Tuberculosis

Tuberculosis is a communicable chronic granulomatous disease caused by Mycobacterium

tuberculosis. It usually involves the lungs but may affect any organ or tissue in the body.

Epidemiology

The World Health Organization (WHO) considers tuberculosis to be the most common cause of
death resulting from a single infectious agent. It is estimated that 1.7 billion individuals are infected
worldwide, with 8 to 10 million new cases and 1.5 million deaths per year. In the Western world,
deaths from tuberculosis peaked in 1800 and steadily declined throughout the 1800s and 1900s.
However, in 1984 the decline in new cases stopped abruptly, a change that resulted from the
increased incidence of tuberculosis in HIV-infected individuals. As a consequence of intensive public
health surveillance and tuberculosis prophylaxis among immunosuppressed individuals, the
incidence of tuberculosis in U.S.-born individuals has declined since 1992. In 2014, there were
approximately 9400 new cases of active tuberculosis in the United States, with nearly 60% of these
occurring in immigrants from countries where tuberculosis is endemic.

Tuberculosis flourishes under conditions of poverty, crowding, and chronic debilitating illness. In the
United States, tuberculosis is a disease of older adults, the urban poor, patients with AIDS, and
members of minority communities. African Americans, Native Americans, the Inuit (from Alaska),
Hispanics, and immigrants from Southeast Asia have higher rates of disease than other segments of
the population. Certain disease states also increase the risk, such as diabetes mellitus, Hodgkin
lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism,
and immunosuppression. In areas of the world where HIV infection is prevalent, HIV infection is the
dominant risk factor for the development of tuberculosis.

It is important that infection be differentiated from disease. Infection implies seeding of a focus with
organisms, which may or may not cause clinically significant tissue damage (i.e., disease). Although
other routes may be involved, most infections are acquired by direct person-toperson transmission
of airborne droplets of organisms from an active case to a susceptible host. In most individuals, an
asymptomatic focus of pulmonary infection appears that is self-limited, although uncommonly,
primary tuberculosis may result in the development of fever and pleural effusions. Generally, the
only evidence of infection, if any remains, is a tiny, telltale fibrocalcific nodule at the site of the
infection. Viable organisms may remain dormant in such loci for decades, and possibly for the life of
the host. Such individuals are infected but do not have active disease and therefore cannot transmit
organisms to others. Yet, if their immune defenses are lowered, the infection may reac tivate to
produce communicable and potentially lifethreatening disease.

Infection with M. tuberculosis typically leads to the development of delayed hypersensitivity, which
can be detected by the tuberculin (Mantoux) test. About 2 to 4 weeks after the infection has begun,
intracutaneous injection of 0.1 mL of sterile purified protein derivative (PPD) induces a visible and
palpable induration (at least 5 mm in diameter) that peaks in 48 to 72 hours. Sometimes, more PPD
is required to elicit the reaction, and unfortunately, in some responders, the standard dose may
produce a large, necrotizing lesion. A positive tuberculin skin test result signifies cell-mediated
hypersensitivity to tubercular antigens, but does not differentiate between infection and disease. A
well-recognized limitation of this test is that false-negative reactions (or skin test anergy) may be
produced by certain viral infections, sarcoidosis, malnutrition, Hodgkin lymphoma,
immunosuppression, and (notably) overwhelming active tuberculous disease. Falsepositive reactions
may result from infection by atypical mycobacteria.
About 80% of the population in certain Asian and African countries is tuberculin-positive. In contrast,
in 2012, approximately, 5% to 10% of the U.S. population was positive, indicating the marked
difference in rates of exposure to the tubercle bacillus. In general, 3% to 4% of previously unexposed
individuals acquire active tuberculosis during the first year after “tuberculin conversion,” and no
more than 15% do so thereafter. Thus, only a small fraction of those who contract an infection
develop active disease.

