferon-γ 
(IFN-γ) receptor 1 chain deficiencies. Tuberculosis infection is 
associated with a humoral antibody response, which appears to 
play little role in host defense. Shortly after infection, tubercle 
bacilli replicate in both free alveolar spaces and within inacti-
vated alveolar macrophages. Sulfatides in the mycobacterial cell 
wall inhibit fusion of the macrophage phagosome and lysosomes, 
allowing the organisms to escape destruction by intracellular 
enzymes. Cell-mediated immunity develops 2-12 wk after infec-
tion, along with tissue hypersensitivity (see Fig. 207-6). After 
bacilli enter macrophages, lymphocytes that recognize mycobac-
terial antigens proliferate and secrete lymphokines and other 
mediators that attract other lymphocytes and macrophages tothe 
area. Certain lymphokines activate macrophages, causing them 
to develop high concentrations of lytic enzymes that enhance 
their mycobactericidal capacity. A discrete subset of regulator 
helper and suppressor lymphocytes modulates the immune 
response. Development of specific cellular immunity prevents 
progression of the initial infection in most persons.
The pathologic events in the initial tuberculosis infection seem 
to depend on the balance among the mycobacterial antigen load; 
cell-mediated immunity, which enhances intracellular killing; and 
tissue hypersensitivity, which promotes extracellular killing. 
When the antigen load is small and the degree of tissue sensitivity 
is high, granuloma formation results from the organization of 
lymphocytes, macrophages, and fibroblasts. When both antigen 
load and the degree of sensitivity are high, granuloma formation 
is less organized. Tissue necrosis is incomplete, resulting in for-
mation of caseous material. When the degree of tissue sensitivity 
is low, as is often the case in infants or immunocompromised 
persons, the reaction is diffuse and the infection is not well con-
tained, leading to dissemination and local tissue destruction. 
Tumor necrosis factor (TNF) and other cytokines released by 
specific lymphocytes promote cellular destruction and tissue 
damage in susceptible persons.
Tuberculin Skin Testing
The development of delayed-type hypersensitivity (DTH) in 
most persons infected with the tubercle bacillus makes the TST 
a useful diagnostic tool. The Mantoux TST is the intradermal 
injection of 0.1 mL purified protein derivative (PPD) stabilized 
with Tween 80. T cells sensitized by prior infection are recruited 
to the skin, where they release lymphokines that induce indura-
tion through local vasodilatation, edema, fibrin deposition, and 
recruitment of other inflammatory cells to the area. The amount 
of induration in response to the test should be measured by a 
trained person 48-72 hr after administration. In some patients 
the onset of induration is >72 hr after placement; this is also a 
positive result. Immediate hypersensitivity reactions to tuberculin 
or other constituents of the preparation are short lived (<24 hr) 
and not considered a positive result. Tuberculin sensitivity devel-
ops 3 wk to 3 mo (most often in 4-8 wk) after inhalation of 
organisms.
Host-related factors can depress the skin test reaction in a 
child infected with M. tuberculosis, including very young age, 
malnutrition, immunosuppression by disease or drugs, viral infec-
tions (measles, mumps, varicella, influenza), vaccination with 
live-virus vaccines, and overwhelming tuberculosis. Corticoste-
roid therapy can decrease the reaction to tuberculin, but the effect 
is variable. TST done at the time of initiating corticosteroid 
therapy is usually reliable. Approximately 10% of immunocom-
petent children with tuberculosis disease (up to 50% of those 
with meningitis or disseminated disease) do not react initially to 
PPD; most become reactive after several months of antitubercu-
losis therapy. Nonreactivity may be specific to tuberculin or more 
global to a variety of antigens, so positive “control” skin tests 
with a negative tuberculin test never rule out tuberculosis. The 
other common reasons for a false-negative skin test are poor 
technique and misreading of the results.
False-positive reactions to tuberculin can be caused by cross 
sensitization to antigens of nontuberculous mycobacteria 
(NTM), which generally are more prevalent in the environment 
as one approaches the equator. These cross reactions are usually 
transient over months to years and produce less than 10-12 mm 
of induration. Previous vaccination with bacille Calmette-Guérin 
(BCG) also can cause a reaction to a TST, especially if 2 or 
more BCG vaccinations have been given. Approximately 50% 
of the infants who receive a BCG vaccine never develop a reac-
tive TST, and the reactivity usually wanes in 2-3 yr in those 
with initially positive skin test results. Older children and adults 
who receive a BCG vaccine are more likely to develop tubercu-
lin reactivity, but most lose the reactivity by 5-10 yr after vac-
cination. When skin test reactivity is present, it usually causes 
<10 mm of induration, although larger reactions occur in some 
persons. In general in the USA, a tuberculin skin reaction of 
≥10 mm in a BCG-vaccinated child or adult is considered posi-
tive and necessitates further diagnostic evaluation and treat-
ment, although many such patients do not have LTBI. Prior 
vaccination with BCG is never a contraindication to tuberculin 
testing.
The appropriate size of induration indicating a positive 
Mantoux TST result varies with related epidemiologic and risk 
factors. In children with no risk factors for tuberculosis, skin test 
reactions are usually false-positive results. The American Academy 
of Pediatrics (AAP) and Centers for Disease Control and Preven-
tion (CDC) discourage routine testing of children and recom-
mend targeted tuberculin testing of children at risk identified 
through periodic screening surveys conducted by the primary care 
provider (Table 207-2). Possible exposure to an adult with or at 
high risk for infectious pulmonary tuberculosis is the most crucial 
risk factor for children. Reaction size limits for determining a 
positive tuberculin test result vary with the person’s risk for infec-
tion (Table 207-3). For adults and children at the highest risk for 
having infection progress to disease (those with recent contact 
with infectious persons, clinical illnesses consistent with tubercu-
losis, or HIV infection or other immunosuppression), a reactive 
area of ≥5 mm is classified as a positive result, indicating infection 
with M. tuberculosis. For other high-risk groups, a reactive area 
of ≥10 mm is considered positive. For low-risk persons, especially 
those residing in communities where the prevalence of tubercu-
losis is low, the cutoff point for a positive reaction is ≥15 mm. 
An increase of induration of ≥10 mm within a 2-yr period is 
considered a TST conversion at any age.
Interferon-γ Release Assays
Two blood tests (T-SPOT.TB and QuantiFERON-TB) detect 
IFN-γ generation by the patient’s T cells in response to specific 
M. tuberculosis antigens (ESAT-6, CFP-10, and TB7.7). The 
QuantiFERON-TB test measures whole blood concentrations of 
IFN-γ, and the T-SPOT.TB test measures the number of lympho-
cytes producing IFN-γ. The test antigens are not present on M. 
bovis–BCG and M. avium complex, the major groups of environ-
mental mycobacteria, so one would expect fewer false-positive 
results. Both tests have internal positive and negative controls. 
