SECTION 2 Syndromes by Body System:
The Respiratory System
31 
Tuberculosis
REINOUT VAN CREVEL  |  PHILIP C. HILL
KEY CONCEPTS
• Tuberculosis, caused by Mycobacterium tuberculosis spread by
aerosols, kills more people than any other infectious disease.
• After exposure to tuberculosis, only around 5–10% of individu-
als will develop active disease, up until decades afterwards.
Risk factors for tuberculosis include HIV, diabetes and use of
immunosuppressive drugs.
• Screening exposed individuals for latent tuberculosis with
the tuberculin skin test (TST) or interferon gamma release
assays (IGRAs), followed by prophylaxis can prevent active
tuberculosis.
• Tuberculosis can occur anywhere in the body, but typically
presents as subacute pulmonary disease with cough, weight
loss (40–75%), fever (30–60%) and night sweats (40–60%).
• Diagnosis depends on microbiological testing of sputum, alve-
olar lavage or tissue biopsies; pulmonary cavities on X-ray and
necrotizing granulomata in biopsies are strongly suggestive of
tuberculosis.
• Tuberculosis requires at least 6 months of treatment with a
4-drug regimen including rifampin and isoniazid; drug-resistant
tuberculosis is a clinical and public health challenge.
Tuberculosis is the most important mycobacterial infection and is the
subject of this chapter. The other mycobacterial infections except for
leprosy are covered in Chapter 32; leprosy in Chapter 108. Details of
antimycobacterial drugs are to be found in Chapter 148. Tuberculosis
and HIV coinfection is also covered separately in Chapter 96. The
clinical microbiology of mycobacterial infections is discussed in
Chapter 185.
Tuberculosis
Tuberculosis, a disease identified in skeletons more than 6000 years
old, remains one of the most prevalent infectious diseases in the world.
This chapter focuses on current understanding of pathophysiology,
epidemiology and clinical aspects of tuberculosis.
Epidemiology
WORLDWIDE INCIDENCE AND PREVALENCE
Mycobacterium tuberculosis is estimated to infect approximately one-
third of the world’s population, over 2 billion people worldwide. The
global burden of tuberculosis probably peaked in 2010 and the number
of new cases per year is now declining slowly; the World Health Orga-
nization (WHO) reported that there were approximately 8.6 million
new cases and 1.3 million deaths from tuberculosis in 2012.1 While the
TB death rate has dropped dramatically since 1990, over 95% of TB
deaths occur in low- and middle-income countries (LMIC). Tubercu-
losis notification rates are adjusted to provide incidence estimates in
LMIC. For this, available data from prevalence surveys and a variety
of different sources, including expert opinion, are used. Historical
incidence rates are continually revised through application of the most
recent methodologies and can change significantly, by as much as 50%.
Therefore they should be interpreted with caution. Recent tuberculosis
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notification data and incidence rate estimates across the world are
shown in Figure 31-1 and show the predominance of the disease in
LMIC.
In wealthier nations, rates of tuberculosis have been falling since at
least as early as 1900, initially mainly due to social improvements and
development, with likely contributions from BCG vaccination and the
use of sanatoria. This was followed by an accelerated decline since
1950, probably due to the introduction of effective chemotherapy for
M. tuberculosis infection and disease. However, tuberculosis persists in
many wealthy nations, especially in particular population groups such
as poorer communities, migrants, homeless populations, intravenous
drug users and prisoners.2. The worldwide prevalence of diabetes mel-
litus is increasing and increases the risk of tuberculosis, threatening TB
control in areas where both diseases predominate.3 Other specific risk
factors are heavy alcohol consumption, smoking, low body mass index,
biomass fuel consumption, outdoor air pollution and a range of
medical conditions with immunocompromise.4
The Impact of HIV
The WHO estimate that there were 1.1 million new cases of tubercu-
losis associated with HIV in 2012 and 320 000 TB deaths were in HIV-
positive people.1 HIV-seropositive patients are more susceptible to
infection by M. tuberculosis. Reactivation of tuberculosis occurs at least
10 times more frequently than in age-matched controls. The majority
of people coinfected with tuberculosis and HIV live in sub-Saharan
Africa (approximately 75%), the Indian subcontinent and South East
Asia (Figure 31-2). Patients tend to be sicker and in greater need of
hospitalization. The relationship between HIV and tuberculosis is such
that all tuberculosis patients should be offered HIV screening. Diag-
nosis of dual infection may be difficult since HIV predisposes to atypi-
cal, nodal and extrapulmonary disease. The subject of HIV–tuberculosis
coinfection is explored in depth in Chapter 96 and is not considered
further here.
SPREAD OF INFECTION
Spread of infection is dependent on inhalation of aerosols from indi-
viduals with pulmonary disease. Proximity to and duration of associa-
tion with an index case are critical factors. Approximately 25–60% of
household contacts of an index case may acquire infection although
the extent to which individual genetic predisposition or immunologic
impairment contribute to this is uncertain. Although contributory, the
exact role of factors such as vitamin D deficiency and iron overload in
the spread of tuberculosis is unknown. Development of disease occurs
in up to 10% of infected persons and is significantly affected by
impaired cell-mediated immunity.
Transmission in Closed Institutions
Overcrowding contributes to the spread of tuberculosis. Close proxim-
ity to infected individuals is a significant issue in any closed institution
and for healthcare workers. Many countries have specific guidelines
for tuberculosis control in institutions. In prisons, the situation is
complicated by the fact that inmates have an increased incidence of
HIV, are frequently moved to other prisons or back into the commu-
nity with little warning and may be poorly managed in terms of health
services. Since release of prisoners is often into poor circumstances and
crowded hostels, the consequence of undetected or inadequately
treated tuberculosis may be rapid spread of disease. Mass incarceration
can lead to an increase in cases of tuberculosis and a rise in
271
272 SECTION 2  Syndromes by Body System: The Respiratory System
Estimated tuberculosis incidence rates worldwide in 2012
Figure 31-1  Estimated tuberculosis incidence rates worldwide in 2012. (Reproduced with permission from the World Health Organization, 2013.)
drug-resistant disease.5 An effective public health program with an
active community care component can overcome such problems.
Genetic techniques using restriction fragment length polymor-
phism (RFLP) analysis (often of the insertion sequence IS6110) or
variable number tandem repeat (VNTR) technology which character-
izes the number of tandem repeats in 24 different loci have proven
useful in documenting outbreaks or clustering of tuberculosis. Whole
genome sequencing is likely to overtake all other tools, providing
improved strain differentiation, and revealing greater genetic diversity
than has been previously recognized.
Pathogenesis and Pathology
THE PATHOGEN
Mycobacteria can be divided into two main groups – slow and rapid
growers. Some mycobacteria, including M. tuberculosis complex and
M. leprae are obligate pathogens, while many other species live freely
in the environment (including some that are able to cause disease in
humans, as described in Chapter 32).
M. tuberculosis, discovered by Robert Koch in 1882, is characterized
by a complex and lipid-rich outer cell wall which is responsible for its
slow growth, staining properties and some of its pathogenic features.
Mycobacteria are often termed acid-fast bacilli (AFB), as they retain
the color of arylmethane dyes when treated with diluted acid.
HOST RESPONSE TO M. TUBERCULOSIS
After inhalation of M. tuberculosis droplet nuclei, different scenarios
may follow (see Figure 31-3), reflecting the balance between the
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Estimated new TB
cases (all forms) per
100,000 population
per year
0–9.9
10–19
20–49
50–124
125–299
300–499
≥500
No data
Not applicable
bacillus and host–defense mechanisms.6,7 M. tuberculosis may be
destroyed by alveolar macrophages or neutrophils. If it is not imme-
diately killed, a primary complex consisting of a small infiltrate and
draining lymph nodes develops. Small calcifications may be seen on
radiographic examination, and the PPD (purified protein derivative of
tuberculin) skin test, as a marker of an M. tuberculosis-specific T-cell
response, becomes positive several weeks after infection. In a minority
of cases active disease develops (progressive primary tuberculosis),
either in the lungs or anywhere else after hematogenous dissemination
of M. tuberculosis. In the remainder, infection is stabilized, but may
reactivate months or years later, usually under conditions of failing
immune surveillance.
Innate Host Response to M. tuberculosis
Alveolar macrophages are the first cells to encounter and phagocytose
M. tuberculosis. Phagocytosis and immune recognition by Toll-like
receptors (TLRs) and other pattern recognition receptors (PRRs)8 may
lead to control of mycobacterial growth, either through acidification
of phagolysosomes, oxidative stress from reactive nitrogen intermedi-
ates, activity of antimycobacterial peptides such as cathelicidin,
or autophagy (a process in which cytoplasmatic cargo is targeted
for degradation in specialized structures termed autophagosomes).
Immune recognition induces cytokines and chemokine production
and an inflammatory response, with influx and activation of mono-
cytes and neutrophils. Neutrophils contribute to phagocytosis, myco-
bacterial killing and stimulation of adaptive immunity, but can also
have a detrimental role through induction of a damaging inflamma-
tory response.9