Etiology and Pathogenesis

Mycobacteria are slender rods that are acid-fast (i.e., they have a high content of complex lipids that
readily bind the Ziehl-Neelsen [carbol fuchsin] stain and subsequently stubbornly resist
decolorization). M. tuberculosis hominis is responsible for most cases of tuberculosis; the reservoir
of infection typically is found in individuals with active pulmonary disease. Transmission usually is
direct, by inhalation of airborne organisms in aerosols generated by expectoration or by exposure to
contaminated secretions of infected individuals. Oropharyngeal and intestinal tuberculosis
contracted by drinking milk contaminated with Mycobacterium bovis infection is now rare except in
those countries with tuberculous dairy cows and sales of unpasteurized milk. Other mycobacteria,
particularly Mycobacterium avium complex, are much less virulent than M. tuberculosis and rarely
cause disease in immunocompetent individuals. However, they cause disease in 10% to 30% of
patients with AIDS.

Pathogenesis

The pathogenesis of tuberculosis in the previously unexposed immunocompetent individual is

centered on the development of cell-mediated immunity, which confers resistance to the organism
and results in development of tissue hypersensitivity to tubercular antigens. The pathologic features
of tuberculosis, such as caseating granulomas and cavitation, are the result of the destructive tissue
hypersensitivity that is part and parcel of the host immune response. Because the effector cells for
both protective immunity and damaging hypersensitivity are the same, the appearance of tissue
hypersensitivity also signals the acquisition of immunity to the organism. The sequence of events
from inhalation of the infectious inoculum to containment of the primary focus is illustrated in Fig.
13.33 and can be outlined as follows:

- Entry into macrophages. A virulent strain of mycobacteria gains entry to macrophage

endosomes, a process mediated by several macrophage receptors, including the
macrophage mannose receptor and complement receptors that recognize several
components of the mycobacterial cell walls.
- Replication in macrophages. Once internalized, the organisms inhibit normal microbicidal
responses by preventing the fusion of the lysosomes with the phagocytic vacuole, allowing
the mycobacterium to persist and proliferate. Thus, the earliest phase of primary
tuberculosis (the first 3 weeks) in the nonsensitized patient is characterized by bacillary
proliferation within the pulmonary alveolar macrophages and air spaces, eventually resulting
in bacteremia and seeding of the organisms to multiple sites. Despite the bacteremia, most
individuals at this stage are asymptomatic or have a mild flulike illness.
- Development of cell-mediated immunity. This occurs approximately 3 weeks after exposure.
Processed mycobacterial antigens reach the draining lymph nodes and are presented to CD4
T cells by dendritic cells and macrophages. Under the influence of macrophage-secreted IL-
12, CD4+ T cells of the TH1 subset are generated that are capable of secreting IFN-γ.
- T cell–mediated macrophage activation and killing of bacteria. IFN-γ released by the CD4+ T
cells of the TH1 subset is crucial in activating macrophages. Activated macrophages, in turn,
 release a variety of mediators and upregulate expression of genes with important
downstream effects, including: (1) TNF, which is responsible for recruitment of monocytes,
which in turn undergo activation and differentiation into the “epithelioid histiocytes” that
characterize the granulomatous response; (2) inducible nitric oxide synthase (iNOS), which
raises nitric oxide (NO) levels, helping to create reactive nitrogen intermediates that appear
to be particularly important in killing of mycobacteria; and (3) anti-microbial peptides
(defensins) that are also toxic to mycobacterial organisms.
- Granulomatous inflammation and tissue damage. In addition to stimulating macrophages to
kill mycobacteria, the TH1 response orchestrates the formation of granulomas and caseous
necrosis. Macrophages activated by IFN-γ differentiate into the “epithelioid histiocytes” that
aggregate to form granulomas; some epithelioid cells may fuse to form giant cells. In many
individuals, this response halts the infection before significant tissue destruction or illness
occur. In other individuals with immune deficits due to age or immunosuppression, the
infection progresses and the ongoing immune response results in caseation necrosis.
Activated macrophages also secrete TNF and chemokines, which promote recruitment of
more monocytes. The importance of TNF is underscored by the fact that patients with
rheumatoid arthritis who are treated with a TNF antagonist have an increased risk for
tuberculosis reactivation.

