1360 PART 5 Infectious Diseases

with high-level transmissibility. When infection is acquired later in

life, the chance is greater that the mature immune system will contain

it at least temporarily. Bacilli, however, may persist for years before

reactivating to produce secondary (or postprimary) TB, which, because

of frequent cavitation, is more often infectious than is primary disease.

Overall, it is estimated that up to 10% of infected persons will eventually develop active TB in their lifetime—half of them during the first

18 months after infection. The risk is much higher among immunocompromised individuals and, particularly, HIV-infected persons. Reinfection of a previously infected individual, which is common in areas with

high rates of TB transmission, may also favor the development of disease. At the height of the TB resurgence in the United States in the early

1990s, molecular typing and comparison of strains of M.  tuberculosis

suggested that up to one-third of cases of active TB in some inner-city

communities were due to recent transmission rather than to reactivation of old infection. Age is an important determinant of the risk of

disease after infection. Among infected persons, the incidence of TB

is highest during late adolescence and early adulthood; the reasons are

unclear. The incidence among women peaks at 25–34 years of age. In

this age group, rates among women may be higher than those among

men, whereas at older ages the opposite is true. The risk increases in the

elderly, possibly because of waning immunity and comorbidity.

A variety of diseases and conditions favor the development of active

TB (Table 178-1). In absolute terms, the most potent risk factor for

TB among infected individuals is clearly HIV co-infection, which suppresses cellular immunity. The risk that infection will proceed to active

disease is directly related to the patient’s degree of immunosuppression.

In a study of HIV-co-infected, tuberculin skin test (TST)–positive

persons, this risk varied from 2.6 to 13.3 cases/100 person-years and

increased as the CD4+ T-cell count decreased.

■ NATURAL HISTORY OF DISEASE

Studies conducted in various countries before the advent of antimicrobial TB therapy showed that untreated TB is often fatal. About

one-third of patients died within 1 year after diagnosis. Historical data

also show that 55% of sputum smear-positive cases were dead within

5 years and up to 86% (weighted mean 70%) within 10 years. A lower

case fatality rate, around 20%, was estimated for untreated paucibacillary smear-negative cases at 5 years. Of the survivors at 5 years, ~60%

had undergone spontaneous remission, while the remainder were still

excreting tubercle bacilli. With effective, timely, and proper antimicrobial TB treatment, patients have a very high chance of being cured.

However, improper use of anti-TB drugs, while reducing mortality

rates, may also result in large numbers of chronic infectious cases, often

with drug-resistant bacilli.

PATHOGENESIS AND IMMUNITY

■ INFECTION AND MACROPHAGE INVASION

The interaction of M. tuberculosis with the human host begins when

droplet nuclei containing viable microorganisms, propelled into the

air by infectious patients, are inhaled by a close bystander. Although

the majority of inhaled bacilli are trapped in the upper airways and

expelled by ciliated mucosal cells, a fraction (usually <10%) reach the

alveoli, a unique immunoregulatory environment. There, in the very

early phases of infection, the predominant cells infected by M. tuberculosis are myeloid dendritic cells. Subsequently, alveolar macrophages

that have not yet been activated (prototypic alternatively activated

macrophages) phagocytose the bacilli. Adhesion of mycobacteria to

macrophages results largely from binding of the bacterial cell wall to

a variety of macrophage cell-surface receptor molecules, including

complement receptors, the mannose receptor, the immunoglobulin

G Fcγ receptor, and type A scavenger receptors. Surfactants may also

play a role in the early phase of interaction between the host and the

pathogen, and surfactant protein D can prevent phagocytosis. Phagocytosis is enhanced by complement activation leading to opsonization

of bacilli with C3 activation products such as C3b and C3bi. Concomitantly, binding of certain receptors, such as the mannose receptor,

regulates postphagocytic events like phagosome–lysosome fusion and

inflammatory cytokine production. After a phagosome forms, the survival of M. tuberculosis in the cell seems to depend in part on reduced

acidification due to lack of assembly of a complete vesicular protonadenosine triphosphatase. A complex series of events is generated by