Estimated HIV prevalence in new TB cases worldwide in 2012
Figure 31-2  Estimated HIV prevalence in new tuberculosis cases worldwide in 2012. (Reproduced with permission from the World Health Organization, 2013.)
Second Stage – Adaptive Immunity to Tuberculosis
The HIV epidemic has dramatically demonstrated the importance of
CD4+ T cells for control of mycobacterial growth. CD4+ T cells exert
their protective effect by the production of cytokines, primarily
interferon-gamma (IFN-γ). This T-cell response increases macrophage
activation and is the basis for diagnosis of latent tuberculosis infection
(LTBI) (see under: Diagnosis). There is a considerable delay in the
onset of detectable T-cell responses when compared with other lung
infections, possibly as a result of increased activity of regulatory T cells.
CD8+ T cells also contribute to anti-M. tuberculosis immunity, by
secreting IFN-γ and products that can directly kill the M. tuberculosis
bacilli. M. tuberculosis lipid antigens can also be processed and pre-
sented to unconventional T cells such as γδ T cells and natural killer
(NK) T cells.6,7 It is important to realize that vaccine-induced T-cell
responses correlate poorly with protective immunity, and that natu-
rally acquired T-cell immunity in tuberculosis patients does not
prevent exogenous re-infection with M. tuberculosis. Clearly, our
understanding of the correlates of protection in tuberculosis is
incomplete.
Virulent mycobacteria counter host defense mechanisms through
inhibition of phagolysosomal fusion, and phagosome maturation and
acidification. M. tuberculosis also induces relatively reduced apoptosis
of macrophages and neutrophils, and higher levels of type I interferons
and other cytokines that counter effective host defense.
Granulomas, Hallmark of Tuberculosis
The host response to M. tuberculosis leads to formation of a granu-
loma, composed of a central mass of infected macrophages, stimulated
macrophages that have differentiated into multinucleated giant cells,
epithelioid cells and neutrophils. This accumulation of cells is sur-
rounded by lymphocytes, largely CD4+ T cells, and fibroblasts that
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Chapter 31  Tuberculosis 273
HIV prevalence in
new TB cases,
all ages (%)
0–4
5–19
20–49
≥50
No data
Not applicable
create a peripheral fibrotic capsule (see Figure 31-4). Classic for tuber-
culosis granulomas is the presence of a necrotic caseous core. Granu-
lomas are believed to benefit the host by containing growth and
dissemination of M. tuberculosis, although there are accumulating data
that challenge this dogma.6
TNF-α plays a critical role in maintenance of tissue granulomas, as
was illustrated by the increased rate of reactivation of latent tubercu-
losis in subjects who received anti-TNF therapy for rheumatoid arthri-
tis.10 From animal models and genetic studies it appears also that the
interleukin (IL)-12/IFN-γ axis is needed for effective granuloma for-
mation.7 Granuloma formation is compromised in individuals suffer-
ing from HIV infection or other types of reduced T-cell immunity.
Immunopathogenesis
A strong and prolonged inflammatory response may contribute to
tissue damage and necrosis, such as is found in typical pulmonary
cavities. The host response also leads to the paradoxical worsening of
disease, which can occur during tuberculosis treatment, especially
among HIV-coinfected patients starting antiretroviral treatment.
These immunopathologic reactions are probably caused by restoration
of T-cell responses and have been termed ‘immune reconstitution
inflammatory syndrome’ (IRIS; see also Chapter 95).
Prevention
PUBLIC HEALTH MEASURES
Many countries have a system, often legally enforced, of infectious
patient notification to a central body which traces infected contacts of
index cases. In addition, high-risk patients or communities such as
intravenous drug users may be screened in order to institute definitive
or prophylactic therapy. In its simplest form, case finding involves
274 SECTION 2  Syndromes by Body System: The Respiratory System

Sequence of events after exposure to a patient

with active tuberculosis

Inhalation of
M. tuberculosis

Immediate Primary
killing of MTB complex
(PPD/IGRA neg) (PPD/IGRA pos)

Stabilization Localized disease Dissemination

(latency) (primary TB) of MTB

Acute disease
Stabilization
(meningitis,
(latency)
miliary TB)
a

Reactivation
(post-primary TB)

Figure 31-3  Sequence of events after exposure to a patient with active tuber-
culosis. IGRA = interferon gamma release assay; MTB, Mycobacterium tuberculo-
sis bacillus; neg = negative; PPD, purified protein derivative of tuberculin.

examining sputum smears, although radiologic examination may be a

useful adjunct. However, sputum smear microscopy will miss about
50% of culture-positive patients who are infectious. Routine screening
for latent infection in countries with low rates of infection is appropri-
ate in individuals particularly likely to reactivate disease such as those
who are immunosuppressed, including renal dialysis patients and
those about to receive immunosuppressive therapy.11
Patients with suspected or confirmed pulmonary TB disease should
be isolated until either tuberculosis disease has been ruled out or effec-
tive treatment established. In high-income nations, laminar airflow
and negative-pressure ventilation rooms are used for known or sus-
pected tuberculosis, particularly in patients with multidrug-resistant
(MDR) disease. The use of an efficient personal protective mask is key
but not always available in many tuberculosis endemic parts of the
world. In many instances, basic patient isolation and possibly specified,
ventilated rooms for procedures that generate aerosols is all that is
feasible. Shortwave ultraviolet illuminators to kill organisms in clinics
and shelters are potentially useful. Appropriate control measures
should be defined in advance in high-risk procedure rooms (e.g. bron-
choscopy suites), during patient transport and in all at-risk institu-
tions, which range from healthcare facilities through to shelters for the
homeless.
TESTING FOR EXPOSURE
The Tuberculin Skin Test (TST)
The TST, or Mantoux test, is the commonest test used to screen for
latent tuberculosis infection and depends on the intradermal injection
of a specified quantity of an internationally standardized purified
protein derivative (PPD) of tuberculin. Tuberculin positivity manifests
as induration at the site of testing after 48 hours. Induration less technique. BCG vaccination, especially when given in early
b
Figure 31-4  Granuloma in cynomolgus macaques, a non-human primate, reca-
pitulate the morphology and architecture of lesions seen in human TB. These
lesions can include epithelioid macrophage-dense non-necrotic granulomas (a)
and necrotic granulomas (b) where a mass of caseous necrosis is surrounded by
epithelioid macrophages, foamy macrophages and a T-cell-dense lymphocyte
cuff. (Images courtesy of Dr Joshua Mattila, University of Pittsburgh.)
than 5 mm diameter following a standard injection of 5 units PPD is
regarded as negative and greater than 10 mm diameter as positive.
PPD may have a booster effect on immunologic memory, which can
cause confusion if re-testing occurs after a few months.
In the USA, induration greater than 5 mm is taken as positive in
patients with HIV, a close contact with tuberculosis or a fibrotic chest
radiograph; induration at or above 10 mm is positive in any other
at-risk groups. Patients who are immunosuppressed such as those with
HIV (particularly if the CD4+ T-cell count is below 0.4 x109/L) or who
have viral infections such as measles, have a strong tendency to anergy.
Systemic illnesses, including miliary tuberculosis, are also associated
with anergy. False-negative tests occur at the extremes of age, and fol-
lowing use of inadequately stored tuberculin or due to poor injection