These tests have several theoretical and practical advantages over 
the TST, including the need for only one patient encounter, lack 
of cross reaction with BCG vaccination and most other mycobac-
teria, and absence of boosting (increasing reaction to the TST 
with serial testing).
When specificity is important, such as in persons who received 
a BCG vaccination, the IFN-γ release assays (IGRAs) are the 
preferred test. However, IGRAs should be interpreted with 
caution when used for children <5 yr of age and immunocom-
promised patients owing to the relative lack of data and the 
increased propensity for indeterminate results (mostly owing to 
failure of the positive control) in these groups.
1002  n   Part XVII Infectious Diseases
CLINICAL MANIFESTATIONS AND DIAGNOSIS
The majority of children with tuberculosis infection develop no 
signs or symptoms at any time. Occasionally, infection is marked 
by low-grade fever and mild cough, and it is rarely marked by 
high fever, cough, malaise, and flulike symptoms that resolve 
within 1 wk. The proportion of extrapulmonary tuberculosis 
cases has increased since 1990 in the USA. About 15% of tuber-
culosis cases in adults are extrapulmonary, and 25-30% of chil-
dren with tuberculosis have an extrapulmonary presentation.
PrimaryPulmonary Disease
The primary complex includes the parenchymal pulmonary 
focus and the regional lymph nodes. About 70% of lung foci 
are subpleural, and localized pleurisy is common. The initial 
parenchymal inflammation usually is not visible on chest radio-
graph, but a localized, nonspecific infiltrate may be seen before 
the development of tissue hypersensitivity. All lobar segments of 
the lung are at equal risk for initial infection. Two or more 
primary foci are present in 25% of cases. The hallmark of primary 
tuberculosis in the lung is the relatively large size of the regional 
lymphadenitis compared with the relatively small size of the 
initial lung focus (see Figs. 207-6 to 207-9). As DTH develops, 
the hilar lymph nodes continue to enlarge in some children, espe-
cially infants, compressing the regional bronchus and causing 
obstruction. The usual sequence is hilar lymphadenopathy, focal 
hyperinflation, and then atelectasis. The resulting radiographic 
shadows have been called collapse-consolidation or segmental 
tuberculosis (see Fig. 207-9). Rarely, inflamed caseous nodes 
attach to the endobronchial wall and erode through it, causing 
endobronchial tuberculosis or a fistula tract. The caseum causes 
complete obstruction of the bronchus, resulting in extensive infil-
trate and collapse. Enlargement of the subcarinal lymph nodes 
can cause compression of the esophagus and, rarely, a broncho-
esophageal fistula.
Most cases of tuberculous bronchial obstruction in children 
resolve fully with appropriate treatment. Occasionally, there is 
residual calcification of the primary focus or regional lymph 
nodes. The appearance of calcification implies that the lesion has 
been present for at least 6-12 mo. Healing of the segment can be 
complicated by scarring or contraction associated with cylindri-
cal bronchiectasis, but this is rare.
Children can have lobar pneumonia without impressive hilar 
lymphadenopathy. If the primary infection is progressively 
destructive, liquefaction of the lung parenchyma can lead to 
formation of a thin-walled primary tuberculosis cavity. Rarely, 
bullous tuberculous lesions occur in the lungs and lead to pneumo-
thorax if they rupture. Erosion of a parenchymal focus of tuber-
culosis into a blood or lymphatic vessel can result in dissemination 
of the bacilli and a miliary pattern, with small nodules evenly 
distributed on the chest radiograph (Fig. 207-10).
The symptoms and physical signs of primary pulmonary 
tuberculosis in children are surprisingly meager considering the 
degree of radiographic changes often seen. When active case 
finding is performed, up to 50% of infants and children with 
radiographically moderate to severe pulmonary tuberculosis have 
no physical findings. Infants are more likely to experience signs 
and symptoms. Nonproductive cough and mild dyspnea are the 
most common symptoms. Systemic complaints such as fever, 
night sweats, anorexia, and decreased activity occur less often. 
Some infants have difficulty gaining weight or develop a true 
failure-to-thrive syndrome that often does not improve signifi-
cantly until several months of effective treatment have been 
taken. Pulmonary signs are even less common. Some infants and 
young children with bronchial obstruction have localized wheez-
ing or decreased breath sounds that may be accompanied by 
tachypnea or, rarely, respiratory distress. These pulmonary symp-
toms and signs are occasionally alleviated by antibiotics, suggest-
ing bacterial superinfection.
Table 207-2  TUBERCULIN SKIN TEST (TST) OR INTERFERON-γ 
RELEASE ASSAY (IGRA) RECOMMENDATIONS FOR INFANTS, 
CHILDREN, AND ADOLESCENTS*
Children for whom immediate TST or IGRA is indicated†:
•  Contacts of people with confirmed or suspected contagious tuberculosis 
(contact investigation)
•  Children with radiographic or clinical findings suggesting tuberculosis disease
•  Children immigrating from countries with endemic infection (e.g., Asia, Middle 
East, Africa, Latin America, countries of the former Soviet Union) including 
international adoptees
•  Children with travel histories to countries with endemic infection and 
substantial contact with indigenous people from such countries‡
Children who should have annual TST or IGRA:
•  Children infected with HIV
•  Incarcerated adolescents
CHILDREN AT INCREASED RISK FOR PROGRESSION OF LTBI  
TO TUBERCULOSIS DISEASE
Children with other medical conditions, including diabetes mellitus, chronic renal 
failure, malnutrition, and congenital or acquired immunodeficiencies deserve 
special consideration. Without recent exposure, these children are not at 
increased risk of acquiring tuberculosis infection. Underlying immunodeficiencies 
associated with these conditions theoretically would enhance the possibility for 
progression to severe disease. Initial histories of potential exposure to 
tuberculosis should be included for all of these patients. If these histories or 
local epidemiologic factors suggest a possibility of exposure, immediate and 
periodic TST should be considered. An initial TST or IGRA should be 
performed before initiation of immunosuppressive therapy, including 
prolonged steroid administration, use of tumor necrosis factor-alpha 
antagonists, or immunosuppressive therapy in any child requiring these 
treatments.
*Bacille Calmette-Guérin immunization is not a contraindication to a TST.
†Beginning as early as 3 mo of age.
‡If the child is well, the TST should be delayed for up to 10 wk after return.
From American Academy of Pediatrics: Red book: 2009 report of the Committee on Infectious 
Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics, p 684.
LTBI, latent tuberculosis infection.