the bacterial cell-wall lipoglycan lipoarabinomannan, which inhibits

the intracellular increase of Ca2+. Thus, the Ca2+/calmodulin pathway

(leading to phagosome–lysosome fusion) is impaired, and the bacilli

survive within the phagosomes by blocking fusion. The M. tuberculosis

phagosome inhibits the production of phosphatidylinositol 3-phosphate,

which normally earmarks phagosomes for membrane sorting and maturation (including phagolysosome formation), which would destroy

the bacteria. Bacterial factors block the host defense of autophagy, in

which the cell sequesters the phagosome in a double-membrane vesicle

(autophagosome) that is destined to fuse with lysosomes. If the bacilli

are successful in arresting phagosome maturation, then replication

begins and the macrophage eventually ruptures and releases its bacillary

contents. This process is mediated by the ESX-1 secretion system that is

encoded by genes contained in the region of difference 1 (RD1). Other

uninfected phagocytic cells are then recruited to continue the infection

cycle by ingesting dying macrophages and their bacillary content, thus,

in turn, becoming infected themselves and expanding the infection.

■ VIRULENCE OF TUBERCLE BACILLI

M. tuberculosis must be viewed as a complex formed by a multitude

of strains that differ in virulence and are capable of producing a

variety of manifestations of disease. Since the elucidation of the M.

tuberculosis genome in 1998, large mutant collections have been generated, and many bacterial genes that contribute to M. tuberculosis virulence have been found. Moreover, different patterns of virulence defects

have been defined in various animal models—predominantly mice but

also guinea pigs, rabbits, and nonhuman primates. The katG gene

encodes for a catalase/peroxidase enzyme that protects against oxidative

stress and is required for isoniazid activation and subsequent bactericidal

activity. RD1 is a 9.5-kb locus that encodes two key small protein antigens—6-kDa early secretory antigen (ESAT-6) and culture filtrate protein-10 (CFP-10)—as well as a putative secretion apparatus that may

facilitate their egress; the absence of this locus in the vaccine strain M.

bovis bacille Calmette-Guérin (BCG) is a key attenuating mutation. In

M. marinum, a mutation in the RD1 virulence locus encoding the ESX-1

secretion system impairs the capacity of apoptotic macrophages to

recruit uninfected cells for further rounds of infection. The results are

less replication and fewer new granulomas. These observations in M.

marinum are similar in part to events related to the virulence of M. tuberculosis; however, ESX-1, although necessary, is probably insufficient to

explain virulence, and other mechanisms may be in play. Mutants lacking key enzymes of bacterial biosynthesis become auxotrophic for the

TABLE 178-1 Risk Factors for Active Tuberculosis in Persons Who

Have Been Infected with Tubercle Bacilli

FACTOR RELATIVE RISK/ODDSa

Recent infection (<1 year) 12.9

Fibrotic lesions (spontaneously healed) 2–20

Comorbidities and iatrogenic causes

HIV infection 21–>30

Silicosis 30

Chronic renal failure/hemodialysis 10–25

Diabetes 2–4

IV drug use 10–30

Excessive alcohol use 3

Immunosuppressive treatment 10

Tumor necrosis factor α inhibitors 4–5

Gastrectomy 2–5

Jejunoileal bypass 30–60

Posttransplantation period (renal, cardiac) 20–70

Tobacco smoking 2–3

Malnutrition and severe underweight 2

a

Old infection = 1.

1361CHAPTER 178 Tuberculosis

missing substrate and often are totally unable to proliferate in animals;

these include the leuCD and panCD mutants, which require leucine and

pantothenic acid, respectively. The isocitrate lyase gene (icl1) encodes a

key step in the glyoxylate shunt that facilitates bacterial growth on fatty

acid substrates; this gene is required for long-term persistence of M.

tuberculosis infection in mice with chronic TB. M. tuberculosis mutants

in regulatory genes such as sigma factor C and sigma factor H (sigC and

sigH) are associated with normal bacterial growth in mice, but they fail

to elicit full tissue pathology. Finally, the mycobacterial protein CarD

(expressed by the carD gene) seems essential for the control of rRNA

transcription that is required for mycobacterial replication and persistence in the host cell. Its loss exposes mycobacteria to oxidative stress,

starvation, DNA damage, and ultimately sensitivity to killing by a variety

of host mutagens and defense mechanisms.

