SECTION 5
CLINICAL PRESENTATIONS OF TUBERCULOSIS
CHAPTER
29
Pulmonary tuberculosisin adults
Christopher J Hoffmann and Gavin J Churchyard
BACKGROUND
The World Health Organization (WHO) defines pulmonary tuber
culosis (TB) as tuberculous disease that involves the lung paren
chyma. Tuberculosis involving the trachea is often also included in
the definition. Extrapulmonary TB is disease involving any part of
the body other than lung parenchyma including other structures
within the thorax such as the pleura, pericardium and perihilar lymph
nodes. This distinction is most important from a public health per
spective because patients with untreated pulmonary TB pose an
infectious risk to the rest of the community, whereas the risk to the
community from extrapulmonary TB is minimal. Thus patients with
pulmonary TB who also have extrapulmonary involvement are clas
sified as cases of pulmonary TB by the WHO.
In addition to classification by location, TB has traditionally been
classified as primary or postprimary disease. Primary infection
includes the symptoms and complications arising from the first con
tact between host and the bacillus and is most clearly defined by
conversion from a negative to a positive tuberculin skin test (TST).
In the minority, the primary complex results in local progression or
distant disease; in the majority, the complex resolves. Postprimary
TB disease usually follows the primary infection by years, occurring
through reactivation or reinfection. Other nearly synonymous
terms with postprimary TB include reactivation TB, recrudescent
TB, endogenous reinfection and adult type progressive TB. In
years past, primary TB was considered a disease of children and post
primary TB a disease of adults. In the era of human immunodefi
ciency virus (HIV) distinctions between primary and postprimary
TB have become increasingly blurred as primary TB is often seen
in HIV infected adults.
This chapter focuses on the clinical presentation of pulmonary
TB and its complications. The classic presentation of primary and
postprimary pulmonary TB among HIV uninfected adults and
the atypical presentations of pulmonary TB associated with HIV
and other immunosuppressive diseases and drugs are described
along with the differential diagnoses. The impact of active TB
case finding on clinical presentation and its public health impor
tance is also included.
EPIDEMIOLOGY
A basic understanding of the epidemiology of pulmonary TB is
useful for estimating a patient’s or a population’s risk for pulmonary
TB. This is especially important when determining the most likely
aetiologies in building a differential diagnosis. In 2004, an estimated
9 million people had new TB diseases and 2 million deaths were
attributable to TB (see Chapter 3). Most new diseases and deaths
occurred in Asia and Africa, where 80% of all cases of TB occur.
1
Of the 9 million new cases, three quarters were pulmonary TB.
2
Multiple factors have contributed to the surge in TB that began
during the late 1980s and 1990s; immunosuppression from HIV is
the most dramatic. However, the impact of HIV on pulmonary TB
epidemiology is complex.
HIV contributes to pulmonary TB epidemiolog y in fou r impor
tant ways. Firstly, HIV associated immunosuppression increases the
risk of tuberculous disease, either from reactivation or from progression
of primary infection. Approximately 3–5% of adults with intact
immune systems develop TB disease w ithin a year of initial infec
tion; subsequent lifetime risk of reactivation is 3–5%.
3
Among
HIV inf ected individuals, nearly two thirds develop symptomatic
TB disease within the first few months of infection.
4
As a result,
a disproportionate number of HIV infected individuals are diagnosed
with pulmonary TB.
1
Secondly, individuals with HIV are at higher risk than HIV
uninfected individuals for recurrence of pulmonary TB from exog
enous infection.
5
Thus, regions with both high HIV prevalence
and pulmonary TB incidence have a high proportion of the popu
lation highly susceptible to recurrence.
Thirdly, HIV coinfection accelerates progression of pulmonary
TB. As a result, HIV infected individuals typically progress to
death or diagnosis in a shorter time after developing pulmonary
TB than HIV uninfected individuals. Several recent studies have
estimated time to diagnosis by comparing incident pulmonary TB
cases identified in clinics with prevalent pulmonary TB identified
through community wide symptom and sputum screens. The esti
mated duration of pulmonary TB before development of signifi
cant symptoms ranges from 6 to 51 weeks among HIV infected
individuals and from 38 to 60 weeks among HIV uninfected indi
viduals.
6–8
Fourthly, HIV coinfection diminishes the infectiousness of pul
monary TB. Although HIV leads to more rapid progression of
pulmonary TB, the burden of TB bacilli in the lungs is lower
among HIV infected individu als, leading to a lower rate of
sputum smear positivity.
9,10
Among acquired immunodeficiency
syndrome (AIDS) patients with pulmonary TB, approximately
30–40% have smear negative disease compared with 20% smear
negative pulmona ry TB among th ose uninfe cted with H IV.
11
Smear negative pulmonary TB is 10 fold less transmissible than
332
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smear positive disease. Possibly as a result, contacts of HIV
infected people with pulmon ary T B are slightly less likely to
become infected with TB.
12–16
Understanding these differences is important from clinical and
public health standpoints. The implication of a much longer period
of contagiousness of an HIV uninfected person with pulmonary
TB than an HIV infected individual is increased opportunity for
the HIV uninfected individual to transmit infection.