Table 207-3  DEFINITIONS OF POSITIVE TUBERCULIN SKIN TEST (TST) 
RESULTS IN INFANTS, CHILDREN, AND ADOLESCENTS*
INDURATION ≥5 mm
Children in close contact with known or suspected contagious people with 
tuberculosis disease
Children suspected to have tuberculosis disease:
•  Findings on chest radiograph consistent with active or previously tuberculosis 
disease
•  Clinical evidence of tuberculosis disease†
•  Children receiving immunosuppressive therapy‡ or with immunosuppressive 
conditions, including HIV infection
INDURATION ≥10 mm
Children at increased risk of disseminated tuberculosis disease:
•  Children younger than 4 yr of age
•  Children with other medical conditions, including Hodgkin disease, lymphoma, 
diabetes mellitus, chronic renal failure, or malnutrition (see Table 207-2)
Children with increased exposure to tuberculosis disease:
•  Children born in high-prevalence regions of the world
•  Children often exposed to adults who are HIV infected, homeless, users of 
illicit drugs, residents of nursing homes, incarcerated or institutionalized, or 
migrant farm workers
•  Children who travel to high-prevalence regions of the world
INDURATION ≥15 mm
Children ≥4 yr of age without any risk factors
*These definitions apply regardless of previous bacille Calmette-Guérin (BCG) immunization; 
erythema at TST site does not indicate a positive test result. Tests should be read at 48 to 
72 hr after placement.
†Evidence by physical examination or laboratory assessment that would include tuberculosis in 
the working differential diagnosis (e.g., meningitis).
‡Including immunosuppressive doses of corticosteroids.
From American Academy of Pediatrics: Red book: 2009 report of the Committee on Infectious 
Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics, p 681.
Chapter 207 Tuberculosis (Mycobacterium tuberculosis)   n   1003
The most specific confirmation of pulmonary tuberculosis is 
isolation of M. tuberculosis. Sputum specimens for culture should 
be collected from adolescents and older children who are able to 
expectorate. Induced sputum with a jet nebulizer and chest per-
cussion followed by nasopharyngeal suctioning is effective in 
children as young as 1 mo. Sputum induction provides samples 
for both cultureand smear staining, whereas gastric aspirates are 
usually cultured. The traditional culture specimen in young chil-
dren is the early morning gastric acid obtained before the child 
has arisen and peristalsis has emptied the stomach of the pooled 
secretions that have been swallowed overnight. However, even 
under optimal conditions, 3 consecutive morning gastric aspirates 
yield the organisms in <50% of cases. The culture yield from 
bronchoscopy is even lower, but this procedure can demonstrate 
the presence of endobronchial disease or a fistula. Negative cul-
tures never exclude the diagnosis of tuberculosis in a child. The 
presence of a positive TST or IGRA, an abnormal chest radio-
graph consistent with tuberculosis, and history of exposure to an 
adult with infectious tuberculosis is adequate proof that the 
disease is present. Drug susceptibility test results of the isolate 
from the adult source can be used to determine the best thera-
peutic regimen for the child. Cultures should be obtained from 
the child whenever the source case is unknown or the source case 
has possible drug-resistant tuberculosis.
Progressive Primary Pulmonary Disease
A rare but serious complication of tuberculosis in a child occurs 
when the primary focus enlarges steadily and develops a large 
caseous center. Liquefaction can cause formation of a primary 
cavity associated with large numbers of tubercle bacilli. The 
enlarging focus can slough necrotic debris into the adjacent bron-
chus, leading to further intrapulmonary dissemination. Signifi-
cant signs or symptoms are common in locally progressive disease 
in children. High fever, severe cough with sputum production, 
weight loss, and night sweats are common. Physical signs include 
diminished breath sounds, rales, and dullness or egophony over 
the cavity. The prognosis for full but usually slow recovery is 
excellent with appropriate therapy.
Reactivation Tuberculosis
Pulmonary tuberculosis in adults usually represents endogenous 
reactivation of a site of tuberculosis infection established previ-
ously in the body. This form of tuberculosis is rare in childhood 
but can occur in adolescence. Children with a healed tuberculosis 
infection acquired at <2 yr of age rarely develop chronic reactiva-
tion pulmonary disease, which is more common in those who 
acquire the initial infection at >7 yr of age. The most common 
pulmonary sites are the original parenchymal focus, lymph nodes, 
or the apical seedings (Simon foci) established during the hema-
togenous phase of the early infection. This form of disease usually 
remains localized to the lungs, because the established immune 
response prevents further extrapulmonary spread. The most 
common radiographic presentations of this type of tuberculosis 
are extensive infiltrates or thick-walled cavities in the upper lobes.
Older children and adolescents with reactivation tuberculosis 
are more likely to experience fever, anorexia, malaise, weight 
loss, night sweats, productive cough, hemoptysis, and chest pain 
than children with primary pulmonary tuberculosis. However, 
physical examination findings usually are minor or absent, even 
when cavities or large infiltrates are present. Most signs and 
symptoms improve within several weeks of starting effective 
treatment, although the cough can last for several months. This 
form of tuberculosis may be highly contagious if there is signifi-
cant sputum production and cough. The prognosis for full recov-
ery is excellent when patients are given appropriate therapy.
Pleural Effusion
Tuberculous pleural effusions, which can be local or general, 
originate in the discharge of bacilli into the pleural space from a 
subpleural pulmonary focus or caseated lymph node. Asymptom-
atic local pleural effusion is so common in primary tuberculosis 
that it is basically a component of the primary complex. Larger 
and clinically significant effusions occur months to years after the 
primary infection. Tuberculous pleural effusion is uncommon in 
children <6 yr of age and rare in children <2 yr of age. Effusions 
are usually unilateral but can be bilateral. They are rarely associ-
ated with a segmental pulmonary lesion and are uncommon in 
disseminated tuberculosis. Often the radiographic abnormality is 
more extensive than would be suggested by physical findings or 
symptoms (Fig. 207-11).
Clinical onset of tuberculous pleurisy is often sudden, charac-
terized by low to high fever, shortness of breath, chest pain on 
deep inspiration, and diminished breath sounds. The fever and 
other symptoms can last for several weeks after the start of anti-
tuberculosis chemotherapy. The TST is positive in only 70-80% 
of cases. The prognosis is excellent, but radiographic resolution 
often takes months. Scoliosis is a rare complication from a long-
standing effusion.