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adolescence as opposed to at birth, may give a positive TST, although
this effect wanes over time. Large indurations are unlikely to be caused
by BCG.
Interferon-Gamma Release Assays
(see also Chapter 185)
There are two main types of IFN-γ release assay (IGRA) in use:
a whole-blood enzyme-linked immunosorbent assay (ELISA)-based
system and an enzyme-linked immunospot (ELISpot)-based detection
of IFN-γ.12 They use the relatively M. tuberculosis-specific RD-1 anti-
gens, early secreted antigen target (ESAT)-6 and culture filtrate protein
(CFP)-10. The main advantages of IGRAs are that they are not affected
by previous BCG vaccination, are not confounded by boosting and do
not require a second visit for reading at 48 hours. They are, however,
relatively expensive compared to the TST.
IGRAs have now been incorporated into national testing guide­
lines for screening and prevention of tuberculosis in a number of
different countries including the USA.11,12 It is generally advised that
they can be used in the same situations where the TST is used. They
may offer some advantages with respect to sensitivity in immunosup-
pressed patients, although both the TST and IGRAs have impaired
performance in these individuals. There is a theoretic advantage in
algorithms that only conduct IGRA testing in those already positive by
TST, although this still requires two clinic visits and can suffer from
combining the suboptimal sensitivity of both tests.13 IGRAs have use
in excluding diagnosis of tuberculosis in children and in the context
of occupational health screening, where the boosting effect places the
TST at a disadvantage. A negative test in a healthy patient helps exclude
M. tuberculosis infection. However, as with other diagnostic tests, the
predictive value depends on the prevalence of M. tuberculosis in the
population that is being tested. There is some evidence that the quan-
titative IGRA test readout reflects M. tuberculosis load, although this
property has not proven to be useful as a treatment efficacy readout.14
CHEMOPROPHYLAXIS
Chemoprophylaxis is an increasingly important component of tuber-
culosis control programs. The combined effect of treatment of disease
and infection is synergistic at the population level.15 Indeed, prophy-
laxis is already recommended for all under-5-year-old contacts of TB
cases in LMICs, once they have been cleared of having TB disease.16
Prophylaxis is practiced most commonly and successfully in tubercu-
losis control programs in higher-income countries. The various
options for treatment regimens are summarized in Table 31-1. Isonia-
zid for 9 months is most commonly used, while shorter alternative
regimens of 3 or 4 months with at least equivalent efficacy, improved
adherence and acceptable side effect profiles are increasingly used.17 A
combination of short-course rifampin and pyrazinamide has unac-
ceptable levels of hepatotoxicity. Chemoprophylaxis is advocated in
HIV-seropositive patients because of the increased incidence of clinical
disease in patients exposed to M. tuberculosis and those in tuberculosis
endemic areas,18 regardless of the results of tests for infection. Chemo-
prophylaxis should also be considered in patients with latent infection
prior to the initiation of TNF inhibitors and all such patients should
be screened. Use of chemoprophylaxis in potential transplant
TABLE
31-1  Possible Regimens for Treating Latent Tuberculosis Infection
Drug Dose Duration
Isoniazid (INH) 300 mg daily or 9 months
900 mg twice weekly
Rifampin 600 mg 4 months
Rifampin + INH 600 mg + 300 mg 3 months
Rifapentin + INH 900 mg + 300 mg 3 months
Rifampin + pyrazinamide No longer recommended because of unacceptable hepatotoxicity
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Chapter 31  Tuberculosis 275
recipients is established. Chemoprophylaxis should be deferred in
pregnant women, a group more prone to isoniazid hepatitis (see also
Practice Point 9).
VACCINES
The live-attenuated BCG vaccine was first used in 1921. Vaccination
leads to a local immune response and scar formation. Adverse reac-
tions other than local irritation are uncommon and anaphylaxis
extremely rare. Adenitis, sometimes suppurative, is the most impor-
tant complication, lupoid reactions, infected osteitis and disseminated
BCG disease are very rare, the latter two necessitating therapy with
rifampin (rifampicin) and isoniazid.
BCG vaccination is more efficacious further from the Equator, and
against tuberculosis meningitis or disseminated tuberculosis in chil-
dren rather than adult pulmonary disease.19 There is a poor correlation
between tuberculin reactivity after vaccination and protection against
disease. There a number of approaches to developing new tuberculosis
vaccines, including genetic modification of BCG and development of
new live attenuated vaccines. The first human efficacy trial of a new
vaccine, based upon M. tuberculosis antigen 85 as a booster to a BCG,
has been disappointing.20
Clinical Features
In this section, the diverse clinical presentations of primary,
pulmonary and miliary tuberculosis are reviewed, together with the
characteristic changes found on radiologic examination. In addition,
the principal extrapulmonary manifestations of tuberculosis are
considered.
PRIMARY AND CHILDHOOD INFECTION
Primary tuberculosis is usually acquired by inhalation of infected par-
ticles. Inhaled bacilli pass into the lung, where damage is usually but
not always confined to one segment with concurrent involvement of
draining, frequently hilar, lymph nodes. This gives rise to the primary
(Ghon) complex. Clinical disease develops in up to 10% of people who
establish an infection with M. tuberculosis. After initial infection, the
only sequela may be scar tissue, which is often calcified and later iden-
tified on routine chest radiography.
Symptomatic patients present with cough with variable amounts of
sputum and hemoptysis together with localized pleuritic chest pain
and dyspnea. In addition, systemic features such as fever, night sweats,
anorexia and weight loss occur. Primary tuberculosis manifests as hilar
adenopathy (often asymmetric) and associated consolidation on chest
radiograph. In children, lymphadenopathy without consolidation is
common. Less typical chest radiographs of primary infection include
those that appear normal or have widespread disease, lobar consolida-
tion and pleural effusions. An unusual complication of primary tuber-
culosis is bronchial obstruction due to pressure of a node on a main
bronchus. This phenomenon, sometimes called epituberculosis, may
lead to secondary bronchiectasis. Untreated primary disease may prog-
ress to involve the entire lung and disseminate, at which stage those
affected may have a continuous cough and sputum production, severe
dyspnea, high fevers, drenching sweats and cachexia. Chest radiograph
Interval Side Effects
Daily or twice weekly Hepatotoxicity, rash, peripheral neuropathy
Daily Hepatotoxicity, leukopenia, thrombocytopenia, drug interactions
Daily Combined
Weekly Hepatotoxicity, hypersensitivity
276 SECTION 2  Syndromes by Body System: The Respiratory System

reveals widespread patchy consolidation with areas of collapse and

cavitation.
Endobronchial tuberculosis is usually a complication of primary
infection although it may occur during reactivation. It may follow
adhesion of inflamed lung parenchyma or lymph nodes to bronchi or
may arise via lymphatic or hematogenous spread of infection and even
from direct seeding of inhaled bacilli. Endobronchial tuberculosis
probably frequently goes undiagnosed. The classic clinical presenta-
tion is with a barking cough and wheeze but onset may be gradual,
mimicking other respiratory diseases ranging from asthma to cancer.
Sputum production may be exacerbated when the mucosa is breached
and caseous material extruded. Parasternal pain, dyspnea, symptoms
due to collapse and consolidation of distal lung tissue and systemic
manifestations of tuberculosis may be found. The most important late
complication of endobronchial infection is bronchiectasis.