Other conditions that increase the risk of pulmonary TB include
silicosis, diabetes, haemodialysis, malnutrition, smoking, underlying
lung disease, diseases affecting the immune system and immuno
suppressive medications.
17,18
Silicosis increases pulmonary TB risk
three to fivefold.
19
Diabetes mellitus, especially insulin dependent
diabetes, increases the risk of TB approximately two to three
fold.
20
Immunosuppression increases risk based on the therapy
and the dose. Tumour necrosis factor alpha (TNF a) antagonists
such as infliximab and etanercept are most strongly associated with
TB disease. The principal mechanism of active disease among
patients receiving these medications is believed to be from reactiva
tion of latent foci. Because of this risk, TST is recommended prior
to initiation of anti TNF a therapy. Crowded conditions such as
those found in dormitories, nursing homes, prisons, naval vessels
and healthcare centres also increase transmission risk.
21
PATHOPH YSIOLOGY
In order to understand the differences in clinical presentation of
primary and postprimary TB a brief outline of the pathophysiology
of TB infection and disease is required. Tuberculosis bacilli are
aerosolized during coughing, sneezing and singing. Once bacilli
laden nuclei are aerosolized they can remain suspended for hours,
presenting an infection risk long after a person with TB has left
an indoor space. Bacilli degrade rapidly in outdoor environments
because ultraviolet light from sunlight destroys the bacilli. When
inhaled, small droplet nuclei, ranging from 1 to 5 mm in diameter
and containing 1–10 bacilli, enter the lung, avoid being trapped
in the lining of the upper respiratory tract and travel to distal
alveoli. The well aerated regions close to the pleura in the lower
lung fields are the most common place for the bacilli containing
droplets to settle.
22
After lodging in the alveoli, non activated alve
olar macrophages ingest the bacilli in an attempt to destroy them. It
is believed that at least 5–200 bacilli are necessary to overcome the
macrophage response and cause infection. These bacilli then multi
ply within macrophages and establish a focus of primary TB. This
occurs in approximately one third of individuals with robust
immune systems. As the quantity of bacilli increases, inflammation
develops, forming a collection of bacilli, macrophages, lympho
cytes and debris known as the Ghon focus. During early mycobac
terial replication, the burden of bacilli in the Ghon focus is
insufficient to trigger a systemic immune response. As the burden
of bacilli grows, additional activated alveolar macrophages and
T lymphocytes are recruited to this site and a systemic response
is activated. Bacilli are also trafficked from the Ghon focus to the
mediastinal and perihilar lymph nodes either within macrophages
or along lymphatic channels and may become haematogenously
distributed, developing foci of replication in regions with high
oxygen tension: the meninges, epiphyses of long bones, kidneys,
vertebral bones, lymph nodes and apicoposterior areas of the lungs.
At the time that activated macrophages and lymphocytes are
recruited, symptoms may become pronounced and conversion to
a positive TST occurs. For most individuals the systemic immune
response is sufficient to control further growth of bacilli. The orig
inal Ghon focus and associated perihilar lymph node infection
(known as the Ranke complex) are often eradicated within months
of infection, whereas disseminated foci become walled off by gran
ulomatous inflammation, which occasionally harbour viable bacilli.
When the disseminated focus is in the lung apex, the site is known
as Simon’s focus. Simon’s focus is usually the nidus of reactivation
in postprimary pulmonary TB.
SYMPTOMS AND SIGNS
PRIMARY PULMONARY TUBE RCULOSIS
Primary TB infection may be asymptomatic, cause fevers and
pleuritic pain o r, rarely, progress to life threaten ing disease. Dur
ing the primary pulmonary infection, symptoms may occur as the
burden o f bacilli increases and the host mounts a systemic
immune response. Fever is the most common symptom. A study
conducted prior to the HIV pandemic reported fever among 70%
of individuals with p rimary TB, often several weeks after expo
sure, that lasted a median of 2–3 weeks, but much longer among
some patients.
23
The fever onset is usually gradual and is not usu
ally accompa nied by other symptoms, although some patients
develop pleuritic or retrosternal pain. Cough, arthralgias and
fatigue occur rarely. While haematogenous seeding of dist ant sites
is common, rarely does it cause symptomatic disease among indi
viduals with intact immune systems. The most common extrapul
monary manifestations, when they occur, are lymphadenitis and
meningitis.
On examination, a patient with primary pulmonary TB may
have erythema nodosum, bluish red tender subcutaneous nodules
several millimetres to several centimetres in diameter appearing
on the legs, and phlyctenular conjunctivitis, hard raised red 1 to
3 mm nodules accompanied by a zone of hyperaemia located near
the limbus on the bulbar conjunctiva of the eye. Both conditions
are an immune phenomenon seen in primary TB and other
infectious and non infectious diseases and do not contain bacilli.