Examination of pleural fluid and the pleural membrane is 
important to establish the diagnosis of tuberculous pleurisy. The 
pleural fluid is usually yellow and only occasionally tinged with 
blood. The specific gravity is usually 1.012-1.025, the protein 
level is usually 2-4 g/dL, and the glucose concentration may be 
low, although it is usually in the low-normal range (20-40 mg/
dL). Typically there are several hundred to several thousand 
white blood cells per cubic millimeter, with an early predomi-
nance of polymorphonuclear cells followed by a high percentage 
of lymphocytes. Acid-fast smears of the pleural fluid are rarely 
Figure 207-10  Posteroanterior (A) and lateral 
(B) chest radiographs of an infant with miliary 
tuberculosis. The child’s mother had failed to 
complete treatment for pulmonary tuberculosis 
twice within 3 yr of this child’s birth. 
A B
1004  n   Part XVII Infectious Diseases
positive. Cultures of the fluid are positive in <30% of cases. 
Biopsy of the pleural membrane is more likely to yield a positive 
acid-fast stain or culture, and granuloma formation usually can 
be demonstrated.
Pericardial Disease
The most common form of cardiac tuberculosis is pericarditis. It 
is rare, occurring in 0.5-4% of tuberculosis cases in children. 
Pericarditis usually arises from direct invasion or lymphatic 
drainage from subcarinal lymph nodes. The presenting symptoms 
are nonspecific, including low-grade fever, malaise, and weight 
loss. Chest pain is unusual in children. A pericardial friction rub 
or distant heart sounds with pulsus paradoxus may be present. 
The pericardial fluid is typically serofibrinous or hemorrhagic. 
Acid-fast smear of the fluid rarely reveals the organism, but cul-
tures are positive in 30-70% of cases. The culture yield from 
pericardial biopsy may be higher, and the presence of granulomas 
often suggests the diagnosis. Partial or complete pericardiectomy 
may be required when constrictive pericarditis develops.
Lymphohematogenous (Disseminated) Disease
Tubercle bacilli are disseminated to distant sites, including liver, 
spleen, skin, and lung apices, in all cases of tuberculosis infection. 
The clinical picture produced by lymphohematogenous dissemi-
nation depends on the quantity of organisms released from the 
primary focus and the adequacy of the host’s immune response. 
Lymphohematogenous spread is usually asymptomatic. Rare 
patients experience protracted hematogenous tuberculosis caused 
by the intermittent release of tubercle bacilli as a caseous focus 
erodes through the wall of a blood vessel in the lung. Although 
the clinical picture may be acute, more often it is indolent and 
prolonged, with spiking fever accompanying the release of organ-
isms into the bloodstream. Multiple organ involvement is common, 
leading to hepatomegaly, splenomegaly, lymphadenitis in super-
ficial or deep nodes, and papulonecrotic tuberculids appearing on 
the skin. Bones and joints or kidneys also can become involved. 
Meningitis occurs only late in the course of the disease. Early 
pulmonary involvement is surprisingly mild, but diffuse involve-
ment becomes apparent with prolongedinfection.
The most clinically significant form of disseminated tuberculo-
sis is miliary disease, which occurs when massive numbers of 
tubercle bacilli are released into the bloodstream, causing disease 
in 2 or more organs. Miliary tuberculosis usually complicates the 
primary infection, occurring within 2-6 mo of the initial infection. 
Although this form of disease is most common in infants and young 
children, it is also found in adolescents and older adults, resulting 
from the breakdown of a previously healed primary pulmonary 
lesion. The clinical manifestations of miliary tuberculosis are 
protean, depending on the load of organisms that disseminate and 
where they lodge. Lesions are often larger and more numerous in 
the lungs, spleen, liver, and bone marrow than other tissues. 
Because this form of tuberculosis is most common in infants and 
malnourished or immunosuppressed patients, the host’s immune 
incompetence probably also plays a role in pathogenesis.
The onset of miliary tuberculosis is sometimes explosive, 
and the patient can become gravely ill in several days. More 
often, the onset is insidious, with early systemic signs, including 
anorexia, weight loss, and low-grade fever. At this time, abnormal 
physical signs are usually absent. Generalized lymphadenopathy 
and hepatosplenomegaly develop within several weeks in about 
50% of cases. The fever can then become higher and more sus-
tained, although the chest radiograph usually is normal and respi-
ratory symptoms are minor or absent. Within several more weeks, 
the lungs can become filled with tubercles, and dyspnea, cough, 
rales, or wheezing occur. The lesions of miliary tuberculosis are 
usually smaller than 2-3 mm in diameter when first visible on 
chest radiograph (see Fig. 207-10). The smaller lesions coalesce 
to form larger lesions and sometimes extensive infiltrates. As the 
pulmonary disease progresses, an alveolar-air block syndrome can 
result in frank respiratory distress, hypoxia, and pneumothorax, 
or pneumomediastinum. Signs or symptoms of meningitis or 
peritonitis are found in 20-40% of patients with advanced disease. 
Chronic or recurrent headache in a patient with miliary tubercu-
losis usually indicates the presence of meningitis, whereas the 
onset of abdominal pain or tenderness is a sign of tuberculous 
peritonitis. Cutaneous lesions include papulonecrotic tuberculids, 
nodules, or purpura. Choroid tubercles occur in 13-87% of 
patients and are highly specific for the diagnosis of miliary tuber-
culosis. Unfortunately, the TST is nonreactive in up to 40% of 
patients with disseminated tuberculosis.
Diagnosis of disseminated tuberculosis can be difficult, and a 
high index of suspicion by the clinician is required. Often the 
patient presents with fever of unknown origin. Early sputum or 
gastric aspirate cultures have a low sensitivity. Biopsy of the liver 
or bone marrow with appropriate bacteriologic and histologic 
examinations more often yields an early diagnosis. The most 
important clue is usually history of recent exposure to an adult 
with infectious tuberculosis.
The resolution of miliary tuberculosis is slow, even with 
proper therapy. Fever usually declines within 2-3 wk of starting 
chemotherapy, but the chest radiographic abnormalities might 
not resolve for many months. Occasionally, corticosteroids 
hasten symptomatic relief, especially when air block, peritonitis, 
or meningitis is present. The prognosis is excellent if the diagnosis 
is made early and adequate chemotherapy is given.
Upper Respiratory Tract Disease
Tuberculosis of the upper respiratory tract is rare in developed 
countries but is still observed in developing countries. Children 
with laryngeal tuberculosis have a croup-like cough, sore throat, 
hoarseness, and dysphagia. Most children with laryngeal tuber-
culosis have extensive upper lobe pulmonary disease, but occa-
sional patients have primary laryngeal disease with a normal 
chest radiograph. Tuberculosis of the middle ear results from 
aspiration of infected pulmonary secretions into the middle ear 
or from hematogenous dissemination in older children. The most 
common signs and symptoms are painless unilateral otorrhea, 
tinnitus, decreased hearing, facial paralysis, and a perforated 
tympanic membrane. Enlargement of lymph nodes in the preau-
ricular or anterior cervical chains can accompany this infection. 