Sequence of events in the natural history of primary pulmonary tuberculosis. This sequence
commences with inhalation of virulent strains of Mycobacterium and culminates in the development
of immunity and delayed hypersensitivity to the organism. (A) Events occurring in the first 3 weeks
after exposure. (B) Events thereafter.The development of resistance to the organism is accompanied
by conversion to a positive result on tuberculin skin testing. Cells and bacteria are not drawn to
scale. IFN-γ, Interferon γ; iNOS, inducible nitric oxide synthase; MHC, major histocompatibility
complex; MTb, Mycobacterium tuberculosis; TNF, tumor necrosis factor

In summary, immunity to a tubercular infection is primarily mediated by TH1 cells, which stimulate
macrophages to kill mycobacteria. This immune response, while largely effective, comes at the cost
of hypersensitivity and the accompanying tissue destruction. Defects in any of the steps of a TH1 T
cell response (including IL-12, IFN-γ, TNF, or nitric oxide production) result in poorly formed
granulomas, absence of resistance, and disease progression. Individuals with inherited mutations in
any component of the TH1 pathway are extremely susceptible to infections with mycobacteria.
Reactivation of the infection or reexposure to the bacilli in a previously sensitized host results in
rapid mobilization of a defensive reaction but also increased tissue necrosis. Just as hypersensitivity
and resistance appear in parallel, so, too, the loss of hypersensitivity (indicated by tuberculin
negativity in a M. tuberculosis-infected patient) is an ominous sign of fading resistance to the
organism.

Primary Tuberculosis

Primary tuberculosis is the form of disease that develops in a previously unexposed and therefore
unsensitized patient. About 5% of those newly infected acquire significant disease. In the large
majority of otherwise healthy individuals, the only consequence of primary tuberculosis are the foci
of scarring discussed earlier. However, these foci may harbor viable bacilli and thus serve as a nidus
for disease reactivation at a later time if host defenses wane. Uncommonly, new infection leads to
progressive primary tuberculosis. This complication occurs in patients who are overtly
immunocompromised or who have more subtle defects in host defenses, as is characteristic of
malnourished individuals. Certain racial groups, such as the Inuit, also are more prone to the
development of progressive primary tuberculosis. The incidence of progressive primary tuberculosis
is particularly high in HIV-positive patients with significant immunosuppression (i.e., CD4+ T cell
counts below 200 cells/µL). Immunosuppression results in an inability to mount a CD4+ T cell–
mediated response that would contain the primary focus; because hypersensitivity and resistance
are most often concomitant factors, the lack of a tissue hypersensitivity reaction results in the
absence of the characteristic caseating granulomas (nonreactive tuberculosis) (see Fig. 13.35D).

MORPHOLOGY

In countries in which bovine tuberculosis and infected milk have largely disappeared, primary
tuberculosis almost always begins in the lungs.The inhaled bacilli usually implant in the distal air
spaces of the lower part of the upper lobe or in the upper part of the lower lobe. They are typically
close to the pleura. During the development of sensitization, a 1-cm to 1.5-cm area of gray-white
inflammatory consolidation emerges. This is called the Ghon focus. In the majority of cases,the
center of this focus undergoes caseous necrosis.Tubercle bacilli, either free or within phagocytes,
travel via the lymphatic vessels to the regional lymph nodes, which also often caseate. This
combination of parenchymal and nodal lesions is called the Ghon complex (Fig. 13.34). Lymphatic
and hematogenous dissemination to other parts of the body also occurs during the first few weeks.
Development of cell-mediated immunity controls the infection in approximately 95% of cases.
Therefore, the Ghon complex undergoes progressive fibrosis, and calcification often follows
(detectable as a Ranke complex on radiograph). Despite seeding of other organs, no lesions develop.
Histologically, sites of infection are involved by a characteristic inflammatory reaction marked by the
presence of caseating and noncaseating granulomas, which consist of epithelioid histiocytes and
multinucleate giant cells (Fig. 13.35A to C)

Secondary Tuberculosis (Reactivation Tuberculosis)

Secondary tuberculosis is the pattern of disease that arises in a previously sensitized host. It may
appear shortly after primary tuberculosis, but more commonly arises from reactivation of dormant
primary lesions many decades after initial infection, particularly when host resistance is weakened. It
also may result from reinfection, which may occur either because the protection afforded by the
primary disease has waned or because of exposure to a large inoculum of virulent bacilli. Whatever
the source of the organism, only a few patients (<5%) with primary disease subsequently develop
secondary tuberculosis.