After the initial inflammation, 90% of individuals with intact
immunity control further replication of the bacilli. The remaining
individuals either develop TB pneumonia with expansion of infil
trates at the site of the initial seeding or near the hilum (Fig. 29.1)
and hilar lymphadenopathy or develop disease at more distant sites,
most commonly cervical lymph nodes, meninges, pericardium or
miliary dissemination. Among individuals with weakened immune
response, including advanced age, HIV, kidney failure and poorly
controlled diabetes mellitus, progression to disseminated or local
disease occurs more frequently.
POSTPRIMARY PULMONARY TUBERCULOSIS
Postprimary pulmonary TB refers to all pulmonary TB resulting
from reactivation of controlled (latent) infection, late progression
of primary infection or exogenous reinfection. The contribution
of any one of these mechanisms to the total number of postprimary
TB cases depends on the local prevalence and the susceptibility of
the individuals in the community to TB. In the past it was believed
that 90% of TB among adults was a result of reactivation.
24
More
recent studies have suggested large population dependent varia
tions in the ratio of reinfection to reactivation.
25
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29Pulmonary tuberculosisin adults
ELSEVIER
Classic presentation of postprimary pulmonary
tuberculosis
The classic presentation of postprimary pulmonary TB is character
ized by weeks to months of chronic cough (chronic usually refer
ring to either > 2 or 3 weeks), weight loss, fatigue, fevers, night
sweats and haemoptysis.
26
Fever in postprimary TB is classically
diurnal with an afebrile period early in the morning and a gradually
rising temperature throughout the day, and a fever peak in the late
afternoon or evening. Nighttime defervescence is often accompa
nied by diaphoresis leading to drenching night sweats. Both fever
and night sweats are more common among patients with advanced
pulmonary TB, often with significant parenchymal disease and cav
itary lesions.
Interestingly, the fraction of individua ls with pulmonary TB
presenting for healthcare with these symptoms has remained
remarkably consistent over multiple decades, continents and clin
ical settings: cough occurs among 70–90%, weight loss among
43–75%, haemoptysis in 21–29%, fatigue or malaise among 58%
and fever among 15–52%.
27–31
However, no single symptom or
constellation of s ymptoms clea rly distinguishes patients who have
pulmonaryTBfromthosewhodonot.
Cough may be absent or subtle early in the disease course. A
mild non productive cough commonly occurs initially in the
morning and may be confused with a ‘smoker’s cough’ by a clini
cian and ignored by the patient. The morning cough is a result of
accumulation of secretions during the sleeping hours (a similar mech
anism to the smoker’s cough). During disease progression, cough
often becomes more continuous throughout the day and may
become productive of yellow or yellow–green and occasionally
blood streaked sputum. Nocturnal coughing is associated with
advanced pulmonary disease, often with cavitations. Pleuritic pain
may occur with coughing. Hoarseness of voice suggests laryngeal
involvement (see below).
Anorexia, wasting and malaise are common features of advanced
disease and may be the only presenting features in some patients,
especially among patients with extrapulmonary TB.
The most salient clinical feature of TB is the chronic nature the
disease can assume. Pulmonary TB may remain undiagnosed and
infectious for 2–3 years, or even longer due to its indolent nature
with symptoms only developing later in the course of the disease.
7
However, as symptoms correlate with extent of disease in patients
with normal immune systems, symptomatic individuals are more
likely to have smear positive sputum.
32
Given the potentially indo
lent nature of the disease, patients with persistent or recurrent
respiratory complaints over months to years should be aggressively
evaluated for pulmonary TB, even if they describe resolution
between episodes of illness, lack classic symptoms and have an
unremarkable physical examination. Even after preliminary nega
tive evaluations, repeat investigation for pulmonary TB is war
ranted if no other diagnosis has been made.
PHYSICAL EXAMINATION
Physical examination of an individual with pulmonary TB is usu
ally non specific. Classic findings are pallor, cachexia, tachycardia
and post tussive crackles over affected lung. Because of the latter
examination finding, it is useful to ask the patient to cough before
auscultation of the lung fields. An additional pulmonary finding in
advanced cases is a cavernous or ‘amphoric’ sound on lung auscul
tation, so named because of a resemblance to the sound made
when blowing across a Greek jug.
ATYPICAL PRESENTATIONS
Culture-negative pulmonary tuberculosis
Some patients present with classic symptoms of pulmonary TB
with chronic and progressive fever, cough and weight loss along
with radiographic findings but do not have Mycobacterium tuberculo
sis identified by sputum direct microscopy or culture. This may be
a result of low mycobacterial burden, suboptimal sputum quality or
improper sputum processing. Among a percentage of such patients,
after extensive evaluation, often including fibreoptic bronchoscopy
with lavage and biopsy and computed tomography of the chest and
abdomen, no aetiology is identified. In some TB treatment pro
grammes over 10% of patients fit this category.
33
These patients
often are preliminarily diagnosed with culture negative TB and
started on standard four drug TB treatment. Failure to respond
clinically after 2 months of treatment places the diagnosis in
question and should prompt a re evaluation of diagnosis and
management; improvement in symptoms helps to confirm the diag
nosis of culture negative TB. Patients with improvement in symp
toms should have treatment completion per local TB guidelines.