■ INNATE RESISTANCE TO INFECTION

Several observations suggest that genetic factors play a key role in

innate resistance to infection with M. tuberculosis and the development of disease. The existence of this resistance, which is polygenic

in nature, is suggested by the differing degrees of susceptibility to TB in

different populations. This mechanism of elimination of the pathogen

may be accompanied by negative results in the TST and interferon-γ

(IFN-γ) release assays (IGRAs). In mice, a gene called Nramp1 (natural

resistance–associated macrophage protein 1) plays a regulatory role in

resistance/susceptibility to mycobacteria. The human homologue

NRAMP1, which maps to chromosome 2q, may play a role in determining susceptibility to TB, as is suggested by a study among West Africans.

Studies of mice identified a novel host resistance gene, ipr1, that is

encoded within the sst1 locus; ipr1 encodes an IFN-inducible nuclear

protein that interacts with other nuclear proteins in macrophages primed

with IFNs or infected by M. tuberculosis. In addition, polymorphisms in

multiple genes, such as those encoding for various major histocompatibility complex alleles, IFN-γ, T-cell growth factor β, interleukin (IL) 10,

mannose-binding protein, IFN-γ receptor, Toll-like receptor 2, vitamin D

receptor, and IL-1, have been associated with susceptibility to TB.

■ THE HOST RESPONSE, GRANULOMA FORMATION,

AND “LATENCY”

In the initial stage of host–bacterium interaction, prior to the onset of

an acquired cell-mediated immune (CMI) response, M. tuberculosis

disseminates widely through the lymph vessels, spreading to other sites

in the lungs and other organs, and undergoes a period of extensive

growth within naïve inactivated macrophages; additional naïve macrophages are recruited to the early granuloma. How the bacillus accesses

the parenchymal tissue still needs to be elucidated: it may directly infect

epithelial cells or transmigrate through infected macrophages across the

epithelium. Infected dendritic cells or monocytes then begin to transport bacilli to the lymphatic system. Studies suggest that M. tuberculosis

uses specific virulence mechanisms to subvert host cellular signaling

and to elicit an early regulated proinflammatory response that promotes

granuloma expansion and bacterial growth during this key early phase.

A study of M. marinum infection in zebrafish has delineated one molecular mechanism by which mycobacteria induce granuloma formation.

The mycobacterial protein ESAT-6 induces secretion of matrix metalloproteinase 9 (MMP9) by nearby epithelial cells that are in contact

with infected macrophages. MMP9 in turn stimulates recruitment of

naïve macrophages, thus inducing granuloma maturation and bacterial

growth. Disruption of MMP9 function results in reduced bacterial

growth. Another study has shown that M. tuberculosis–derived cyclic

AMP is secreted from the phagosome into host macrophages, subverting the cell’s signal transduction pathways and stimulating an elevation

in the secretion of tumor necrosis factor α (TNF-α) as well as further

proinflammatory cell recruitment. Ultimately, the chemoattractants and

bacterial products released during the repeated rounds of cell lysis and

infection of newly arriving macrophages enable dendritic cells to access

bacilli; these cells migrate to the draining lymph nodes and present

mycobacterial antigens to T lymphocytes. At this point, the development of cell-mediated and humoral immunity begins. These initial

stages of infection are usually asymptomatic.

About 2–4 weeks after infection, two host responses to M. tuberculosis develop: a macrophage-activating CMI response and a tissue-damaging response. The macrophage-activating response is a T-cell

mediated phenomenon resulting in the activation of macrophages that

are capable of killing and digesting tubercle bacilli. The tissue-damaging

response is the result of a delayed-type hypersensitivity reaction to various bacillary antigens; it destroys inactivated macrophages that contain

multiplying bacilli but also causes caseous necrosis of the involved

tissues (see below). Although both of these responses can inhibit mycobacterial growth, it is the balance between the two that determines the

forms of TB that will develop subsequently. With the development of

specific immunity and the accumulation of large numbers of activated

macrophages at the site of the primary lesion, granulomatous lesions

(tubercles) are formed. These lesions consist of accumulations of lymphocytes and activated macrophages that evolve toward epithelioid and

giant cell morphologies. Initially, the tissue-damaging response can

limit mycobacterial growth within macrophages. As stated above, this

response, mediated by various bacterial products, not only destroys

macrophages but also produces early solid necrosis in the center of the

tubercle. Although M. tuberculosis can survive, its growth is inhibited

within this necrotic environment by low oxygen tension and low pH.