Diagnosis is difficult, because stains and cultures of ear fluid are 
often negative, and histology of the affected tissue often shows a 
Figure 207-11  Pleural tuberculosis in a 16 yr old girl. 
Chapter 207 Tuberculosis (Mycobacterium tuberculosis)   n   1005
nonspecific acute and chronic inflammation without granuloma 
formation.
Lymph Node Disease
Tuberculosis of the superficial lymph nodes, often referred to as 
scrofula, is the most common form of extrapulmonary tuber-
culosis in children (Fig. 207-12). Historically, scrofula was usually 
caused by drinking unpasteurized cow’s milk laden with M. 
bovis. Most current cases occur within 6-9 mo of initial infection 
by M. tuberculosis, although some cases appear years later. The 
tonsillar, anterior cervical, submandibular, and supraclavicular 
nodes become involved secondary to extension of a primary 
lesion of the upper lung fields or abdomen. Infected nodes in the 
inguinal, epitrochlear, or axillary regions result from regional 
lymphadenitis associated with tuberculosis of the skin or skeletal 
system. The nodes usually enlarge gradually in the early stages 
of lymph node disease. They are discrete, nontender, and firm 
but not hard. The nodes often feel fixed to underlying or overly-
ing tissue. Disease is most often unilateral, but bilateral involve-
ment can occur because of the crossover drainage patterns of 
lymphatic vessels in the chest and lower neck. As infection pro-
gresses, multiple nodes are infected, resulting in a mass of matted 
nodes. Systemic signs and symptoms other than a low-grade fever 
are usually absent. The TST is usually reactive, but the chest 
radiograph is normal in 70% of cases. The onset of illness is 
occasionally more acute, with rapid enlargement, tenderness, and 
fluctuance of lymph nodes and with high fever. The initial pre-
sentation is rarely a fluctuant mass with overlying cellulitis or 
skin discoloration.
Lymph node tuberculosis can resolve if left untreated but more 
often progresses to caseation and necrosis. The capsule of the 
node breaks down, resulting in the spread of infection to adjacent 
nodes. Rupture of the node usually results in a draining sinus 
tract that can require surgical removal. Tuberculous lymphadeni-
tis can usually be diagnosed by fine-needle aspiration of the node 
and responds well to antituberculosis therapy, although the 
lymph nodes do not return to normal size for months or even 
years. Surgical removal is not usually necessary and must be 
combined with antituberculous medication because the lymph 
node disease is only one part of a systemic infection.
A definitive diagnosis of tuberculous adenitis usually requires 
histologic or bacteriologic confirmation, which is best accom-
plished by fine-needle aspiration for culture, stain, and histology. 
If fine-needle aspiration is not successful in establishing a diag-
nosis, excisional biopsy of the involved node is indicated. Culture 
of lymph node tissue yields the organism in only about 50% of 
cases. Many other conditions can be confused with tuberculous 
adenitis, including infection due to NTM, cat scratch disease 
(Bartonella henselae), tularemia, brucellosis, toxoplasmosis, 
tumor, branchial cleft cyst, cystic hygroma, and pyogenic 
infection. The most common problem is distinguishing infection 
due to M. tuberculosis from lymphadenitis caused by NTM in 
geographic areas where NTM are common. Both conditions are 
usually associated with a normal chest radiograph and a reactive 
TST. An important clue to the diagnosis of tuberculous adenitis 
is an epidemiologiclink to an adult with infectious tuberculosis. 
In areas where both diseases are common, the only way to dis-
tinguish them may be culture of the involved tissue.
Central Nervous System Disease
Tuberculosis of the central nervous system (CNS) is the most 
serious complication in children and is fatal without prompt and 
appropriate treatment. Tuberculous meningitis usually arises 
from the formation of a metastatic caseous lesion in the cerebral 
cortex or meninges that develops during the lymphohematoge-
nous dissemination of the primary infection. This initial lesion 
increases in size and discharges small numbers of tubercle bacilli 
into the subarachnoid space. The resulting gelatinous exudate 
infiltrates the corticomeningeal blood vessels, producing inflam-
mation, obstruction, and subsequent infarction of cerebral cortex. 
The brain stem is often the site of greatest involvement, which 
accounts for the commonly associated dysfunction of cranial 
nerves III, VI, and VII. The exudate also interferes with the 
normal flow of cerebrospinal fluid (CSF) in and out of the ven-
tricular system at the level of the basilar cisterns, leading to a 
communicating hydrocephalus. The combination of vasculitis, 
infarction, cerebral edema, and hydrocephalus results in the 
severe damage that can occur gradually or rapidly. Profound 
abnormalities in electrolyte metabolism due to salt wasting or the 
syndrome of inappropriate antidiuretic hormone secretion also 
contribute to the pathophysiology of tuberculous meningitis.
Tuberculous meningitis complicates about 0.3% of untreated 
tuberculosis infections in children. It is most common in children 
between 6 mo and 4 yr of age. Occasionally, tuberculous menin-
gitis occurs many years after the infection, when rupture of 1 or 
more of the subependymal tubercles discharges tubercle bacilli 
into the subarachnoid space. The clinical progression of tubercu-
lous meningitis may be rapid or gradual. Rapid progression tends 
to occur more often in infants and young children, who can 
experience symptoms for only several days before the onset of 
acute hydrocephalus, seizures, and cerebral edema. More com-
monly, the signs and symptoms progress slowly over several 
weeks and can be divided into 3 stages.
The 1st stage typically lasts 1-2 wk and is characterized by 
nonspecific symptoms such as fever, headache, irritability, drows-
iness, and malaise. Focal neurologic signs are absent, but infants 
can experience a stagnation or loss of developmental milestones. 
The 2nd stage usually begins more abruptly. The most common 
features are lethargy, nuchal rigidity, seizures, positive Kernig 
and Brudzinski signs, hypertonia, vomiting, cranial nerve palsies, 
and other focal neurologic signs. The accelerating clinical illness 
usually correlates with the development of hydrocephalus, 
increased intracranial pressure, and vasculitis. Some children 
have no evidence of meningeal irritation but can have signs of 
encephalitis, such as disorientation, movement disorders, or 
speech impairment. The 3rd stage is marked by coma, hemiplegia 
Figure 207-12  Axial CT image of the neck in an 8 yr old boy shows calcified right 
cervical lymphadenopathy (black arrow) with tonsillar swelling (white arrow). (From 
Lighter J, Rigaud M: Diagnosing childhood tuberculosis: traditional and innovative 
modalities, Curr Prob Pediatr Adolesc Health Care 39:55–88, 2009.)
