Wetscherek et al.

Insights into Imaging (2022) 13:3

https://doi.org/10.1186/s13244-021-01138-8 Insights into Imaging

EDUCATIONAL REVIEW Open Access

Active pulmonary tuberculosis: something

old, something new, something borrowed,
something blue
Maria T. A. Wetscherek1,2* , Timothy J. Sadler1, Janice Y. J. Lee1, Sumit Karia1 and Judith L. Babar1

Abstract
Tuberculosis remains a major global health issue affecting all countries and age groups. Radiology plays a crucial
role in the diagnosis and management of pulmonary tuberculosis (PTB). This review aims to improve understand-
ing and diagnostic value of imaging in PTB. We present the old, well-established findings ranging from primary TB to
the common appearances of post-primary TB, including dissemination with tree-in-bud nodularity, haematogenous
dissemination with miliary nodules and lymphatic dissemination. We discuss new concepts in active PTB with special
focus on imaging findings in immunocompromised individuals. We illustrate PTB appearances borrowed from other
diseases in which the signs were initially described: the reversed halo sign, the galaxy sign and the cluster sign. There
are several radiological signs that have been shown to correlate with positive or negative sputum smears, and radiolo-
gists should be aware of these signs as they play an important role in guiding the need for isolation and empirical
anti-tuberculous therapy.
Keywords: Pulmonary tuberculosis, X-ray, Computed tomography, Imaging, Immunocompromised

Key points Background

According to the World Health Organisation (WHO),
• Radiology plays a crucial role in the diagnosis of tuberculosis (TB) remains in the top 10 causes of death
active pulmonary tuberculosis (PTB). worldwide with approximately 10 million cases diag-
• Imaging appearances of PTB depend on immune sta- nosed in 2019. TB is present in all countries and age
tus. groups. Substantial efforts have been made as part of the
• Radiological findings of PTB may mimic other dis- WHO End TB strategy with a resulting 9% decrease in
eases. global incidence between 2015 and 2019. An estimated
• CT findings correlate with sputum smear positivity. 60 million lives have been saved through improved diag-
nosis and treatment since 2000. However, there is con-
cern that the COVID-19 pandemic will reverse the recent
progress in reducing the TB global burden due to TB ser-
vices disruption leading to delayed diagnosis, including
active case finding and contact tracing, as well as treat-
ment interruption [1].
*Correspondence: maria.wetscherek@addenbrookes.nhs.uk
1
Department of Radiology, Addenbrooke’s Hospital, Cambridge University Radiology plays a crucial role in the diagnosis and
Hospitals NHS Foundation Trust, Hills Rd, Cambridge CB2 0QQ, UK monitoring of pulmonary tuberculosis (PTB). In this
2
Department of Pneumology, Iuliu Hatieganu University of Medicine review we aim to update radiologists on four main top-
and Pharmacy, 8 Victor Babeș Street, 400000 Cluj‑Napoca, Romania.
Full list of author information is available at the end of the article ics to improve the understanding and diagnostic value of
imaging in PTB. We will present the old, well-established