HIV
Immunosuppression with advancing AIDS alters the presenting
symptoms of pulmonary TB. Patients with advanced HIV are more
likely to have progression of primary infection to persistent and
often disseminated (miliary) disease and less likely to have typical
symptoms. Fever may be more common among HIV coinfected
patients while cough is less common.
34
Along with a lower pro
portion with cough, more HIV infected individuals are sputum
smear negative. In addition to fever, other non specific symptoms
such as wasting and malaise are more common among individuals
coinfected with HIV and pulmonary TB. AIDS patients with pul
monary TB are more likely to also have extrapulmonary infection:
60% have extrapulmonary sites of infection compared with 28% of
pulmonary TB patients without AIDS.
35
Fig. 29.1 Chest radiograph showing right hilar adenopathy from primary
pulmonary TB. From Mason RJ, Broaddus VC, Murray JF (eds).
Murray & Nadel’s Textbook of Respiratory Medicine, 4th edn.
Philadelphia: WB Saunders, 2005: Figure 31.16.
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Advanced age
The presentation of infectious diseases is often atypical in older
individuals, pulmonary TB included. Most notably older indivi
duals (> 65 years old) are less likely to present with fevers, night
sweats or haemoptysis and are more likely to present with the non
specific findings of dyspnoea and fatigue. Because chronic lung dis
ease is common in older populations, the diagnosis of pulmonary
TB can easily be overlooked in a patient with chronic obstructive
pulmonary disease (COPD) presenting with worsening dyspnoea
and malaise. Furthermore, cavitary disease is less common and mul
tilobar and lower lobe involvement more common.
36
Thus the
presentation of pulmonary TB in the elderly can be similar to that
of COPD or pyogenic bacterial pneumonia. However, the incidence
of pulmonary TB is two to three times higher among the elderly,
especially those in institutions such as old age homes, and the risk
of death considerably higher.
37
Laryngeal tuberculosis
Before the advent of effective chemotherapy for TB, laryngeal TB
was considered a terminal event during the progression of pulmo
nary TB, developing soon before death, and possibly occurring in
over 50% of patients. In the era of effective chemotherapy, laryn
geal TB has become rare (< 1% of TB cases). It can occur in iso
lation or in association with pulmonary TB or extrapulmonary TB.
The true vocal cords, epiglottis and false vocal cords are the most
common sites of involvement. Symptoms almost always include dys
phonia, which is often accompanied by cough, dysphagia, odyno
phagia, stridor and haemoptysis.
38
Findings on laryngoscopy may
be areas of hyperaemia, nodules, ulcerations or exophytic masses.
Recurrent pulmonary tuberculosis
Pulmonary TB should be more strongly suspected among patients
who have been previously treated for TB disease as both relapse
and new infection are more frequent. The specific frequency of
recurrence depends on local disease prevalence and the effective
ness of local TB treatment programmes.
25,39,40
HIV, other immu
nodeficiency states and cavitary pulmonary disease further increase
the risk of recurrent pulmonary TB, commonly due to reinfec
tion.
25,41
Recurrent pulmonary TB may present with classic pul
monary TB symptoms of fever, night sweats, weight loss, malaise
and worsening chronic cough or atypical symptoms. However,
the proportion of patients with recurrent pulmonary TB presenting
with classic versus atypical symptoms has not been well described.
Diagnosis is often complicated because pulmonary fibrosis and cav
itary lesions from previous disease can obscure new infiltrates and
complicate interpretation of chest radiographs.
DIFFERENTIAL DIAGNOSIS
Differential diagnoses for pulmonary TB are listed in Table 29.1.
INVESTIGATIONS
A major reason for misdiagnosis of pulmonary TB is the absence of
typical symptoms or radiographic features.
42,43
Many patients with
pulmonary TB lack fever, night sweats, chronic cough and wasting
or have only one of these symptoms. Thus, in the right clinical
and epidemiological setting, the absence of classic symptoms should
not diminish the vigilance and aggressiveness of evaluation for pul
monary TB. This problem is illustrated by a community wide
cross sectional pulmonary TB prevalence study using sputum culture
and clinical interviews, conducted in an area with very high TB
prevalence.
44
Two or more of cough, night sweats, weight loss
and anorexia were present among only 25% of previously
Table 29.1 Differential diagnoses of tuberculosis
Disease Characteristics
Mycobacterium kansasii Mycobacterium kansasii disease may have a presentation similar to that of TB, especially among individuals with
advanced AIDS (CD4 < 100 mm
3
). A distinction is that M. kansasii is more likely to cause cavitary pulmonary disease
when the CD4 count is very low. M. kansasii disease is uncommon with higher CD4 counts. Chest radiography may be
similar and culture is often needed to distinguish between the two conditions.
75
Lung tumour Upper lobe tumours and pulmonary TB both can be associated with chronic cough, malaise and weight loss and can be
radiographically indistinguishable. Biopsy may be needed to confirm a diagnosis.