PULMONARY INFECTION
Risk Factors for Reactivation
Reactivation of tuberculosis mostly occurs in the absence of any known
risk factors, but is strongly associated with HIV-infection or use of
immunosuppressive medication (e.g. TNF-inhibitors or corticoste-
roids) for autoimmune diseases or organ transplantation, and to a
lesser extent with milder immunosuppressive states such as diabetes,
‘immunosenescence’ in old age, kidney failure, use of inhalation cor-
ticosteroids, malnutrition or vitamin D deficiency. Co-morbid disease
may mimic tuberculosis symptoms, while immunodeficiency or use of
immunosuppressive drugs can mask symptoms and delay diagnosis. Figure 31-5  Typical chest radiograph from a patient with tuberculosis showing
Especially in low-incidence areas or in the absence of typical chest upper lobe shadowing and elevation of hilar lymph nodes. (Courtesy of Prof. Dr
Christoph Lange, University of Lübeck, Germany.)
radiograph findings, other diagnoses should be considered: lung
cancer in elderly (smoking) individuals, lung abscess and infection
with nontuberculous mycobacteria, Burkholderia pseudomallei (in
South East Asia and Australia), Nocardia, Rhodococcus etc.
Clinical Presentation
The classic presentation of reactivation tuberculosis is characterized by
weeks to months of chronic cough; other symptoms include weight
loss (40–75%), fatigue (60–80%), fever (30–60%) and night sweats
(40–60%). Initially, the cough is usually mild and non-productive,
only occurring in the morning as a result of accumulation of secretions
during sleeping, similar to and often confused with a smoker’s cough.
During disease progression the cough may become more continuous
throughout the day and productive of yellow, yellow–green or blood-
streaked sputum. Hemoptysis may be massive from either enlarged
bronchial arteries around tuberculous cavities (Rasmussen’s aneu-
rysms) or more frequently from erosions involving other bronchial or
pulmonary arteries. Dyspnea suggests extensive disease and is a late
symptom. Pleuritic chest pain indicates inflammation in and possibly
infection of adjacent pleura.
Clinical examination may be misleading in the early stages of
disease when radiologically apparent changes of consolidation and
cavitation are hard to detect. Noninfectious complications of tubercu-
losis may be present (see below). Conversely, along with the infre-
quency of dyspnea, a distinguishing feature from other bacterial
pneumonias is the relative lack of auscultatory signs in TB cases, even
in the presence of extensive changes seen on the chest radiograph. A
small minority of patients with rapidly progressive disease present in Figure 31-6  Chest radiograph of a patient with bilateral infiltration and cavities.
acute respiratory failure and may develop the adult respiratory distress (Courtesy of Prof. Dr Christoph Lange, University of Lübeck, Germany.)
syndrome (ARDS).
Chest radiography shows disease localized to apical and posterior
segments of the upper lobes of the lung in more than 85% of cases described, such as more subtle infiltration (Figure 31-7). It can be dif-
with other sites often secondarily affected. The apical segment of the ficult to distinguish early reactivation from chronic healed lesions
lower lobe is also frequently involved. Infiltration and cavitation sec- without follow-up. Computed tomography (CT) scan findings include
ondary to caseous necrosis may be associated with air–fluid levels. On cavitation with scarring as well as characteristic nodules and branching
treatment, most cavities heal completely leaving residual scarring, linear structures, sometimes referred to as a tree-in-bud pattern
often calcific. Tuberculous chest radiographs frequently show bilateral (Figure 31-8).
shadowing with upper zone predominance and fibrotic changes, lobar Laboratory investigations in pulmonary tuberculosis may reveal
atelectasis, elevation of hilar nodes and deviation of the trachea leukocytosis and a monocytosis, but more commonly the leukocyte
(Figures 31-5 and 31-6). A wide range of less common findings are count is normal and, more rarely, it is leukopenic. Anemia, generally