1006  n   Part XVII Infectious Diseases
or paraplegia, hypertension, decerebrate posturing, deterioration 
of vital signs, and eventually death.
The prognosis of tuberculous meningitis correlates most 
closely with the clinical stage of illness at the time treatment is 
initiated. The majority of patients in the 1st stage have an excel-
lent outcome, whereas most patients in the 3rd stage who survive 
have permanent disabilities, including blindness, deafness, para-
plegia, diabetes insipidus, or mental retardation. The prognosis 
for young infants is generally worse than for older children. It is 
imperative that antituberculosis treatment be considered for any 
child who develops basilar meningitis and hydrocephalus, cranial 
nerve palsy, or stroke with no other apparent etiology. Often the 
key to the correct diagnosis is identifying an adult who has infec-
tious tuberculosis and is in contact with the child. Because of the 
short incubation period of tuberculous meningitis, the illness has 
not yet been diagnosed in the adult in many cases.
The diagnosis of tuberculous meningitis can be difficult early 
in its course, requiring a high degree of suspicion on the part of 
the clinician. The TST is nonreactive in up to 50% of cases, and 
20-50% of children have a normal chest radiograph. The most 
important laboratory test for the diagnosis of tuberculous men-
ingitis is examination and culture of the lumbar CSF. The CSF 
leukocyte count usually ranges from 10 to 500 cells/mm3. Poly-
morphonuclear leukocytes may be present initially, but lympho-
cytes predominate in the majority of cases. The CSF glucose is 
typically <40mg/dL but rarely <20mg/dL. The protein level is 
elevated and may be markedly high (400-5,000mg/dL) secondary 
to hydrocephalus and spinal block. Although the lumbar CSF is 
grossly abnormal, ventricular CSF can have normal chemistries 
and cell counts because this fluid is obtained from a site proximal 
to the inflammation and obstruction. During early stage I, the 
CSF can resemble that of viral aseptic meningitis only to progress 
to the more-severe CSF profile over several weeks. The success 
of the microscopic examination of acid-fast-stained CSF and 
mycobacterial culture is related directly to the volume of the CSF 
sample. Examinations or culture of small amounts of CSF are 
unlikely to demonstrate M. tuberculosis. When 5-10 mL of 
lumbar CSF can be obtained, the acid-fast stain of the CSF sedi-
ment is positive in up to 30% of cases and the culture is positive 
in 50-70% of cases. Cultures of other fluids, such as gastric 
aspirates or urine, can help confirm the diagnosis.
Radiographic studies can aid in the diagnosis of tuberculous 
meningitis. CT or MRI of the brain of patients with tuberculous 
meningitis may be normal during early stages of the disease. As 
disease progresses, basilar enhancement and communicating 
hydrocephalus with signs of cerebral edema or early focal isch-
emia are the most common findings. Some small children with 
tuberculous meningitis can have one or several clinically silent 
tuberculomas, occurring most often in the cerebral cortex or 
thalamic regions.
Another manifestation of CNS tuberculosis is the tubercu-
loma, a tumor-like mass resulting from aggregation of caseous 
tubercles that usually manifests clinically as a brain tumor. 
Tuberculomas account for up to 40% of brain tumors in some 
areas of the world but are rare in North America. In adults 
tuberculomas are most often supratentorial, but in children they 
are often infratentorial, located at the base of the brain near the 
cerebellum. Lesions are most often singular but may be multiple. 
The most common symptoms are headache, fever, and convul-
sions. The TST is usually reactive, but the chest radiograph is 
usually normal. Surgical excision is sometimes necessary to dis-
tinguish tuberculoma from other causes of brain tumor. However, 
surgical removal is not necessary because most tuberculomas 
resolve with medical management. Corticosteroids are usually 
administered during the 1st few weeks of treatment or in the 
immediate postoperative period to decrease cerebral edema. On 
CT or MRI of the brain, tuberculomas usually appear as discrete 
lesions with a significant amount of surrounding edema. Contrast 
medium enhancement is often impressive and can result in a ring-
like lesion. Since the advent of CT, the paradoxical development 
of tuberculomas in patients with tuberculous meningitis who are 
receiving ultimately effective chemotherapy has been recognized. 
The cause and nature of thesetuberculomas are poorly under-
stood, but they do not represent failure of antimicrobial treat-
ment. This phenomenon should be considered whenever a child 
with tuberculous meningitis deteriorates or develops focal neuro-
logic findings while on treatment. Corticosteroids can help allevi-
ate the occasionally severe clinical signs and symptoms that occur. 
These lesions can persist for months or even years.
Cutaneous Disease
Cutaneous tuberculosis is rare in the USA but occurs worldwide 
and accounts for 1-2% of tuberculosis (Chapter 657).
Bone and Joint Disease
Bone and joint infection complicating tuberculosis is most likely 
to involve the vertebrae. The classic manifestation of tuberculous 
spondylitis is progression to Pott disease, in which destruction of 
the vertebral bodies leads to gibbus deformity and kyphosis 
(Chapter 671.4). Skeletal tuberculosis is a late complication of 
tuberculosis and has become a rare entity since the availability of 
antituberculosis therapy but is more likely to occur in children 
than in adults. Tuberculous bone lesions can resemble pyogenic 
and fungal infections or bone tumors. Multifocal bone involvement 
can occur. A bone biopsy is essential to confirm the diagnosis.
Abdominal and Gastrointestinal Disease
Tuberculosis of the oral cavity or pharynx is quite unusual. The 
most common lesion is a painless ulcer on the mucosa, palate, or 
tonsil with enlargement of the regional lymph nodes. Tuberculosis 
of the parotid gland has been reported rarely in endemic countries. 
Tuberculosis of the esophagus is rare in children but may be 
associated with a tracheoesophageal fistula in infants. These forms 
of tuberculosis are usually associated with extensive pulmonary 
disease and swallowing of infectious respiratory secretions. 
However, they can occur in the absence of pulmonary disease, 
presumably by spread from mediastinal or peritoneal lymph nodes.
Tuberculous peritonitis occurs most often in young men and 
is uncommon in adolescents and rare in children. Generalized 
peritonitis can arise from subclinical or miliary hematogenous 
dissemination. Localized peritonitis is caused by direct extension 
from an abdominal lymph node, intestinal focus, or genitourinary 
tuberculosis. Rarely, the lymph nodes, omentum, and peritoneum 
become matted and can be palpated as a doughy irregular non-
tender mass. Abdominal pain or tenderness, ascites, anorexia, 
and low-grade fever are typical manifestations. The TST is usually 
reactive. The diagnosis can be confirmed by paracentesis with 
appropriate stains and cultures, but this procedure must be per-
formed carefully to avoid entering a bowel that is intertwined 
with the matted omentum.