Secondary pulmonary tuberculosis is classically localized to the apex of one or both upper lobes. The
reason is obscure but may relate to high oxygen tension in the apices. Because of the preexistence of
hypersensitivity, the bacilli excite a prompt and marked tissue response that tends to wall off the
focus. As a result of this localization, the regional lymph nodes are less prominently involved early in
the disease than they are in primary tuberculosis. On the other hand, cavitation occurs readily in the
secondary form, leading to erosion into and dissemination along airways. Such changes become an
important source of infectivity, because the patient now produces sputum containing bacilli.

Secondary tuberculosis should always be an important consideration in HIV-positive patients who

present with pulmonary disease. Of note, although an increased risk for tuberculosis exists at all
stages of HIV disease, the manifestations differ depending on the degree of immunosuppression. For
example, patients with less severe immunosuppression (CD4+ T cell counts >300 cells/µL) present
with “usual” secondary tuberculosis (apical disease with cavitation) while those with more advanced
immunosuppression (CD4+ T cell counts below 200 cells/µL) present with a clinical picture that
resembles progressive primary tuberculosis (lower and middle lobe consolidation, hilar
lymphadenopathy, and noncavitary disease). The extent of immunosuppression also determines the
frequency of extrapulmonary involvement, rising from 10% to 15% in mildly immunosuppressed
patients to greater than 50% in those with severe immune deficiency.

MORPHOLOGY

The initial lesion usually is a small focus of consolidation, less than 2 cm in diameter, within 1 to 2 cm
of the apical pleura. Such foci are sharply circumscribed, firm, gray-white to yellow areas that have a
variable amount of central caseation and peripheral fibrosis. In favorable cases, the initial
parenchymal focus undergoes progressive fibrous encapsulation, leaving only fibrocalcific
scars.Histologically,the active lesions show characteristic coalescent tubercles with central caseation.
Although tubercle bacilli can be demonstrated by appropriate methods in early exudative and
caseous phases of granuloma formation, it is usually impossible to find them in the late, fibrocalcific
stages. Localized, apical, secondary pulmonary tuberculosis may heal with fibrosis either
spontaneously or after therapy,or the disease may progress and extend along several different
pathways. In progressive pulmonary tuberculosis, the apical lesion enlarges and the area of
caseation expands. Erosion into a bronchus evacuates the caseous center, creating a ragged,
irregular cavity lined by caseous material that is poorly walled off by fibrous tissue (Fig. 13.36).
Erosion of blood vessels results in hemoptysis. With adequate treatment, the process may be
arrested, although healing by fibrosis often distorts the pulmonary architecture. Irregular cavities,
now free of caseous necrosis, may remain intact or collapse and become fibrotic. If the treatment is
inadequate or host defenses are impaired, the infection may spread by direct extension and by
dissemination through airways, lymphatic channels, and the vascular system. Miliary pulmonary
disease occurs when organisms reach the bloodstream through lymphatic vessels and then
recirculate to the lung via the pulmonary arteries.The lesions appear as small (2-mm) foci of yellow-
white consolidation scattered through the lung parenchyma (the word miliary is derived from the
resemblance of these foci to millet seeds).With progressive pulmonary tuberculosis,the pleural
cavity is invariably involved and serous pleural effusions, tuberculous empyema, or obliterative
fibrous pleuritis may develop. Endobronchial, endotracheal, and laryngeal tuberculosis may develop
when infective material is spread either through lymphatic channels or from expectorated infectious
material.The mucosal lining may be studded with minute granulomatous lesions, sometimes
apparent only on microscopic examination. Systemic miliary tuberculosis ensues when the
organisms disseminate hematogenously throughout the body. Systemic miliary tuberculosis is most
prominent in the liver, bone marrow, spleen, adrenal glands, meninges, kidneys, fallopian tubes, and
epididymis (Fig. 13.37).