At this point, some lesions may heal by fibrosis, with subsequent calcification, whereas inflammation and necrosis occur in other lesions.

Some observations have challenged the traditional view that any

encounter between mycobacteria and macrophages results in chronic

infection. It is possible that an immune response capable of eradicating

early infection may sometimes develop as a consequence, for instance,

of disabling mutations in mycobacterial genomes rendering their

replication ineffective. Individual granulomas that are formed during

this phase of infection can vary in size and cell composition; some can

contain the spread of mycobacteria, while others cannot. TB infection

ensues as a result of this dynamic balance between the microorganism

and the host. For many years, TB infection has been called “latent

TB infection (LTBI).” This terminology was used to define a state of

persistent immune response to stimulation by M. tuberculosis antigens

with no evidence of clinically manifest, active TB. The qualification

“latent” may offer some convenience of distinguishing infection from

disease, albeit an inaccurate description of a process that encompasses

bacterial generations that are not dormant. It has been speculated that

latency may therefore be an inaccurate term because bacilli may remain

active during this “latent” stage, forming biofilms in necrotic areas

within which they temporarily hide. Thus some have proposed the

term persister as more accurate to indicate the behavior of the bacilli in

this phase. It is important to recognize that infection and disease represent not a binary state but rather a continuum along which infection

will eventually move in the direction of full containment or disease.

The ability to predict, through systemic biomarkers, which affected

individuals will progress toward disease would be of immense value in

devising prophylactic interventions at scale.

■ MACROPHAGE-ACTIVATING RESPONSE

Cell-mediated immunity is critical at this early stage. In the majority

of infected individuals, local macrophages are activated when bacillary

antigens processed by macrophages stimulate T lymphocytes to release

a variety of lymphokines. These activated macrophages aggregate

around the lesion’s center and effectively neutralize tubercle bacilli

without causing further tissue destruction. In the central part of the

lesion, the necrotic material resembles soft cheese (caseous necrosis)—a

phenomenon that may also be observed in other conditions, such as

neoplasms. Even when healing takes place, viable bacilli may remain

dormant within macrophages or in the necrotic material for many

years. These “healed” lesions in the lung parenchyma and hilar lymph

nodes may later undergo calcification.

■ DELAYED-TYPE HYPERSENSITIVITY

In a minority of cases, the macrophage-activating response is weak,

and mycobacterial growth can be inhibited only by intensified delayed

hypersensitivity reactions, which lead to lung tissue destruction.

The lesion tends to enlarge further, and the surrounding tissue is

1362 PART 5 Infectious Diseases

progressively damaged. At the center of the lesion, the caseous material

liquefies. Bronchial walls and blood vessels are invaded and destroyed,

and cavities are formed. The liquefied caseous material, containing

large amount of bacilli, is drained through bronchi. Within the cavity,

tubercle bacilli multiply, spill into the airways, and are discharged into

the environment through expiratory maneuvers such as coughing and

talking. In the early stages of infection, bacilli are usually transported

by macrophages to regional lymph nodes, from which they gain access

to the central venous return; from there they reseed the lungs and

may also disseminate beyond the pulmonary vasculature throughout

the body via the systemic circulation. The resulting extrapulmonary

lesions may undergo the same evolution as those in the lungs, although

most tend to heal. In young children with poor natural immunity,

hematogenous dissemination may result in fatal miliary TB or tuberculous meningitis.