Pneumocystis jiroveci
pneumonia (PCP)
Opportunistic infection, which is very common among HIV-infected individuals with CD4 count < 200 mm
3
. Usually
presents with hazy bilateral infiltrates, more rarely with nodules or small cavities.
Nocardia spp. Opportunistic infection of compromised hosts including people with AIDS, immunosuppressive therapy and pulmonary
alveolar proteinosis. Can present with chronic cough, fevers and night sweats. May be associated with central nervous
system abscesses.
Rhodococcus equi Opportunistic infection seen in advanced AIDS. May present with infiltrates, hilar lymphadenopathy or cavitary lesions or
chest radiography. Patients most likely to acquire Rhodococcus infection have CD4 counts < 50 mm
3
.
Kaposi’s sarcoma Common malignancy with advanced AIDS. Cutaneous lesions are often present when pulmonary disease develops.
Radiographic findings are usually bilateral infiltrates spreading from hilum.
Cryptococcus In advanced AIDS (CD4 < 100 mm
3
) this is a common cause of meningitis. It can cause pulmonary infiltrates, nodules or
cavitary disease, especially with advanced AIDS or immunosuppression from glucocorticoids or cancer chemotherapy.
The serum cryptococcal antigen may be negative with localized pulmonary disease.
76
Salmonella Non-typhi species of Salmonella are common causes of bacteraemia with advanced AIDS (CD4 < 100 mm
3
). In rare
cases salmonella pneumonia develops, presenting with infiltrates or cavitary lung lesions.
77
Bacterial pneumonia Bacterial pneumonia can appear on chest radiography similar to pulmonary TB, especially if perihilar infiltrates or apical
cavities are present. Evolution of disease over hours to days is more suggestive of a bacterial pneumonia caused by
Streptococcus pneumoniae, Panton Valentine leucocidin-producing Staphylococcus aureus, Pseudomonas aeruginosa or
Klebsiella pneumoniae.
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29Pulmonary tuberculosisin adults
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undiagnosed pulmonary TB (prevalence cases). However, two or
more of these symptoms were present among 22% of the population
without pulmonary TB. Thus, in that study population, classic
symptoms for pulmonary TB lacked both sensitivity and specificity.
Another African study reported similar findings: 20% of individuals
with pulmonary TB detected on a community survey were
asymptomatic.
45
SPUTUM SMEAR AND CULTURE
The diagnosis of pulmonary TB (especially postprimary disease) is
usually based on sputum examination and, optimally, culture. Thus
quality assurance of collection, handling and processing of sputum is
essential. The first sputum sample should be collected at the time of
evaluation when the diagnosis of TB is considered with, ideally, at
least one more specimen collected early in the morning on subsequent
days. See Chapter 18 for details on sputum smear and culture.
LABORATORY INVESTIGATIONS
Some patients with pulmonary TB are anaemic and have leucocy
tosis. Normochromic, normocytic anaemia occurs most com
monly. Tuberculosis also can cause a leukaemoid reaction with
markedly elevated leucocyte counts (>50,000 cells/mm
3
). How
ever, normal or low leucocyte counts are also consistent with the
diagnosis of pulmonary TB. Mild monocytosis or eosinophilia
may also be observed. The erythrocyte sedimentation rate may
be normal or increased. The platelet count, alkaline phosphatase,
lactate dehydrogenase and ferritin may also be increased; however,
these findings are not sensitive or specific for the diagnosis of pul
monary TB.
28
TUBERCULIN SKIN TESTING
The TST is a test of delayed type, cell mediated hypersensitivity to
purified protein derivative. TST has substantial limitations that
diminish its value in diagnosing pulmonary TB. The TST lacks
sensitivity and specificity. Prior to the emergence of HIV, false
negative TSTs among patients with pulmonary TB were well
recognized and reported to occur in over 2% of patients.
46
Among
patients with immunosuppression (HIV, renal dialysis, malignancy,
immunosuppressive medications), false negative TSTs are much
more common.
47
A positive TST may represent latent TB infec
tion unrelated to illness being evaluated. In addition, exposure to
environmental Mycobacteria spp. and Bacillus Calmette–Gue
´
rin vac
cination can result in a false positive TST.
CHEST RADIOGRAPHY
In primary pulmonary TB, chest radiography is often normal.
When present, typical pathological findings of primary pulmonary
TB are hilar enlargement with or without perihilar infiltrate and
pleural effusions (Figs 29.2 and 29.3).
48
In primary pulmonary
TB 85% of infiltrates are in the mid to lower lung fields.
In postprimary pulmonary TB most patients have abnormalities
on chest radiography, even in the absence of respiratory symp
toms.
27,49
Conversely the chest radiograph may be normal in a
small fraction of symptomatic individuals, especially in the setting
of HIV coinfection. Classic findings in postprimary pulmonary
TB are alveolar infiltrates, interstitial infiltrates or cavitary lesions
in the lung apex or upper zones of the lower lobes (Figs 29.4
and 29.5; Table 29.2). Effusions, lymphadenopathy, lower lung
zone infiltrates and a miliary pattern (diffuse 2 to 3 mm nodules
evenly distributed throughout the lung fields) are atypical
(Fig. 29.6).