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Figure 31-7  Less typical radiograph: retrocostal infiltrate right upper lobe.
(Courtesy of Prof. Dr Christoph Lange, University of Lübeck, Germany.)
Figure 31-8  CT scan of pulmonary tuberculosis showing tree-in-bud pattern.
(Courtesy of Prof. Dr Christoph Lange, University of Lübeck, Germany.)
normochromic and normocytic, is typical. An acute-phase response is
almost invariably present with moderately elevated C-reactive protein
(CRP) concentrations in plasma, raised erythrocyte sedimentation rate
(ESR) and in more chronic cases, decreased serum albumin. Hypona-
tremia occurs in >10% of patients due to antidiuretic hormone-like
activity (SIADH) although it may be a manifestation of concurrent
extrapulmonary infection. A small number of patients have hypercal-
cemia, probably due to abnormal vitamin D processing or production
of PTH-related peptide by granuloma macrophages.21
Complications
The principal acute complications of pulmonary tuberculosis are
hemoptysis (discussed above) and pneumothorax. Bronchopleural fis-
tulae may heal spontaneously or require tube drainage and, rarely,
surgery. Chronic complications of lung tuberculosis relate to paren-
chymal damage and scarring. Aspergillomas may develop within
healed cavitating lesions; patients typically present with hemoptysis.
Localized bronchiectasis (see Chapter 27) may only become clinically
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Chapter 31  Tuberculosis 277
significant years later and is best defined by high-resolution CT scan-
ning. Tissue destruction may be so great as to cause respiratory failure.
Patients with a history of tuberculosis are also at increased risk of a
second episode of tuberculosis and probably also to infection with
nontuberculous mycobacteria, as a result of reduced pulmonary or
systemic host defense.
PLEURAL TUBERCULOSIS
Pleural tuberculosis classically occurs 6–12 weeks after primary disease
but onset may be delayed and pleuritis may be the first sign of reactiva-
tion. Chest radiograph usually demonstrates a unilateral effusion, with
or without pulmonary involvement. Bilateral effusions occur in
approximately 10% of patients, especially in patients with miliary
tuberculosis. Ultrasound or CT scan may reveal loculated effusions to
aid diagnostic and therapeutic aspirations. Effusions are usually straw-
colored but may be bloodstained and occasionally frankly bloody.
Pleural aspirates typically show elevated protein (>30 g/L), glucose
values below serum glucose concentration, a moderately reduced pH
(~7.3), and a leukocyte count between 0.5 and 5 x109/L with a pre-
dominance of lymphocytes. In the majority of cases, pleural tubercu-
losis develops as a result of an immunologic response to tubercle bacilli
that reach the pleural space from a subpleural granuloma. As a result,
microscopic examination for mycobacteria is rarely (<15%) positive,
and even culture and molecular testing (PCR) of pleural fluid are often
negative. Elevated IFN-γ has a particularly high sensitivity and specific-
ity for diagnosing pleural tuberculosis, while IGRAs on pleural fluid
has no clear added value.22 Two other biochemical tests, pleural fluid
lysozyme and adenosine deaminase (ADA), have also proven useful. A
pleural biopsy may be needed to make a final diagnosis.
Rare cases are caused by a true empyema, in which case frank pus
from a ruptured pulmonary cavity or adjacent parenchymal focus is
found in the pleural compartment, with large numbers of mycobacte-
ria and neutrophils present. Pleural exudates can also be caused by
malignancy (characterized by the presence of malignant cells on cyto-
logic examination), connective tissue diseases like SLE, while especially
in HIV-infected patients there may be a wider differential diagnosis,
including Kaposi’s sarcoma (classically with bloody pleural fluid) and
primary effusion lymphoma (PEL).
MILIARY TUBERCULOSIS
Disseminated or miliary tuberculosis is a severe form of tuberculosis
which results from hematogenous spread of tubercle bacilli which may
occur if they reach the circulation via the lymphatics. In 1700 John
Jacob Manget likened the innumerable tubercles he found in visceral
sites like liver, spleen, bone marrow, brain and lungs, to millet seeds
(miliarius in Latin) and introduced the term miliary tuberculosis.
Nowadays, the term is restricted to disseminated tuberculosis with
miliary shadows on chest radiography (Figure 31-9). It was tradition-
ally thought to occur mostly during progressive primary infection,
especially in young children, but it is also found in reactivation tuber-
culosis and in adults, often in the context of decreased cellular immu-
nity such as in HIV/AIDS, malnutrition, or organ transplantation.
Disseminated infection may also follow BCG when given into the
bladder in patients with bladder cancer.
Patients may present with an acute sepsis-like syndrome with
severe respiratory symptoms, or with a more chronic presentation with
cachexia, fever and and night sweats.23 Hepatomegaly is often present,
and dyspnea, neurologic symptoms, cardiac complaints or signs of
adrenal insufficiency may develop depending on the localization and
burden of granulomas. Widespread macular and papular skin lesions
(tuberculosis miliaris disseminata) are suggestive of miliary infection.
Choroidal tubercles 0.5–3.0 mm in diameter are essentially diagnostic
of miliary disease (Figure 31-10). The chest radiograph of miliary
tuberculosis has well-defined nodules less than 5 mm in diameter
throughout both lung fields (Figure 31-9). Radiographic changes may
only develop after a patient has been admitted to hospital, so patients
must be reassessed frequently. Larger nodules and a pulmonary focus
occur in approximately one-third of patients. CT or magnetic
278 SECTION 2  Syndromes by Body System: The Respiratory System
Figure 31-9  Chest radiograph of miliary tuberculosis, showing characteristic
mottled shadowing throughout both lung fields. (Courtesy of Prof. Dr Christoph
Lange, University of Lübeck, Germany.)
Figure 31-10  Choroidal tuberculosis. Choroidal disease is a manifestation of TB
which is highly suggestive of miliary disease. (With permission from James DG,
Studdy PR. A color atlas of respiratory diseases, 2nd ed. London: Mosby; 1992.)
resonance imaging (MRI) scanning may show smaller nodules not
apparent on radiography. Abdominal ultrasound scanning may show
increased echogenicity and focal lesions in the liver. Laboratory tests
are often abnormal with anemia, thrombocytopenia, leukopenia or
leukocytosis; elevated liver function tests and ESR, low albumin, signs
of SIADH of sterile pyuria. Sputum examination, bronchoscopy and
bone marrow or liver biopsy may help confirm the diagnosis.
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Figure 31-11  MRI scan of cervical tuberculosis with massive paravertebral
abscess which extends through the left C7 to T1 neural exit foramen causing an
extradural collection compressing the spinal cord. (Courtesy of Dr J Jackson,
Imperial College Healthcare NHS Trust, London, UK.)
EXTRAPULMONARY TUBERCULOSIS
This section reviews extrapulmonary tuberculosis not considered in
detail elsewhere and refers readers to other relevant chapters. Up to
40% of all cases of tuberculosis diagnosed in northern Europe and the
USA are extrapulmonary. It is very likely that in resource-poor areas
of the world, where the focus is on diagnosis of people who are poten-
tially infectious, a large amount of extrapulmonary disease goes
undetected.
Lymph Node Disease (see also Chapter 15)
Lymphadenitis is the most common extrapulmonary presentation of
tuberculosis. Mycobacterial lymphadenitis may be casued by M. bovis
in settings where bovine tuberculosis is not well controlled and milk
is not pasteurized, while nontuberculous mycobacteria, especially M.
avium, are the primary cause in countries with low tuberculosis trans-
mission. The most commonly involved nodes are those in the cervical
region (called scrofula in the historical literature), sometimes in asso-
ciation with axillary, inguinal or hilar lymphadenopathy. Patients
usually present with painless lymphadenopathy along the upper border
of the sternocleidomastoid muscle, systemic symptoms are mostly
mild. If left untreated, lymph nodes may liquify, rupture and cause
sinus formation. Diagnosis is made by fine-needle aspiration; incision
biospies should be avoided as they may result in sinus formation.
Isolated mediastinal lymphadenopathy, classically a feature of
primary tuberculosis, is often found in HIV-infected individuals. Mes-
enteric lymphadenitis in the absence of peritoneal or intestinal tuber-
culosis is rare.
Musculoskeletal Infection
Spinal tuberculosis (Pott’s disease) accounts for 50% of tuberculous
osteomyelitis (Figure 31-11). The thoracic spine is most frequently
involved, followed by lumbar and then cervical regions. Presentation