■ ROLE OF MACROPHAGES AND MONOCYTES

While cell-mediated immunity confers partial protection against M.

tuberculosis, humoral immunity plays a less well-defined role in protection (although evidence is accumulating on the existence of antibodies

to lipoarabinomannan, which may prevent dissemination of infection

in children). In cell-mediated immunity, two types of cells are essential:

macrophages, which directly phagocytose tubercle bacilli, and T cells

(mainly CD4+ T lymphocytes, although the role of CD8+ T cells has

recently been the subject of much research), which induce protection

through the production of cytokines, especially IFN-γ. After infection

with M. tuberculosis, alveolar macrophages secrete various cytokines

responsible for a number of events (e.g., the formation of granulomas)

as well as systemic effects (e.g., fever and weight loss). However, alternatively activated alveolar macrophages may be particularly susceptible

to M. tuberculosis growth early on, given their more limited proinflammatory and bactericidal activity, which is related in part to being bathed

in surfactant. New monocytes and macrophages attracted to the site are

key components of the immune response. Their primary mechanism

is probably related to production of oxidants (such as reactive oxygen

intermediates or nitric oxide) that have antimycobacterial activity and

increase the synthesis of cytokines such as TNF-α and IL-1, which in

turn regulate the release of reactive oxygen intermediates and reactive

nitrogen intermediates. In addition, macrophages can undergo apoptosis—a defensive mechanism to prevent the release of cytokines and

bacilli via their sequestration in the apoptotic cell. Recent work also

describes the involvement of neutrophils in the host response, although

the timing of their appearance and their effectiveness remain uncertain.

■ ROLE OF T LYMPHOCYTES

Alveolar macrophages, monocytes, and dendritic cells are also critical

in processing and presenting antigens to T lymphocytes, primarily

CD4+ and CD8+ T cells; the result is the activation and proliferation

of CD4+ T lymphocytes, which are crucial to the host’s defense against

M. tuberculosis. Qualitative and quantitative defects of CD4+ T cells

explain the inability of HIV-infected individuals to contain mycobacterial proliferation. Activated CD4+ T lymphocytes can differentiate

into cytokine-producing TH1 or TH2 cells. TH1 cells produce IFN-γ—an

activator of macrophages and monocytes—and IL-2. TH2 cells produce

IL-4, IL-5, IL-10, and IL-13 and may also promote humoral immunity.

The interplay of these various cytokines and their cross-regulation

determine the host’s response. The role of cytokines in promoting

intracellular killing of mycobacteria, however, has not been entirely

elucidated. IFN-γ may induce the generation of reactive nitrogen intermediates and regulate genes involved in bactericidal effects. TNF-α is

also important. Although its precise mechanisms are complex and not

yet fully clarified, a model has been suggested that foresees an ideal

setting for TNF-α between excessive activation—with consequent worsening of immunopathological reactions—and insufficient activation—

with resulting lack of containment—in the control of TB infection.

Observations made originally in transgenic knockout mice and more

recently in humans suggest that other T-cell subsets, especially CD8+

T cells, may play an important role. CD8+ T cells have been associated

with protective activities via cytotoxic responses and lysis of infected

cells as well as with production of IFN-γ and TNF-α. Finally, natural

killer cells act as co-regulators of CD8+ T-cell lytic activities, and γδ

T cells are increasingly thought to be involved in protective responses

in humans.

■ MYCOBACTERIAL LIPIDS AND PROTEINS

Lipids are involved in mycobacterial recognition by the innate immune

system, and lipoproteins (such as 19-kDa lipoprotein) trigger potent

signals through Toll-like receptors present in blood dendritic cells. M.

tuberculosis possesses various protein antigens. Some are present in the

cytoplasm and cell wall; others are secreted. That the latter are more

important in eliciting a T lymphocyte response is suggested by experiments documenting the appearance of protective immunity in animals

after immunization with live, protein-secreting mycobacteria. Among

the antigens that may play a protective role are the 30-kDa (or 85B)

and ESAT-6 antigens. Protective immunity is probably the result of

reactivity to many different mycobacterial antigens. These antigens are

being incorporated into newly designed vaccines on various platforms.

■ SKIN-TEST REACTIVITY

Coincident with the appearance of immunity, delayed-type hypersensitivity to M. tuberculosis develops. This reactivity is the basis of the TST,

which is used primarily for the diagnosis of M. tuberculosis infection

in persons without symptoms. The cellular mechanisms responsible

for TST reactivity are related mainly to previously sensitized CD4+

T lymphocytes, which are attracted to the skin-test site. There, they

proliferate and produce cytokines. Although delayed hypersensitivity

is associated with protective immunity (TST-positive persons are

less susceptible to a new M. tuberculosis infection than TST-negative

persons), it by no means guarantees protection against reactivation. In

fact, cases of active TB are often accompanied by strongly positive skintest reactions. There is also evidence of reinfection with a new strain

of M. tuberculosis in patients previously treated for active disease. This

evidence underscores the fact that previous infection or active TB may

not confer fully protective immunity.