Underlying lung diseases such as chronic obstructive pulmonary
disease, silicosis and tumours of the lung can increase the risk for
TB while making radiographic interpretation more difficult.
Immunosuppression further complicates interpreting radiographs,
especially when it is more profound. With HIV, at high CD4
counts, typical findings, including apical cavitary lesions, are
common. HIV infected patients with more advanced immunodefi
ciency (CD4 < 200 cells/mm
3
) very rarely develop cavitary lesions
from pulmonary TB and are much more likely to have the atypical
findings of lymphadenopathy, effusions or mid and lower zone
infiltrates.
50
When a patient with profound immunodeficiency
Fig. 29.2 Chest radiograph showing a Ghon focus with hilar adenopathy
and bilateral infiltrates. From Marx J, Hockberger R, Walls R (eds). Rosen’s
Emergency Medicine: Concepts and Clinical Practice, 6th edn. St Louis:
Mosby, 2006: Figure 133.3.
Fig. 29.3 Primary TB effusion in a 26-year-old adult. Grainger RG,
Allison DJ, Dixon AK (eds). Grainger amd Allison’s Diagnostic Radiology:
A Textbook of Medical Imaging, 4th edn. Edinburgh: Churchill Livingstone,
2001: Figure 18.21.
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develops a cavitary lesion, the differential diagnosis should be
broadened to include additional causative pathogens such as
M. kansasii and Nocardia (Table 29.1).
The limited accuracy of chest radiography is illustrated in a recent
study from Kenya in which sputum culture results were compared
with an experienced radiologist ’s interpretation of a chest radiograph.
In that study, 13% of chest radiographs with no abnormal findings and
27% with findings not considered consistent with TB were from
subjects with positive sputum culture. Of note, approximately half of
subjects in that study who were tested were HIV infected.
51
TRIAL OF ANTIBIOTICS
The administration of empiric antibiotics was previously used in
situations when the sputum smear is negative and a chest radiograph
either is equivocal or cannot be obtained to aid in differentiating
pulmonary TB from bacterial pneumonia and was widely used in
resource constrained settings. With this approach, symptomatic
Fig. 29.4 Left hilar infiltrate in postprimary pulmonary TB. Cohen J,
Powderly W (eds). Cohen & Powderly: Infectious Diseases, 2nd edn. St
Louis: Mosby, 2003: Figure 31.16.
Fig. 29.5 Upper lobe cavitary lesion typical of postprimary pulmonary
TB. Mason RJ, Broaddus VC, Murray JF (eds). Murray & Nadel’s Textbook
of Respiratory Medicine, 4th edn. Philadelphia: WB Saunders, 2005:
Figure 33.17.
Fig. 29.6 Postprimary TB: miliary TB. Diffuse nodulation is present in all
zones. Nodules are approximately 1 mm in diameter and well defined.
Grainger RG, Allison DJ, Dixon AK (eds). Grainger and Allison’s Diagnostic
Radiology: A Textbook of Medical Imaging, 4th edn. Edinburgh: Churchill
Livingstone, 2001: Image 18.
Table 29.2 Chest radiograph findings for patients with
symptomatic pulmonarytuberculosis and approximate
percentage of cases with a given finding based on HIV
status or other immunodeficiency
HIV( )
(%)
HIV(þ)
CD4 >
200 mm
3
(%)
HIV(þ)
CD4 <
200 mm
3
(%)
HIV( )
immuno-
compromised
(%)
Typical
Upper lobe
infiltrates
60 >50 20 10 30
Cavitation 30 66 30 10 20
Atypical
Reticulonodular 2 5 5 10 10 30
Effusion 5 20 10 20 10 30 30
Adenopathy 2 15 5 15 20 30 15
Miliary 2 10 15 18
Normal 0 5 15
From studies of symptomatic patients presenting for
healthcare.
31 50 51 78–80
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29Pulmonary tuberculosisin adults
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patients with a negative sputum smear received a 5 to 10 day course
of antibiotics for bacterial pneumonia (e.g. amoxicillin). Lack of
response to antibiotics suggests a process other than pyogenic bacterial
pneumonia, possibly pulmonary TB. However, response to antibiotics
does not eliminate the possibility of pulmonary TB for two reasons:
1. symptoms of pulmonary TB may wax and wane; and
2. both bacterial pneumonia and pulmonary TB may be present
at the same time.
52
Because of the frequency of coinfection with community acquired
bacterial pathogens and M. tuberculosis, patients should be re evalu
ated for pulmonary TB with repeat sputum examinations and culture
even if they recover while taking empiric antibiotics. Although a
clinical evaluation conducted in Guinea supported using empiric
antibiotics,
53
as 8% of patients who responded to amoxicillin had
pulmonary TB, and 94% of patients who did not respond either
had a positive culture for mycobacterium or responded to TB ther
apy despite a negative sputum culture. This approach is no longer
advised by the WHO. Fluoroquinolones should not be used to treat
presumptive bacterial pneumonia where TB is common because
they have activity against M. tuberculosis and some other mycobacte
rial species, potentially confounding the diagnosis of pulmonary TB
and promoting fluoroquinolone resistant TB.