is usually with back or neck pain, and systemic symptoms tend to be
less marked than in pulmonary disease. External pressure on the spinal
cord or penetration of the dura leads to neurologic symptoms like
paraplegia in about a third of cases. Some patients have an associated
flank mass or other evidence of extraspinal tuberculosis. In more
chronic cases, vertebral body collapse and gibbus formation lead to
kyphosis of the spine. Typically, infection begins in the vertebral
metaphysis and erodes into the vertebral end-plate with relative
sparing of the intervertebral disc as seen on plain radiographs. CT or
ideally MRI scanning is needed for proper evaluation of the spinal
cord, and visualization of paraspinal (e.g. psoas) abscesses (Figure
31-11). Diagnosis is confirmed by vertebral biopsy or aspiration of
paraspinal abscess. Neurologic symptoms often disappear with medical
treatment only, but surgery is probably indicated for marked or wors-
ening neurologic deficits, vertebral instability and draining of large
abscesses. Osteomyelitis is otherwise most frequently found in the
metaphyses of long bones, sometimes accompanied by sinus tracts or
soft tissue masses. Diagnosis may be difficult since lesions can appear
osteolytic or sclerotic on radiography and malignancy may be sus-
pected at first.
Tuberculous arthritis most frequently presents in the hips and
other weight-bearing joints although any joint may be involved. Poly-
articular disease occurs in less than 20% of patients but evidence of
tuberculosis elsewhere, generally the lung, is present in about 50% of
cases. Synovial fluid has a high leukocyte count, but microscopy and
culture are often negative. Ideally a synovial biopsy should be exam-
ined histologically and microbiologically. Rare cases of prosthetic joint
infection have been described. Tenosynovitis is rare.
Tuberculous abscesses may form in most soft tissues including
muscle and may be multiple. The classic abscess site is in the psoas
muscle, which can present with or without localizing signs.
Abdominal Infection
In the absence of HIV infection the abdomen is only rarely affected.
Disease is usually secondary to hematogenous spread of mycobacteria
but can be secondary to local invasion or ingestion of organisms. In
the gut, tuberculosis most frequently affects the ileocecal region, then
the small bowel and then the colon; involvement of the duodenum,
stomach and esophagus is extremely rare. Approximately one-third primary disease. Other rare noninfectious manifestations of tubercu-
of patients have evidence of tuberculosis elsewhere, usually in the losis include reactive (poly)arthritis, cutaneous vasculitis, interstitial
lung.
Symptoms reflect the site of involvement but may be nonspecific
with fever, weight loss, chronic abdominal pain, nausea and anorexia.
Ileocecal tuberculosis may present as an acute abdomen secondary to
either obstruction of the bowel lumen or appendix or following bowel
perforation. Any tuberculous lesion, particularly those in the colon,
may present with massive gastrointestinal bleeding but this is rare.
Unusual sites of intra-abdominal tuberculosis include the pancreas
and the adrenal glands, where disease presents very rarely as an adrenal
crisis but more commonly with an insidious onset. Tuberculous peri-
tonitis is an important manifestation of disease and is discussed in
Chapter 41. Tuberculosis of the urogenital tract is specifically explored
in Practice Point 18.
Pericardial Infection (see Chapter 50)
The onset is often insidious although acute pericarditis may occur.
Common symptoms include breathlessness, chest pain and nonspe-
cific changes such as fever and weight loss. Signs of cardiac tamponade
such as raised jugular venous pressure, hepatomegaly, ascites and
edema may be present, and in a minority of cases develops acutely,
requiring urgent pericardiocentesis. ECG may show low voltage or ST
elevation consistent with acute pericarditis. An effusion may be seen
on chest radiography but is better characterized by echocardiography
or CT scanning. Pericardial calcification occurs late and in less than
25% of cases, although data are limited. Diagnosis may be extremely
difficult; failure to identify the organism and to detect granuloma on
biopsy specimens does not rule out infection. Constrictive pericarditis
may develop after active infection has resolved or been treated.
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Chapter 31  Tuberculosis 279
Central Nervous System and Eye Disease
Tuberculous meningoencephalitis and central nervous system tuber-
culomas are extremely important, carrying high morbidity and mor-
tality rates. These topics are considered further in Chapter 19.
Ocular tuberculosis is relatively uncommon but important since, if
overlooked, may result in blindness. The commonest manifestation is
choroidal disease (Figure 31-10) secondary to hematogenous spread
in the context of miliary tuberculosis which may rarely spread to the
retina.
Tuberculosis of the Head and Neck
Aside from cervical node disease, tuberculosis of the head and neck is
relatively uncommon and usually arises secondarily to pulmonary
infection. Laryngeal tuberculosis may present with hoarseness, pain on
speaking or swallowing, hemoptysis and respiratory obstruction.
Cough may reflect lung disease or involvement of the superior laryn-
geal nerve. Untreated, widespread local tissue destruction may occur
with secondary laryngeal stenosis.
Tuberculosis in the oral cavity generally presents as a solitary, often
inflamed ulcer with irregular borders. There may be secondary infec-
tion of salivary glands.
Dermatologic Disease
Dermatologic manifestations of primary and miliary infection are to
be found in Chapter 13.
CLINICAL MANIFESTATIONS IN HIV-POSITIVE
PATIENTS
The clinical manifestations of tuberculosis in HIV-seropositive and
-seronegative patients are often similar and are reviewed in Chapter
96. Initiation of HIV therapy may lead to ‘unmasking’ of tuberculosis,
either pulmonary or extrapulomary, due to a restoration of T-cell
immunity (Chapter 95).
NONINFECTIOUS COMPLICATIONS
Erythema nodosum is the most common noninfectious complication
of primary tuberculosis although it may occur in other granulomatous
diseases (e.g. leprosy, sarcoid). It is particularly associated with
nephritis, retinal vasculitis and hypertrophic pulmonary osteoarthro­
pathy. The syndrome of inappropriate antidiuretic hormone secretion
(SIADH) may lead to hyponatremia. Hypercalcemia may occur as a
result of tuberculous granulomas secreting vitamin D or PTH-like
peptides.21
Diagnosis
CLINICAL APPROACH
The definitive diagnosis of tuberculosis requires identification of the
pathogen in a patient’s secretions or tissues. Empiric therapy is often
initiated before a definitive diagnosis has been made but this should
always be pursued to determine the drug susceptibility of the organism
which guides individual treatment regimens. Sputum microscopy
and culture has a high diagnostic yield, identifies the majority of infec-
tious patients and is cheap to perform. Sputum should be collected on
at least two separate occasions. Although induced sputum obtained in
properly ventilated and isolated areas can be useful, bronchoscopy
with alveolar lavage has the best diagnostic yield. M. tuberculosis
is infrequently seen on aspiration of pleural fluid and cultured in
less than 50% of cases. Pleural biopsy reveals granuloma or results
in culture of the pathogen in more than 90% of cases. Thoracoscopy,
in exceptional circumstances, may be indicated since it allows for
visually guided biopsy of lesions. 2-Fluorodeoxyglucose positron
emission tomography combined with CT (FDG PET–CT) can localize
and grade tuberculosis-associated inflammation. It is expensive and
cannot always distinguish tuberculosis from malignancy, bacterial
infections or other inflammatory processes, but PET–CT may have a
280 SECTION 2  Syndromes by Body System: The Respiratory System

Figure 31-13  Ziehl–Neelsen-stained sputum specimens containing Mycobacte-

a rium tuberculosis. (Courtesy of Dr J van Ingen, Radboud University Medical
Center, Nijmegen, The Netherlands.)

move from the diagnostic trial to full therapy. A diagnostic trial of

therapy should last a minimum of 2–4 weeks.

b cases positive by culture. Culture of the organism with subsequent
Figure 31-12  2-Fluorodeoxyglucose–positron emission tomography (FDG PET)
scan in untreated bilateral pulmonary tuberculosis: (a) three-dimensional rendered
image and (b) transverse image at the level of the carina. (Courtesy of Dr S. Mal-
herbe, Stellenbosch University, South Africa.)
role in diagnosis of extrapulmonary (e.g. spinal) tuberculosis, and
in evaluating extent of pulmonary disease and treatment response
(Figure 31-12).24
In extrapulmonary or miliary infection, appropriate body fluids
and/or tissues must be obtained for microbiologic and histologic
examination, with the aid of ultrasound, CT or MRI scanning if of the most important antituberculous drugs. These drugs are fre-
available. Liver biopsy and bone marrow aspiration are useful investi-
gations in disseminated or occult disease.25 For tuberculous lymphad-
enitis, fine needle aspiration (FNA) is the initial investigation of detail as to mechanisms, dosage regimens and complications are to be
choice since it is easy to perform and has a high specificity and sensitiv-
ity when both microbiologic and cytologic specimens are collected.
FNA does not preclude subsequent lymph node biopsy. In pericardial
tuberculosis, aspiration of pericardial fluid may recover the pathogen
but is frequently nondiagnostic and pericardial biopsy is often
indicated.
Specimens from potentially infected patients are normally analyzed
in local laboratories but drug sensitivity testing and more specialized
facilities are ideally concentrated in centralized laboratories.
If no diagnostic results are forthcoming in patients in whom tuber-
culosis is a possibility, the clinician may reasonably resort to a trial of
therapy. Improvement of symptoms and a decrease in the acute phase
response (monitored by ESR, CRP, etc.) are sufficient indications to
MICROBIOLOGIC DIAGNOSIS
The standard method for staining clinical specimens for M. tuberculo-
sis is that of Ziehl–Neelsen (Figures 31-13 and 31-14). Diagnostic
microscopy is most successful in patients with extensive disease and
cavitation on chest radiography but only diagnoses about 50–70% of
testing for drug sensitivity from clinical specimens is the cornerstone
of diagnosis and ultimate treatment; this is particularly important with
the emergence of drug-resistant TB, as ‘blind’ therapy in the absence
of sensitivity testing may increase the risk of multidrug resistance. The
clinical microbiology and further diagnostic testing for tuberculosis is
reviewed in detail in Chapter 185.
Management
FIRST-LINE ANTIMYCOBACTERIAL DRUGS AND
THEIR TOXICITIES
This and the next section briefly outline the principal characteristics
quently used in fixed-dose regimens in various combination tablets in
order to simplify regimens and improve patient compliance. More
found in Chapter 148.
Isoniazid
Isoniazid (INH) is a bactericidal drug that is well absorbed, minimally
bound to plasma proteins, has a half-life of 1–3 hours depending on
patient acetylator status and is excreted in urine. Concentrations
achieved in most tissues are similar to those in serum.
The most important, potentially fatal side effect of isoniazid is
hepatotoxicity which is more common in patients older than 60 years,
in the presence of coexisting liver disease and possibly in pregnancy
(see Practice Point 9). Asymptomatic, usually transient rises in trans-
aminases occur in about 20% of patients. A greater than threefold
increase in enzyme levels above the normal range is an indication to

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 Chapter 31  Tuberculosis 281