Tuberculous enteritis is caused by hematogenous dissemina-
tion or by swallowing tubercle bacilli discharged from the 
patient’s own lungs. The jejunum and ileum near Peyer patches 
and the appendix are the most common sites of involvement. The 
typical findings are shallow ulcers that cause pain, diarrhea or 
constipation, weight loss, and low-grade fever. Mesenteric adeni-
tis usually complicates the infection. The enlarged nodes can 
cause intestinal obstruction or erode through the omentum to 
cause generalized peritonitis. The clinical presentation of tuber-
culous enteritis is nonspecific, mimicking other infections and 
conditions that cause diarrhea. The disease should be suspected 
in any child with chronic GI complaints and a reactive TST or 
positive IGRA. Biopsy, acid-fast stain, and culture of the lesions 
are usually necessary to confirm the diagnosis.
Genitourinary Disease
Renal tuberculosis is rare in children, because the incubation 
period is several years or longer. Tubercle bacilli usually reach 
Chapter 207 Tuberculosis (Mycobacterium tuberculosis)   n   1007
the kidney during lymphohematogenous dissemination. The 
organisms often can be recovered from the urine in cases of 
miliary tuberculosis and in some patients with pulmonary tuber-
culosis in the absence of renal parenchymal disease. In true renal 
tuberculosis, small caseous foci develop in the renal parenchyma 
and release M. tuberculosis into the tubules. A large mass devel-
ops near the renal cortex that discharges bacteria through a 
fistula into the renal pelvis. Infection then spreads locally to the 
ureters, prostate, or epididymis. Renal tuberculosis is often clini-
cally silent in its early stages, marked only by sterile pyuria and 
microscopic hematuria. Dysuria, flank or abdominal pain, and 
gross hematuria develop as the disease progresses. Superinfec-
tion by other bacteria is common and can delay recognition of 
the underlying tuberculosis. Hydronephrosis or ureteral stric-
tures can complicate the disease. Urine cultures for M. tubercu-
losis are positive in 80-90% of cases, and acid-fast stains of 
large volumes of urine sediment are positive in 50-70% of cases. 
The TST is nonreactive in up to 20% of patients. An intrave-
nous pyelogram or CT scan often reveals mass lesions, dilatation 
of the proximal ureters, multiple small filling defects, and hydro-
nephrosis if ureteral stricture is present. Disease is most often 
unilateral.
Tuberculosis of the genital tract is uncommon in both boys 
and girls before puberty. This condition usually originates from 
lymphohematogenous spread, although it can be caused by direct 
spread from the intestinal tract or bone. Adolescent girls can 
develop genital tract tuberculosis during the primary infection. 
The fallopian tubes are most often involved (90-100% of cases), 
followed by the endometrium (50%), ovaries (25%), and cervix 
(5%). The most common symptoms are lower abdominal pain 
and dysmenorrhea or amenorrhea. Systemic manifestations are 
usually absent, and the chest radiograph is normal in the majority 
of cases. The TST is usually reactive. Genital tuberculosis in 
adolescent boys causes epididymitis or orchitis. The condition 
usually manifests as a unilateral nodular painless swelling of the 
scrotum. Involvement of the glans penis is extremely rare. Genital 
abnormalities and a positive TST in an adolescent boy or girl 
suggests genital tract tuberculosis.
Disease in HIV-Infected Children
Most cases of tuberculosis in HIV-infected children are seen in 
developing countries. The rate of tuberculosis disease in HIV-
infected children is 30 times higher than in non–HIV-infected 
children in the USA. Establishing the diagnosis of tuberculosis in 
an HIV-infected child may be difficult, because skin test reactivity 
can be absent (with a negative IGRA), culture confirmation is 
difficult, and the clinical features of tuberculosis are similar to 
many other HIV-related infections and conditions. Tuberculosis 
in HIV-infected children is often more severe, progressive, and 
likely to occur in extrapulmonary sites. Radiographic findings are 
similar to those in children with normal immune systems, but 
lobar disease and lung cavitation are more common. Nonspecific 
respiratory symptoms, fever, and weight loss are the most 
common complaints. Rates of drug-resistant tuberculosis tend to 
be higher in HIV-infected adults and probably are also higher in 
HIV-infected children.
The mortality rate of HIV-infected children with tuberculosis 
is high, especially as the CD4 lymphocyte numbers decrease. In 
adults, the host immune response to tuberculosis infection 
appears to enhance HIV replication and accelerate the immune 
suppression caused by HIV. Increased mortality rates are attrib-
uted to progressive HIV infection rather than tuberculosis. There-
fore, HIV-infected children with potential exposures and/or 
recent infection should be promptly evaluated and treated for 
tuberculosis. Conversely, all children with tuberculosis disease 
should be tested for HIV co-infection, because of the potential 
benefits of early diagnosis and treatment of HIV infection and 
because the presence of HIV can necessitate a longer duration of 
treatment.
Perinatal Disease
Symptoms of congenital tuberculosismay be present at birth but 
more commonly begin by the 2nd or 3rd wk of life. The most 
common signs and symptoms are respiratory distress, fever, 
hepatic or splenic enlargement, poor feeding, lethargy or irritabil-
ity, lymphadenopathy, abdominal distention, failure to thrive, ear 
drainage, and skin lesions. The clinical manifestations vary in 
relation to the site and size of the caseous lesions. Many infants 
have an abnormal chest radiograph, most often with a miliary 
pattern. Some infants with no pulmonary findings early in the 
course of the disease later develop profound radiographic and 
clinical abnormalities. Hilar and mediastinal lymphadenopathy 
and lung infiltrates are common. Generalized lymphadenopathy 
and meningitis occur in 30-50% of patients.
The clinical presentation of tuberculosis in newborns is similar 
to that caused by bacterial sepsis and other congenital infections, 
such as syphilis, toxoplasmosis, and cytomegalovirus. The diag-
nosis should be suspected in an infant with signs and symptoms 
of bacterial or congenital infection whose response to antibiotic 
and supportive therapy is poor and in whom evaluation for other 
infections is unrevealing. The most important clue for rapid diag-
nosis of congenital tuberculosis is a maternal or family history of 
tuberculosis. Often, the mother’s disease is discovered only after 
the neonate’s diagnosis is suspected. The infant’s TST is negative 
initially but can become positive in 1-3 mo. A positive acid-fast 
stain of an early morning gastric aspirate from a newborn usually 
indicates tuberculosis. Direct acid-fast stains on middle-ear dis-
charge, bone marrow, tracheal aspirate, or biopsy tissue (espe-
cially liver) can be useful. The CSF should be examined and 
cultured, although the yield for isolating M. tuberculosis is low. 