54,55
ACTIVE CASE FINDING AND SCREENING ALGORITHMS
The WHO directly observed treatment, short course (DOTS)
strategy is reliant on symptomatic individuals self presenting for
healthcare, which is how most cases of pulmonary TB are currently
diagnosed. However, the new Global Plan to Stop TB recom
mends adding active case finding for TB in order to find cases ear
lier and reduce transmission and morbidity and mortality from
TB.
56
Active case finding involves symptom screens and, in some
settings, chest radiography, sputum smear and culture as part of
annual physical examinations, workplace screening, antenatal
clinics and HIV care clinics, and at prison intake and release, school
evaluations, HIV voluntary counselling and testing centres
(VCT) and community TB surveillance programmes. However,
pulmonary TB identified during active case finding activities is
more likely to be asymptomatic or mildly symptomatic, below
the threshold for seeking medical care, and more likely to have
limited radiological disease and to be smear negative. This is true
for both HIV infected and uninfected individuals.
6
Identification
of these cases is also vital to controlling the spread of the disease.
PATHOLOGY
Gross pathology of pulmonary TB ischaracterized byareas ofcaseation
with surrounding fibrosis. As areas of caseation enlarge and empty into
patent bronchi, cavities may form (Fig. 29.7). A smear of contents of a
cavity is typically laden with acid fast M. tuberculosis bacilli.
MANAGEMENT
CHEMOTHERAPY
Three components of management need to be considered when
pulmonary TB is diagnosed:
1. which anti TB chemotherapy regimen is appropriate;
2. how to assure adherence; and
3. how to monitor treatment success.
Please refer to Chapter 62 for details on chemotherapy for TB.
PROGNOSIS
Patients with pulmonary TB who are adherent to therapy to which
the bacilli are sensitive have an excellent chance of cure. Even
patients with other underlying illnesses, such as AIDS, have equal
rates of cure to HIV uninfected individuals.
57
However, such indi
viduals cured of pulmonary TB are at higher risk for recurrence. In
addition, permanent lung injury may occur, leading to decreased
pulmonary function and risk for chronic lung disease.
58
COMPLICATIONS
HAEMOPTYSIS
Haemoptysis usually only occurs with advanced cavitary pulmo
nary disease and is usually mild. The typical presentation is
blood streaked sputum. Massive, sometimes fatal, haemorrhage is
rare. When it occurs it is a result of erosion into a bronchial artery
or rupture of an aneurysm (Rasmussen aneurysm) within the TB
cavity.
59
Haemoptysis may also occur after completion of TB treat
ment due to bronchiectasis, a mycetoma invading and colonizing a
healed cavity or recurrence of TB disease itself. Medical manage
ment is appropriate, even for major or massive haemoptysis, except
in the cases of impending exsanguination which require immediate
surgical care. Initial care includes bed rest, postural management,
volume replacement, cough suppression and intravenous vasopres
sin. When medical management fails (25–50% of patients after 24
hours), options include surgical ligation of arteries, resection of a
lung lobe, endobronchial tamponade and bronchial artery emboli
zation. Both ligation and embolization can be complex because of
the frequent presence of multiple feeder arteries often connecting
systemic with bronchial circulation.
60–62
Careful identification
and ligation or embolization of feeder arteries is required to reduce
the chance of recurrent haemoptysis.
Fig. 29.7 Gross pathology showing lungs with postprimary pulmonary
TB. The upper parts of both lungs are riddled with grey white areas of
caseation and multiple areas of softening and cavitation. Kumar V, Abbas
AK, Fausto N (eds). Robbins and Cotran: Pathologic Basis of Disease, 7th
edn. Philadelphia: WB Saunders, 2004: Figure 8.32.
338
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CLINICAL PRESENTATIONS OF TUBERCULOSIS
ELSEVIER
PNEUMOTHORAX
Pneumothorax is a rare complication of pulmonary TB in the era
of TB therapy. A case series from Turkey reported pneu
mothoraces in 1.5% of cases of pulmonary TB.
31
However, in set
tings with high TB prevalence, pulmonary TB is a leading cause of
secondary pneumothorax.
63
The pneumothorax can be associated
with active or inactive pulmonary TB.
RIGHT MIDDLE LOBE SYNDROME
The rare occurrence of atelectasis of the right middle lobe occurs
when bulky perihilar lymphadenopathy compresses the middle
lobe bronchus, leading to collapse of its feeding lung. Initial
management should focus on therapy for TB. Persistence of
lymphadenopathy or failure of the middle lobe to re expand should
lead to consideration of other or additional diagnoses.
MYCETOMA
Healed pulmonary cavitary lesions can become colonized by Asper
gillus spp., resulting in formation of a mycetoma (aspergilloma).
These are usually asymptomatic and are often incidental findings
on chest radiography, appearing as an ‘air crescent’ sign in a
cavitary lesion (Fig. 29.8). However, scant haemoptysis may be
a harbinger of massive haemoptysis; thus surgical intervention
should be considered if feasible, when cardiopulmonary function
allows.