TABLE
31-2  Drug Interactions with Rifampin*
Drug Category Example

Antibacterials Chloramphenicol

Antifungals Fluconazole

Antimalarials Mefloquine

HIV treatment Most anti-HIV drugs, especially protease

inhibitors†

Corticosteroids Prednisolone

Anticoagulants Warfarin

Analgesics Methadone

Immunosuppressive therapy Ciclosporin

Ulcer-healing drugs Cimetidine

Respiratory drugs Theophylline

Cardiac drugs
  Beta-blockers Propranolol
  Calcium-channel blockers Diltiazem
  Cardiac glycosides Digitoxin (only member of class affected)
  Antiarrhythmics Disopyramide
  Lipid-lowering drugs Fluvastatin

CNS drugs
  Antiepileptics Phenytoin
  Anxiolytics Diazepam
  Antidepressants Tricyclic compounds
  Antipsychotics Haloperidol

Figure 31-14  Mycobacterium tuberculosis in sputum detected by auramine Endocrine drugs

staining. (Courtesy of Dr J van Ingen, Radboud University Medical Center, Nijme-
Antidiabetics All antidiabetic drugs except metformin
gen, The Netherlands.)
and insulin

Estrogens and progesterones Combined and progesterone-only

discontinue therapy. In practice, it is often impossible to separate contraceptive pill
isoniazid hepatotoxicity from that due to rifampin or pyrazinamide Thyroid replacement Thyroxine
but interestingly, re-introduction of these drugs singly rather than in
combination usually avoids a second episode of hepatotoxicity. The *These are the principal classes of drugs for which metabolism is increased
other major side effect is a peripheral and rarely optic neuritis due to (plasma concentration decreased) when taken with rifampin (rifampicin). The
examples are not exhaustive and clinicians should check interactions with
interference with niacin metabolism. This is prevented by concomitant related drugs in appropriate formularies.
administration of vitamin B6 (pyridoxine 10 mg daily). †
Discussed separately in Chapter 103.

Rifampin
Rifampin is a bactericidal drug that undergoes first-pass metabolism
in the liver where it is deacylated, excreted into bile and then into ophthalmologist prior to starting treatment but lack of this facility
the gut where there is a minor degree of enterohepatic circulation.
Rifampin is a potent inducer of hepatic enzymes and therefore has
many clinically significant interactions with other drugs (Table 31-2).
Patients should be warned that rifampin turns all body secretions,
including urine and tears, orange. This is a useful side effect in terms
of monitoring compliance.
Pyrazinamide
Pyrazinamide, a structural analog of nicotinamide, is a bactericidal
drug which is well absorbed via the gut and distributed widely includ-
ing in the central nervous system (CNS). Serum half-life is about 10
hours and excretion is urinary.
Hepatotoxicity ranging from elevation of liver transaminases to
frank jaundice and liver failure is the principal side effect of
pyrazinamide.
Ethambutol
Ethambutol is a bactericidal drug that is rapidly and well absorbed in
the gut, with peak serum levels occurring 2 hours after a dose. It is
then rapidly excreted in urine.
The most important complication of ethambutol therapy is retro-
bulbar neuritis manifested by impaired visual acuity, color blindness
and restricted visual fields. Except in patients with pre-existing oph-
thalmic disease, optic neuritis is extremely rare when ethambutol is
used at standard doses (15 mg/kg). Patients can be assessed by an
should not prevent use of ethambutol. Patients should be warned to
report symptoms of visual change immediately and ethambutol should
generally be avoided in children.
Streptomycin
Streptomycin, is an aminoglycoside that has to be given intramuscu-
larly. Resistance mutations arise readily in response to isolated strep-
tomycin therapy and lead to drug resistance. The principal side effects
of aminoglycosides are ototoxicity and nephrotoxicity.
SECOND-LINE DRUGS
Second-line agents are becoming increasingly important with the rise
in drug-resistant organisms. Basic information about such drugs is
provided in Table 31-3 and discussed in detail in Chapter 148. Quino-
lones such as levofloxacin and moxifloxacin are being investigated as
agents that may reduce the duration of therapy required for treatment
of drug-sensitive disease. In a recent randomized controlled trial
(RCT), linezolid, when added to an optimal background regimen
greatly increased treatment success in patients with extensively drug-
resistant (XDR) TB.26 Limitations of linezolid include its cost and
toxicity (myelosuppression and neuropathy). Clofazimine, used in
treatment of M. leprae, is a rediscovered compound, with proven effi-
cacy.27 Other drugs not normally considered as useful treatment for
tuberculosis include meropenem and clavulanic acid.28

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282 SECTION 2  Syndromes by Body System: The Respiratory System

TABLE
31-3  Second-Line Therapy in Tuberculosis (see also text and Chapter 148)
Modification of
Usual Initial Adult Dose Drug Dose in
Drug Mechanism of Action Toxicity (70 kg) Route Renal Impairment
GROUP II
Amikacin Binds 30S ribosome Ototoxicity, nephrotoxicity 7.5 mg/kg q12h* im or iv Yes (TDM)
Capreomycin Binds 30S and 50S 1 g q24h im or iv Yes
ribosomes

Kanamycin Binds 30S ribosome 15 mg q12h* im or iv Yes

GROUP III
Moxifloxacin Inhibits topoisomerase II GI disturbances, tendinitis, 400 mg q24h po or iv No
insomnia, QT prolongation
Levofloxacin Inhibits topoisomerase II GI disturbances, tendinitis, insomnia 500 mg q12h po or iv Yes

GROUP IV
Para-aminosalicylic Competes with Gastrointestinal intolerance, 12 g q24h (divided po or iv No
acid (PAS) mycobacterial hypersensitivity, hypothyroidism, doses)
dihydropteroate crystalluria
synthetase
May decrease
proinflammatory
immune responses
Ethionamide Inhibits cell wall mycolic Gastrointestinal intolerance, 750 mg q24h (or divided po No
(prothionamide) acid synthesis hepatitis, hypersensitivity, in two doses)
convulsions, depression, alopecia

Cycloserine Competitive D-alanine Seizures, psychoses, various CNS 750 mg q24h po Yes
analog effects

GROUP V
Amoxicillin/clavulanic Inhibits cell wall Hypersensitivity (penicillin allergy), 1200 mg q12h po or iv Yes
acid synthesis GI disturbances
Clofazimine Skin discoloration, GI disturbances 100 mg q24h po No

Meropenem Hypersensitivity, neurotoxicity 1000 mg q8/q12h iv Yes

Imipenem 500 mg q8/q12h iv Yes

Linezolid Anemia, thrombocytopenia, 600 mg q24h po or iv No

peripheral neuropathy,
hypersensitivity

NEW COMPOUNDS
Delamanid Blocks mycolic acid QT prolongation 100 mg q12h po No
synthesis
Bedaquiline Inhibits mycobacterial QT prolongation, hepatotoxicity 400 mg q24h po No
ATP synthase

*Peak drug levels should be less than 3 mg/dL (30 mg/L) and trough less than 1 mg/dL (10 mg/L).