The mortality rate of congenital tuberculosis remains very high 
because of delayed diagnosis; many children have a complete 
recovery if the diagnosis is made promptly and adequate chemo-
therapy is started.
TREATMENT
The basic principles of management of tuberculosis disease in 
children and adolescents are the same as those in adults. Several 
drugs are used to effect a relatively rapid cure and prevent the 
emergence of secondary drug resistance during therapy (Tables 
207-4 and 207-5). The choice of regimen depends on the extent 
of tuberculosis disease, the host, and the likelihood of drug resis-
tance (Chapter 206 and Table 206-1). The standard therapy of 
intrathoracic tuberculosis (pulmonary disease and/or hilar lymph-
adenopathy) in children recommended by the CDC and AAP is 
a 6 mo regimen of isoniazid and rifampin supplemented in the 
1st 2 mo of treatment by pyrazinamide and ethambutol. Several 
clinical trials have shown that this regimen yields a success rate 
approaching 100%, with an incidence of clinically significant 
adverse reactions of <2%. Nine month regimens of only isoniazid 
and rifampin are also highly effective for drug-susceptible tuber-
culosis, but the necessary length of treatment, the need for good 
adherence by the patient, and the relative lack of protection 
against possible initial drug resistance have led to the use of 
shorter regimens with additional medications. Most experts rec-
ommend that all drug administration be directly observed, 
meaning that a health care worker is physically present when the 
medications are administered to the patients. When directly 
observed therapy is used, intermittent (twice weekly) administra-
tion of drugs after an initial period as short as 2 wk of daily 
therapy is as effective in children as daily therapy for the entire 
course.
Extrapulmonary tuberculosis is usually caused by small 
numbers of mycobacteria. In general, the treatment for most 
forms of extrapulmonary tuberculosis in children, including cer-
vical lymphadenopathy, is the same as for pulmonary tuberculo-
sis. Exceptions are bone and joint, disseminated, and CNS 
tuberculosis, for which there are inadequate data to recommend 
1008  n   Part XVII Infectious Diseases
Table 207-4  COMMONLY USED DRUGS FOR THE TREATMENT OF TUBERCULOSIS IN INFANTS, CHILDREN, AND ADOLESCENTS
DRUG DOSAGE FORMS DAILY DOSAGE, mg/kg
TWICE A WEEK DOSAGE, 
mg/kg PER DOSE MAXIMUM DOSE ADVERSE REACTIONS
Ethambutol Tablets:
  100 mg
  400 mg
20 50 2.5 g Optic neuritis (usually reversible), decreased red-green 
color discrimination, gastrointestinal tract disturbances, 
hypersensitivity
Isoniazid* Scored tablets:
  100 mg
  300 mg
Syrup: 10 mg/ mL
10-15† 20-30 Daily, 300 mg
Twice a week, 900 mg
Mild hepatic enzyme elevation, hepatitis,† peripheral 
neuritis, hypersensitivity
Pyrazinamide* Scored tablets: 500 mg 20-40 50 2 g Hepatotoxic effects, hyperuricemia, arthralgias, 
gastrointestinal tract upset
Rifampin* Capsules:
  150 mg
  300 mg
Syrup formulated in 
syrup from capsules
10-20 10-20 600 mg Orange discoloration of secretions or urine, staining of 
contact lenses, vomiting, hepatitis, influenza-like reaction, 
thrombocytopenia, pruritus; oral contraceptives may be 
ineffective
*Rifamate is a capsule containing 150 mg of isoniazid and 300 mg of rifampin. Two capsules provide the usual adult (>50 kg) daily doses of each drug. Rifater is a capsule containing 50 mg of 
isoniazid, 120 mg of rifampin, and 300 mg of pyrazinamide. Isoniazid and rifampin also are available for parenteral administration.
†When isoniazid in a dosage exceeding 10 mg/kg per day is used in combination with rifampin, the incidence of hepatotoxic effects may be increased.
From American Academy of Pediatrics: Red book: 2009 report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics, p 689.
Table 207-5  LESS COMMONLY USED DRUGS FOR TREATING DRUG-RESISTANT TUBERCULOSIS IN INFANTS, CHILDREN, AND ADOLESCENTS*
DRUGS DOSAGE, FORMS DAILY DOSAGE, mg/kg MAXIMUM DOSE ADVERSE REACTIONS
Amikacin† Vials, 500 mg, 1 g 15-30 (IV or IM administration) 1 g Auditory and vestibular toxic effects, nephrotoxic effects
Capreomycin† Vials, 1 g 15-30 (IM administration) 1 g Auditory and vestibular toxicity and nephrotoxic effects
Cycloserine Capsules, 250 mg 10-20, given in 2 divided doses 1 g Psychosis, personality changes, seizures, rash
Ethionamide Tablets, 250 mg 15-20, given in 2-3 divided doses 1 g Gastrointestinal tract disturbances, hepatotoxic effects, 
hypersensitivity reactions, hypothyroidism
Kanamycin Vials:
  75 mg/2 mL
  500 mg/2 mL
  1 g/3 mL
15-30 (IM or IV administration) 1 g Auditory and vestibular toxic effects, nephrotoxic effects
Levofloxacin‡ Tablets:
  250 mg
  500 mg
Vials, 25 mg/ mL
Adults: 500-1000 mg (once daily)
Children: not recommended
1 g Theoretic effect on growing cartilage, gastrointestinal tract 
disturbances, rash, headache, restlessness, confusion
para-Aminosalicylic acid (PAS) Packets, 3 g 200-300 (bid-qid) 10 g Gastrointestinal tract disturbances, hypersensitivity, 
hepatotoxic effects
Streptomycin† Vials:
  1 g
  4 g
20-40 (IM administration) 1 g Auditory and vestibular toxic effects, nephrotoxic effects, 
rash
*These drugs should be used in consultation with a specialist in tuberculosis.
†Dose adjustment in renal insufficiency.
‡Levofloxacin currently is not approved for use in children younger than 18 yr of age; its use in younger children necessitates assessment of the potential risks and benefits.
From American Academy of Pediatrics: Red book: 2009 report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics, p 692.
6 mo therapy. These infections are treated for 9-12 mo. Surgical 
débridement in bone and joint disease and ventriculoperitoneal 
shunting in CNS disease are often necessary.
The optimal treatment of tuberculosis in HIV-infected chil-
dren has not been established. HIV-seropositive adults with 
tuberculosis can be treated successfully with standard regimens 
that include isoniazid, rifampin, pyrazinamide, and ethambutol. 
The total duration