Isolated-organ tuberculosis may appear in any one of the organs or tissues seeded hematogenously
and may be the presenting manifestation of tuberculosis. Organs typically involved include the
meninges (tuberculous meningitis), kidneys (renal tuberculosis), adrenal glands, bones
(osteomyelitis), and fallopian tubes (salpingitis).When the vertebrae are affected,the condition is
referred to as Pott disease. Paraspinal “cold” abscesses containing necrotic tissues may track along
the tissue planes to present as an abdominal or pelvic mass. Lymphadenitis is the most frequent
form of extrapulmonary tuberculosis, usually occurring in the cervical region (“scrofula”).
Lymphadenopathy tends to be unifocal, and most patients do not have concurrent extranodal
disease.HIV-positive patients, on the other hand, almost always have multifocal disease, systemic
symptoms, and either pulmonary or other organ involvement by active tuberculosis. In years past,
intestinal tuberculosis contracted by the drinking of contaminated milk was fairly common as a
primary focus of tuberculosis. In developed countries today, intestinal tuberculosis is more often a
complication of protracted advanced secondary tuberculosis,secondary to the swallowing of
coughedup infective material. Typically, the organisms are trapped in mucosal lymphoid aggregates
of the small and large bowel, which then undergo inflammatory enlargement with ulceration of the
overlying mucosa, particularly in the ileum. The many patterns of tuberculosis are depicted in Fig.
13.38.

Clinical Features

Localized secondary tuberculosis may be asymptomatic. When manifestations appear, they are
usually insidious in onset, with gradual development of both systemic and localizing symptoms and
signs. Systemic manifestations, probably related to the release of cytokines by activated
macrophages (e.g., TNF and IL-1), often appear early in the disease course and include malaise,
anorexia, weight loss, and fever. Commonly, the fever is low grade and remittent (appearing late
each afternoon and then subsiding), and night sweats occur. With progressive pulmonary
involvement, increasing amounts of sputum, at first mucoid and later purulent, appear. When
cavitation is present, the sputum contains tubercle bacilli. Some degree of hemoptysis is present in
about half of all cases of pulmonary tuberculosis. Pleuritic pain may result from extension of the
infection to the pleural surfaces. Extrapulmonary manifestations of tuberculosis are legion and
depend on the organ system involved (e.g., tuberculous salpingitis may present as infertility,
tuberculous meningitis with headache and neurologic deficits, Pott disease with back pain and
paraplegia). The diagnosis of pulmonary disease is based in part on the history and on physical and
radiographic findings of consolidation or cavitation in the apices of the lungs. Ultimately, however,
tubercle bacilli must be identified. The most common methodology for diagnosis of tuberculosis
remains demonstration of acid-fast organisms in sputum by staining or by use of fluorescent
auramine rhodamine. Conventional cultures for mycobacteria require up to 10 weeks, but liquid
media–based radiometric assays that detect mycobacterial metabolism are able to provide an
answer within 2 weeks. PCR amplification can be performed on liquid media with growth, as well as
on tissue sections, to identify the mycobacterium. However, culture remains the standard diagnostic
modality because it can identify the occasional PCR-negative case and also allows testing of drug
susceptibility. Of concern, multidrug resistance (MDR), defined as resistance of mycobacteria to two
or more of the primary drugs used for treatment of tuberculosis, is becoming more common, and
the WHO estimated that 500,000 individuals were newly infected with multidrug-resistant
tuberculosis in 2014. This represents approximately 3% of new cases and 20% of previously treated
cases. The epicenter of this troubling epidemic lies in Eastern Europe and Russia, where in some
locales up to 20% of new infections are with multidrug-resistant strains. Of even greater concern,
approximately 5% to 10% of such cases exhibit extensive multidrug resistance, defined by resistance
to a broad spectrum of antibiotics in current use against tuberculosis. The prognosis is determined
by the extent of the infection (localized versus widespread), the immune status of the host, and the
antibiotic sensitivity of the organism. Understandably, the prognosis is guarded in those with
multidrug-resistant tuberculosis. Amyloidosis may develop in persistent cases.