CLINICAL MANIFESTATIONS

TB is classified as pulmonary, extrapulmonary, or both. Depending

on several factors linked to host immunological status and bacterial

strains, extrapulmonary TB may occur in 10–40% of patients. Furthermore, up to two-thirds of HIV-infected patients with TB may have

both pulmonary and extrapulmonary TB or extrapulmonary TB alone.

■ PULMONARY TB

Pulmonary TB is conventionally categorized as primary or postprimary (adult-type, secondary). This distinction has been challenged

by molecular evidence from TB-endemic areas indicating that a large

percentage of cases of adult pulmonary TB result from recent infection

(either primary infection or reinfection) and not from reactivation.

Primary Disease Primary pulmonary TB occurs soon after the

initial infection. It may be asymptomatic or may present with fever

and occasionally pleuritic chest pain. In areas of high TB transmission,

this form of disease is often seen in children. Because most inspired

air is distributed to the middle and lower lung zones, these areas are

most commonly involved in primary TB. The lesion forming after

initial infection (Ghon focus) is usually peripheral and accompanied by

transient hilar or paratracheal lymphadenopathy, which may or may

not be visible on standard chest radiography (CXR) (Fig. 178-4). Some

patients develop erythema nodosum on the legs (see Fig. A1-39) or

phlyctenular conjunctivitis. In the majority of cases, the lesion heals

spontaneously and becomes evident only as a small calcified nodule.

Pleural reaction overlying a subpleural focus is also common. The

Ghon focus, with or without overlying pleural reaction, thickening,

and regional lymphadenopathy, is referred to as the Ghon complex.

In young children with immature cell-mediated immunity and in

persons with impaired immunity (e.g., those with malnutrition or HIV

infection), primary pulmonary TB may progress rapidly to clinical

illness. The initial lesion increases in size and can evolve in different

ways. Pleural effusion, which is found in up to two-thirds of cases,

1363CHAPTER 178 Tuberculosis

results from the penetration of bacilli into the pleural space from an

adjacent subpleural focus. In severe cases, the primary site rapidly

enlarges, its central portion undergoes necrosis, and cavitation develops (progressive primary TB). TB in young children is almost invariably

accompanied by hilar or paratracheal lymphadenopathy due to the

spread of bacilli from the lung parenchyma through lymphatic vessels.

Enlarged lymph nodes may compress bronchi, causing total obstruction with distal collapse, partial obstruction with large-airway wheezing, or a ball-valve effect with segmental/lobar hyperinflation. Lymph

nodes may also rupture into the airway with development of pneumonia, often including areas of necrosis and cavitation, distal to the

obstruction. Bronchiectasis (Chap. 290) may develop in any segment/

lobe damaged by progressive caseating pneumonia. Occult hematogenous dissemination commonly follows primary infection. However, in

the absence of a sufficient acquired immune response, which usually

contains the infection, disseminated or miliary disease may result

(Fig. 178-5). Small granulomatous lesions develop in multiple organs

and may cause locally progressive disease or result in tuberculous meningitis; this is a particular concern in very young children and immunocompromised persons (e.g., patients with HIV infection).

Postprimary (Adult-Type) Disease Also referred to as reactivation or secondary TB, postprimary TB is probably most accurately

termed adult-type TB because it may result from endogenous reactivation of distant or recent infection (primary infection or reinfection). It is usually localized to the apical and posterior segments of

the upper lobes, where the substantially higher mean oxygen tension

(compared with that in the lower zones) favors mycobacterial growth.

The superior segments of the lower lobes are also frequently involved.