64
There is little evidence that anti fungal therapies improve
prognosis, although they are often administered peri operatively
when surgical management is pursued. Resection is the only
known effective cure; however, bronchial artery embolization
can be used to treat haemoptysis.
65
IMMUNE RECONSTITUTION INFLAMMATORY
SYNDROME
After initiation of antiretroviral therapy for patients with AIDS, serum
HIV RNA levels decline and CD4 counts rise. As immune function is
restored, antigens from ongoing or past infections can provoke an
inflammatory response, leading to a syndrome known as immune
reconstitution inflammatory syndrome (IRIS). Mycobacterial disease
has been reported to cause at least one third of IRIS cases.
66
The frac
tion attributable to TB is likely much higher in regions with high TB
prevalence. Symptoms of mycobacterium associated IRIS usually
present 4–12 weeks after highly active antiretroviral therapy
(HAART) initiation in patients who have experienced a significant
rise in CD4 count from a low nadir (often <100 cells/mm
3
) and sup
pression of HIV replication
67,68
Symptoms are often systemic, but
may include prominent pulmonary symptoms including pneumonitis
and acute respiratory distress syndrome.
66
In addition to treating TB
disease, corticosteroids may relieve symptoms.
PARADOXICAL REACTION
After weeks or months of clinical and radiological improvement,
some individuals experience a dramatic worsening in clinical status.
When this occurs during treatment of susceptible disease it is known
as a ‘paradoxical reaction’ or ‘paradoxical response’. A paradoxical
reaction involves clinical or radiographic worsening of symptoms
that is sometimes accompanied by fever. It is probably a immunologi
cal phenomenon and is usually characterized by increased cell
mediated response to tuberculin antigens (increased induration with
TST) and may share some immunological similarities with the HIV
associated IRIS. However, the biological mechanisms of the reaction
have not been elucidated. A recent study identified paradoxical
reaction among 16% of 104 patients treated for any TB and 7% of
patients treated for exclusively pulmonary TB. Patients with HIV have
an increased rate of paradoxical reaction.
69
The most common finding
among patients with pulmonary TB is a new or worsening pleural
effusion and the median time to development of the paradoxical
reaction is 56 days, ranging from 20 to 109 days.
70
Before the diag
nosis of paradoxical reaction can be made, other potential causes of
decline, including emergence of drug resistance, should be ruled out.
PREVENTION
The foundation of TB control is identifying individuals with pul
monary TB, ideally through community wide active case finding,
and completing TB therapy so they are no longer infectious. Thus
identifying individuals at highest risk for transmitting TB – sputum
smear positive with chronic cough – is the first priority of TB con
trol programmes. However, smear negative individuals account for
a fifth of transmission.
71
In addition, the large fraction of asymp
tomatic or subclinical disease adds to delays in diagnosis with half
of individuals asymptomatic at the time of screening in some
cross sectional prevalence surveys.
6
Patients with chronic cough (and suspected pulmonary TB)
should be identified and, ideally, isolated. Once patients are diag
nosed and started on treatment, they should avoid crowded places,
ideally staying in their place of residence, until they become spu
tum smear negative. Although patients have a significant initial
reduction in bacilli, 90% by 2 weeks, they may remain sputum
Fig. 29.8 Chest radiograph showing a fungus ball (mycetoma or
aspergilloma) in a preexisting tuberculous cavity. Note the characteristic
crescent of air (arrowheads) over the superior margin of the fungus ball.
Mason RJ, Broaddus VC, Murray JF (eds). Murray & Nadel’s Textbook of
Respiratory Medicine, 4th edn. Philadelphia: WB Saunders, 2005:
Figure 33.15.
339
CHAPTER
29Pulmonary tuberculosisin adults
ELSEVIER
smear positive for 4–6 weeks.
72,73
Furthermore, patients with
drug resistant TB or who are non adherent to therapy may remain
potentially contagious for a longer duration. There is no evidence
that a family member being treated for TB places family members
at high risk for infection. Most family members either were
infected prior to diagnosis of the index case or will not become
infected during this brief period of continued infectivity.
74
Another important method for preventing TB disease is to treat
for latent TB infection (Chapter 77). This reduces the pool of indi
viduals at risk for reactivation and eventual transmission.
CONCLUSION
Lack of sensitivity and accuracy of symptoms and radiological find
ings combined with slow and imperfect investigative tests hamper
the diagnosis and control of TB. Clinicians need to have a high
index of suspicion and investigate early appropriately. In addition,
all contacts with the medical system should be considered opportu
nities for active case finding. Additional diagnostic tools for TB are
also urgently needed.
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29Pulmonary tuberculosisin adults
ELSEVIER
. When
inhaled, small droplet nuclei, ranging from 1 to 5 mm in diameter
and containing 1–10 bacilli, enter the lung, avoid being trapped
in the lining of. may be normal in a
small fraction of symptomatic individuals, especially in the setting
of HIV coinfection. Classic findings in postprimary pulmonary
TB