SUMMARY TUBERCULOSIS

- Tuberculosis is a chronic granulomatous disease caused by M. tuberculosis, usually affecting

the lungs, but virtually any extrapulmonary organ can be involved.
- Initial exposure to mycobacteria results in development of a cellular immune response that
confers resistance and leads to hypersensitivity (as determined by a positive result on the
tuberculin skin test).
- • The TH1 subset of CD4+ T cells has a crucial role in cellmediated immunity against
mycobacteria; mediators of inflammation and bacterial containment include IFN-γ,TNF, and
nitric oxide.
- The histopathologic hallmark of host reaction to tuberculosis in immunocompetent
individuals is the presence of granulomas, usually with caseous necrosis.
- Primary pulmonary tuberculosis in immunocompetent individuals is asymptomatic and
results only in healed lesions, typically in a sub-pleural focus and a draining lymph node.
- Secondary (reactivation) tuberculosis arises in previously exposed individuals when host
immune defenses are compromised, and usually manifests as cavitary lesions in the lung
apices.
- Both progressive primary tuberculosis and secondary tuberculosis can result in systemic
seeding, causing life-threatening forms of disease such as miliary tuberculosis and
tuberculous meningitis.
- HIV-seropositive status is an important risk factor for development or recrudescence of
active tuberculosis.
Benign Prostatic Hyperplasia

Benign prostatic hyperplasia (BPH) is an extremely common cause of prostatic enlargement resulting
from proliferation of of stromal and glandular elements. It is present in a significant number of men
by 40 years of age, and its frequency rises progressively thereafter, reaching 90% by the eighth
decade of life. The enlargement of the prostate in men with BPH is an important cause of urinary
obstruction. Although the cause of BPH is incompletely understood, excessive androgen-dependent
growth of stromal and glandular elements has a central role. BPH does not occur in males who are
castrated before the onset of puberty or in males with genetic diseases that block androgen activity.
Dihydrotestosterone (DHT), the ultimate mediator of prostatic growth, is synthesized in the prostate
from circulating testosterone by the action of the enzyme 5α-reductase, type 2. DHT binds to nuclear
androgen receptors, which regulate the expression of genes that support the growth and survival of
prostatic epithelium and stromal cells. Although testosterone can also bind to androgen receptors
and stimulate growth, DHT is 10 times more potent.

MORPHOLOGY

BPH virtually always occurs in the inner transition zone of the prostate. The affected prostate is
enlarged, typically weighing between 60 and 100 g, and contains many wellcircumscribed nodules
that bulge from the cut surface (Fig. 18.11). The nodules may appear solid or contain cystic spaces,
the latter corresponding to dilated glands.The urethra is usually compressed, often to a narrow slit,
by the hyperplastic nodules. In some cases, hyperplastic glandular and stromal elements lying just
under the epithelium of the proximal prostatic urethra project into the bladder lumen as a
pedunculated mass, producing a ball-valve type of urethral obstruction. Microscopically, the
hyperplastic nodules are composed of variable proportions of proliferating glandular elements and
fibromuscular stroma. The hyperplastic glands are lined by tall, columnar epithelial cells and a
peripheral layer of flattened basal cells (Fig. 18.12). The glandular lumina often contain laminated
proteinaceous secretory material known as corpora amylacea.

Clinical Features

Because BPH preferentially involves the inner portions of the prostate, the most common
manifestations are related to lower urinary tract obstruction, often in the form of difficulty in
starting the stream of urine (hesitancy) and intermittent interruption of the urinary stream while
voiding. These symptoms frequently are accompanied by urinary urgency, frequency, and nocturia,
all indicative of bladder irritation. Clinical manifestations of prostatic hyperplasia occur in only about
10% of men with pathologic evidence of BPH. The presence of residual urine in the bladder due to
chronic obstruction increases the risk for urinary tract infections. In some affected men, BPH leads to
complete urinary obstruction, with resultant painful distention of the bladder and, in the absence of
appropriate treatment, hydronephrosis (Chapter 14). Initial treatment is pharmacologic, using
targeted therapeutic agents that inhibit the formation of DHT from testosterone (such as 5-alpha
reductase inhibitors) or that relax prostatic smooth muscle by blocking α1-adrenergic receptors.
Various surgical techniques are reserved for severely symptomatic cases that are recalcitrant to
medical therapy.