Several newly developed agents clearly hold big promise for MDR-
and XDR-TB. Bedaquiline is the first new tuberculosis drug released
in 40 years. It is a diarylquinolone targeting mycobacterial ATP syn-
thase, with promising activity against both drug-sensitive and drug-
resistant tuberculosis. However, concern is still present regarding the
safety of the drug.29 Delamanid, which blocks mycolic acid production,
is another promising compound, improving MDR-TB treatment and
reducing mortality.30
TREATMENT REGIMENS
The aim of multidrug therapeutic regimens is to kill actively growing
and semi-dormant M. tuberculosis bacilli, and prevent the emergence
of drug-resistant mutants. The potent antituberculous drugs isoniazid
and rifampin should be used throughout a 6-month course, with pyra-
zinamide during the first 2 months. As a fourth drug ethambutol is
now routinely added for the first 2 months; streptomycin is a less
acceptable alternative, largely because of its higher resistance rates and
parenteral administration.
The standard treatment protocol is given in Table 31-4. For sensi-
tive organisms, drug therapy in compliant patients is very efficacious,
with cure rates approaching 100%. However, it may be 2 weeks before
clinical improvement becomes apparent, which is important in both
empiric trials of therapy and for appropriate patient expectations.
Radiologic improvement lags further behind and it may take 3–5
months before all that remains is residual scarring seen on the chest
radiograph. Drug therapy must be linked with the public health mea-
sures discussed above.
The standard dose of rifampin (~10 mg/kg) is currently debated.
Higher doses of rifampin are generally well tolerated and not more
toxic. High-dose rifampin significantly lowered mortality in an RCT
in tuberculous meningitis,31 and shorter regimens using high-dose
rifampin are being evaluated for pulmonary TB. For isoniazid, a higher
dose of 10 mg/kg (versus standard 5 mg/kg) has been advocated in
children and in adults who are rapid metabolizers of INH.
The necessary duration of treatment for extrapulmonary tubercu-
losis is debated. Limited trials in osteomyelitis, regarded as a difficult

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 Chapter 31  Tuberculosis 283

TABLE
31-4  Standard Treatment Regimen and Necessary Dose Modifications in Renal Impairment
Drug Adult Dose (Orally) Duration of Treatment Modification of Drug Dose in Renal Impairment

(1) Isoniazid* 5 mg/kg (maximum 300 mg) 6 months No

(2) Rifampin (rifampicin)* 10 mg/kg (maximum 600 mg) 6 months No

(3) Pyrazinamide* 30 mg/kg (maximum 2.0 g) 2 months ↓ dose or ↑ dosage interval

(4) Ethambutol 15 mg/kg †

2 month ↓ dose or ↑ dosage interval

or

Streptomycin 15 mg/kg im (maximum 1.0 g) 2 months ↓↓ dose or ↑↑ dosage interval

*Isoniazid and rifampin (rifampicin) are marketed as a single combination tablet ± pyrazinamide which may facilitate compliance.
†
Some authorities use ethambutol at 25 mg/kg for 2 months only (longer courses should be at 15 mg/kg).

Estimated proportion of multidrug-resistant tuberculosis among newly diagnosed cases worldwide in 2012

Percentage
of cases
0–2.9
3–5.9
6–11.9
12–17.9
≥18
No data
Subnational data only
Not applicable

Figure 31-15  Estimated proportion of multidrug-resistant tuberculosis among newly diagnosed cases worldwide in 2012. Figures are based on the most recent year
for which data have been reported, which varies among countries. (Reproduced with permission from the World Health Organization, 2013.)

site to treat, indicate that 9 months of therapy is effective providing
both isoniazid and rifampin are used. In miliary disease, the 6-month
regimens have been very successful. Intermittent regimens adminis-
tered three times weekly are used, but it is generally recommended to
use daily treatment throughout to reduce the risk of emerging drug
resistance, failure and relapse.32
Treating Multidrug- and Extensively
Drug-Resistant Organisms
Multidrug resistance (MDR) is defined as resistance to at least isonia-
zid and rifampin and has become a major international problem. In
2012, the estimated global burden of MDR-TB was 450 000, including
300 000 incident cases (Figure 31-15). An estimated 10% of MDR-TB
cases are extensively drug-resistant (XDR), defined as also resistant to
second-line injectable drugs and fluorquinolones, and a total of 92
countries had reported at least one XDR-TB case by mid-2013.1
MDR-TB and XDR-TB are the results of mismanagement including
intermittent or interrupted use of TB drugs, errors in prescription,
poor compliance, and low quality of drugs. Failure to detect and initi-
ate timely treatment of MDR-TB increases transmission, often within
health facilities; in some areas between 5 and 10% of primary TB is
MDR-TB. Treatment success of MDR-TB varies between 50% and
80%, and the prognosis of patients with XDR-TB often approaches
that of patients in the pre-antibiotic era.33,34

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284 SECTION 2  Syndromes by Body System: The Respiratory System

Treatment protocols for MDR and XDR disease must be designed
for the individual but the aim is to use as many of the first-line drugs
as possible before adding in second-line drugs. Dependent on resis-
tance testing, the first-line drugs pyrazinamide (PZA) and ethambutol,
WHO group 2 (the ‘injectables’) and group 3 (fluoroquinolones)
should be core drugs (see Table 31-3), with accompanying drugs from
groups 4 and 5 to prevent further resistance formation.35 The newer
compounds delamanid and bedaquilin are both very promising. Treat-
ment duration beyond 18 months, and use of directly observed and
individualized treatment regimens, probably increase treatment
success.33,35
The Use of Steroids (see also Practice Point 8)
Adjunctive steroids have been shown to reduce mortality associated
with tuberculous meningitis, although neurologic disability is proba-
bly not affected. The effect of adjuvant corticosteroids may be depen-
dent on the inflammatory status of the affected meningitis patient;
patient survival in a landmark trial on corticosteroids in Vietnam36 was
associated with a functional single nucleotide polymorphism (SNP) in
the promoter region of the Leukotriene A4 Hydrolase (LTA4H) gene,
which determines the balance between pro-inflammatory leukotriene
B4 (LTB4) and anti-inflammatory lipoxin A4 (LXA4).37 The role of
steroid therapy for pericardial tuberculosis is unclear; a recent large
randomized trial suggested that adjunctive steroids do not reduce the
risk of tamponade or death.38 Steroids may have a role in pleural
disease, and a very mild effect on pulmonary tuberculosis, although
this is generally not recommended.39 Corticosteroids are effective in
treating the immune-reconstitution inflammatory syndrome (IRIS) in
HIV-associated tuberculosis.40 In all cases, steroid metabolism is
increased by rifampin.
PREGNANCY
Tuberculosis treatment during pregnancy should not be deferred. Iso-
niazid, rifampin and ethambutol are not teratogenic but few data exist
on pyrazinamide. Streptomycin is associated with fetal hearing loss
and should be avoided. Little is known about second-line drugs in
pregnancy except para-aminosalicylic acid (PAS), which appears to be
safe. The presence of antituberculous drugs in breast milk is seldom a
problem unless both mother and child are on treatment, in which case
up to 20% more isoniazid than indicated may be received by the child
and bottle-feeding is preferable. Breast-feeding children of mothers
taking isoniazid require pyridoxine supplementation.
SURGERY FOR TUBERCULOSIS
Surgical techniques such as artificial pneumothoraces, phrenic nerve
paralysis, plombage and thoracoplasty, are part of the history of tuber-
culosis before the era of chemotherapy, but have not been evaluated
with randomized trials. Now surgeons are most often involved in
diagnostic rather than therapeutic procedures. Resection of tissue may
be very useful in patients with MDR or XDR tuberculosis and circum-
scribed disease.41 Other indications include massive hemoptysis (after
embolization has failed) and tuberculous empyema and bronchopleu-
ral fistulae. Surgery has been widely used in the treatment of spinal
tuberculosis but is only indicated in the presence of progressive neu-
rologic abnormality and spinal instability and to drain large paraver-
tebral abscesses where CT-guided drainage is not possible. Surgery
may be required following destructive tuberculosis involving weight-
bearing joints, and in nodal tuberculosis if a fluctuant mass persists.
In pericardial disease, a pericardial window removes the need for
repeated drainage. Pericardectomy may be required in constrictive
pericarditis; success rates are probably greater if surgery is performed
before extensive calcification develops.
IMMUNOTHERAPY AND THE FUTURE
Use of new drugs such as delaminid and bedaquiline, or new drug
combinations including higher dose rifampin will lead to more effec-
tive and hopefully shorter treatment regimens. Evaluation of newer
regimens is still hampered by inadequate biomarkers of disease and
treatment response. Increasing understanding of immune and inflam-
matory responses including the processes that drive tissue damage and
development of cavitation may allow the development of novel thera-
pies or treatment vaccines.
References available online at expertconsult.com.

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Chapter 31  Tuberculosis 284.e1
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