The extent of lung parenchymal involvement varies greatly, from

small infiltrates to extensive cavitary disease. With cavity formation,

liquefied necrotic contents are ultimately discharged into the airways

and may undergo bronchogenic spread, resulting in satellite lesions

within the lungs that may in turn undergo cavitation (Figs. 178-6

and 178-7). Massive involvement of pulmonary segments or lobes,

FIGURE 178-4 Chest radiograph showing right hilar lymph node enlargement with

infiltration into the surrounding lung tissue in a child with primary tuberculosis.

(Courtesy of Prof. Robert Gie, Department of Paediatrics and Child Health,

Stellenbosch University, South Africa; with permission.)

FIGURE 178-5 Chest radiograph showing bilateral miliary (millet-sized) infiltrates

in a child. (Courtesy of Prof. Robert Gie, Department of Paediatrics and Child Health,

Stellenbosch University, South Africa; with permission.)

FIGURE 178-6 Chest radiograph showing a right-upper-lobe infiltrate and a cavity

with an air-fluid level in a patient with active tuberculosis. (Courtesy of Dr. Andrea

Gori, Infectious Diseases Unit, Fondazione IRCCS Ca’ Granda Ospediale Maggiore

Policlinico, University of Milan, Milan, Italy; with permission.)

FIGURE 178-7 CT scan showing a large cavity in the right lung of a patient with

active tuberculosis. (Courtesy of Dr. Elisa Busi Rizzi, National Institute for Infectious

Diseases, Spallanzani Hospital, Rome, Italy; with permission.)

1364 PART 5 Infectious Diseases

with coalescence of lesions, produces caseating pneumonia. While

up to one-third of untreated patients reportedly succumb to severe

pulmonary TB within a few months after onset (the classic “galloping

consumption” of the past), others may undergo a process of spontaneous remission or proceed along a chronic, progressively debilitating

course (“consumption” or phthisis). Under these circumstances, some

pulmonary lesions become fibrotic and may later calcify, but cavities

persist in other parts of the lungs. Individuals with such chronic disease continue to discharge tubercle bacilli into the environment. Most

patients respond to treatment, with defervescence, decreasing cough,

weight gain, and a general improvement in well-being within several

weeks.

Early in the course of disease, symptoms and signs are often nonspecific and insidious, consisting mainly of fever, often diurnal and

night sweats due to defervescence, weight loss, anorexia, general malaise, and weakness. However, in up to 90% of cases, cough eventually

develops—often initially nonproductive and limited to the morning

and subsequently accompanied by the production of purulent sputum,

sometimes with blood streaking. Hemoptysis develops in 20–30% of

cases, and massive hemoptysis may ensue as a consequence of the

erosion of a blood vessel in the wall of a cavity. Hemoptysis, however,

may also result from rupture of a dilated vessel in a cavity (Rasmussen’s

aneurysm) or from aspergilloma formation in an old cavity. Pleuritic

chest pain sometimes develops in patients with subpleural parenchymal lesions or pleural disease. Extensive disease may produce dyspnea

and, in rare instances, adult respiratory distress syndrome. Physical

findings are of limited use in pulmonary TB. Many patients have no

abnormalities detectable by chest examination, whereas others have

detectable rales in the involved areas during inspiration, especially after

coughing. Occasionally, rhonchi due to partial bronchial obstruction

and classic amphoric breath sounds in areas with large cavities may

be heard. Systemic features include fever (often low-grade and intermittent) in up to 80% of cases and wasting. Absence of fever, however,

does not exclude TB. In some recurrent cases and among people with

low Karnofsky score, finger clubbing has been reported. The most

common hematologic findings are mild anemia, leukocytosis, and

thrombocytosis with a slightly elevated erythrocyte sedimentation rate

and/or C-reactive protein level. None of these findings is consistent or

sufficiently accurate for diagnostic purposes. Hyponatremia due to the

syndrome of inappropriate secretion of antidiuretic hormone has also

been reported.

■ EXTRAPULMONARY TB

In descending order of frequency, the extrapulmonary sites most commonly involved in TB are the lymph nodes, pleura, genitourinary tract,

bones and joints, meninges, peritoneum, and pericardium. However,

virtually any organ system may be affected. As a result of hematogenous dissemination in HIV-infected individuals, extrapulmonary TB

is seen more commonly today than in the past in settings of high HIV

prevalence.

Lymph Node TB (Tuberculous Lymphadenitis) The most

common presentation of extrapulmonary TB in both HIV-seronegative

individuals and HIV-infected patients (35% of cases worldwide and

>40% of cases in the United States in recent series), lymph node disease is particularly frequent among HIV-infected patients and among

children (Fig. 178-8). In the United States, besides children, women

(particularly non-Caucasians) seem to be especially susceptible. Once

caused mainly by M. bovis, tuberculous lymphadenitis today is due

largely to M. tuberculosis. Lymph node TB presents as painless swelling of the lymph nodes, most commonly at posterior cervical and

supraclavicular sites (a condition historically referred to as scrofula).

Lymph nodes are usually discrete in early disease but develop into a

matted nontender mass over time; a fistulous tract draining caseous

material may result. Associated pulmonary disease is present in fewer

than 50% of cases, and systemic symptoms are uncommon except

in HIV-infected patients. The diagnosis is established by fine-needle

aspiration biopsy (with a yield of up to 80%) or surgical excision biopsy.

Bacteriologic confirmation is achieved in the vast majority of cases,

granulomatous lesions with or without visible AFBs are typically seen,

and cultures are positive in 70–80% of cases. Among HIV-infected

patients, granulomas are less well organized and are frequently absent

entirely, but bacterial loads are heavier than in HIV-seronegative

patients, with higher yields from microscopy and culture. Differential

diagnosis includes a variety of infectious conditions, neoplastic diseases such as lymphomas or metastatic carcinomas, and rare disorders

like Kikuchi’s disease (necrotizing histiocytic lymphadenitis), Kimura’s

disease, and Castleman’s disease.

Pleural TB Involvement of the pleura accounts for ~20% of

extrapulmonary cases in the United States and elsewhere. Isolated pleural effusion usually reflects recent primary infection, and the collection

of fluid in the pleural space represents a hypersensitivity response to

mycobacterial antigens. Pleural disease may also result from contiguous parenchymal spread, as in many cases of pleurisy accompanying

postprimary disease. Depending on the extent of reactivity, the effusion

may be small, remain unnoticed, and resolve spontaneously or may be

sufficiently large to cause symptoms such as fever, pleuritic chest pain,

and dyspnea. Physical findings are those of pleural effusion: dullness

to percussion and absence of breath sounds. CXR reveals the effusion

and, in up to one-third of cases, also shows a parenchymal lesion.

Thoracentesis is required to ascertain the nature of the effusion and

to differentiate it from manifestations of other etiologies. The fluid is

straw-colored and at times hemorrhagic; it is an exudate with a protein

concentration >50% of that in serum (usually ~4–6 g/dL), a normal

to low glucose concentration, a pH of ~7.3 (occasionally <7.2), and

detectable white blood cells (usually 500–6000/μL). Neutrophils may

predominate in the early stage, but lymphocyte predominance is the

typical finding later. Mesothelial cells are generally rare or absent.

AFBs are rarely seen on direct smear, and cultures often may be falsely

negative for M. tuberculosis; positive cultures are more common among

postprimary cases. Determination of the pleural concentration of

adenosine deaminase may be a useful screening test, and TB may be

excluded if the value is very low. Lysozyme is also present in the pleural

effusion. Measurement of IFN-γ, either directly or through stimulation

of sensitized T cells with mycobacterial antigens, can be diagnostically

helpful. Needle biopsy of the pleura is often required for diagnosis

and is recommended over pleural fluid analysis; it reveals granulomas

and/or yields a positive culture in up to 80% of cases. Pleural biopsy

can yield a positive result in ~75% of cases when real-time automated

nucleic acid amplification is used (the Xpert MTB/RIF assay [Cepheid;

Sunnyvale, CA]; see “Nucleic Acid Amplification Technology,” below);

testing of pleural fluid with this assay is not recommended because of

low sensitivity. This form of pleural TB responds rapidly to chemotherapy and may resolve spontaneously. Concurrent glucocorticoid

FIGURE 178-8 Tuberculous lymphadenitis affecting the cervical lymph nodes in a

2-year-old child from Malawi. (Courtesy of Prof. S. Graham, Centre for International

Child Health, University of Melbourne, Australia; with permission.)