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 2 of 13

findings in PTB, the new concepts in active PTB with resistance of the host, and hypersensitivity influence the
special focus on immune status, the borrowed appear- extent of the primary infection [12]. Disease progression
ances from other disease in which the signs were initially can manifest as: local progression (consolidation, cavi-
described, and finally the imaging findings which com- tation), bronchogenic dissemination (centrilobular and
monly correlate with sputum smear positivity. tree-in-bud nodularity), haematogenous dissemination
(miliary nodules) and lymphatic dissemination [13]. Cor-
Something old, something new responding histopathology features of active TB are pre-
Tuberculosis is classified as primary if the onset of clini- sented in Additional file 1: Table S1.
cal disease falls within 1 year of the initial infection with Lower lobe disease, adenopathy, and pleural effusions
Mycobacterium tuberculosis. Post-primary includes reac- are common in children but less common in adults.
tivation if the disease onset is more than 1 year after the These findings therefore became known as atypical dis-
initial exposure [2, 3], and reinfection with a different ease in adults, whilst the upper lobe disease observed
strain (especially in endemic areas) [4, 5]. Primary TB in most adults became known as typical reactivation
is most common in infants and children, with the high- tuberculosis [2]. The term “atypical” might be misleading
est prevalence under 5 years of age [6]. The prevalence because certain patterns are in fact typical for the immu-
of primary TB in adults is increasing, accounting for up nocompromised status [14]. Although most tuberculosis
to 34% of all adult cases of TB [6], particularly in devel- cases in immunocompromised individuals are related to
oped countries [7]. Post-primary TB occurs in patients reactivation of latent tuberculosis, the radiological and
previously sensitised to M. tuberculosis and is considered clinical manifestations more frequently resemble pri-
a disease of adolescence and adulthood. Approximately mary TB [4]. Upper lobe cavitary disease is usually seen
1 in 10 people with primary PTB present clinically. If in infected immunocompetent hosts, whereas immu-
untreated, approximately 1 in 10 cases reactivate, pre- nocompromised patients often present with lower-lung
dominantly in a state of immunodeficiency [8]. disease, adenopathy and effusions [2]. In the paediatric
Primary TB and post-primary TB are thought to be two population of active TB, an upper lobe predominant dis-
distinct entities on the basis of clinical, pathologic and tribution was identified in 36–82% of cases [2, 15] which
imaging findings [6]. Primary TB manifests radiologically was associated with lymphadenopathy in up to 15% of
as four main entities: dense, homogeneous consolidation cases [15]. Imaging appearances of active PTB are inde-
with lower and middle lobes predominance, lymphade- pendent of the time since infection [16, 17] and thus can-
nopathy, miliary disease and pleural effusion [5]. Classical not differentiate primary from post-primary TB [2, 17].
CT findings in post-primary PTB include centrilobular In fact, the advances in molecular epidemiology in the
nodules, “tree-in-bud” sign, consolidation, ground-glass 1990s have led to the discovery that the radiographic
opacities, cavitation, bronchial wall thickening, miliary appearances of TB depends on immune status and there-
nodules, an isolated pulmonary nodule, parenchymal fore the suggested terminology for TB infection is “active
bands and interlobular septal thickening [8, 9]. TB” [2].
The pathophysiology of primary TB has been described Tuberculoma represents a pulmonary nodule and may
by Buzan et al. [10]. The disease is contracted through be the only abnormality seen on chest radiographs in
inhalation of 2–10 μm droplets laden with bacilli from approximately 5% of patients with active TB [6]. Satellite
an infected host. The mycobacteria reach the pulmo- nodules around the tuberculoma, with typically smooth,
nary alveoli preferentially in the best ventilated areas of sharply defined margins, may be present in up to 80% of
the lungs, where they invade and replicate within alveo- cases. When solitary, active tuberculomas may be mis-
lar macrophages. Granulomas develop after a few weeks, taken for malignancy [6] (Fig. 1).
which can later progress to larger tuberculomas. Four to Patchy, poorly defined areas of heterogeneous con-
ten weeks after initial infection, delayed hypersensitivity solidation are among the earliest manifestations of active
manifests leading to a positive tuberculin reaction. Sub- PTB. The distribution is primarily in the apical and pos-
sequently, caseous necrosis develops in the pulmonary terior segments of the upper lobes and less frequent in
focus—known as the Ghon focus—and/or in the involved the apical segments of the lower lobes, with commonly
lymph nodes. The primary focus and the involved lymph more than one pulmonary segment involved [5]. Tuber-
nodes form the primary complex, called the Ranke or culous consolidation can be challenging to distinguish
Ghon complex. Typically the Ghon focus undergoes from bacterial pneumonia in absence of associated find-
healing resulting in a visible scar that may contain foci ings such as lymphadenopathy or cavitation and the lack
of calcification [7, 11], though in some cases it enlarges of response to conventional antibiotics [6]. In their evolu-
as disease progresses. Different factors such as number tion, these regions liquefy and form cavities by draining
and virulence of the mycobacteria, natural and acquired through the tracheobronchial tree [10, 18, 19]. Cavitation
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 3 of 13

Fig. 1 A 37-year-old female had a routine chest radiograph (a) which demonstrated a solitary pulmonary nodule in the left mid zone (arrow). CT
(lung window, axial plane—(b) confirms the presence of a 27 mm nodule in the lingula (arrow) with adjacent tiny satellite nodules (arrowheads)
but no lymphadenopathy. Sputum smears were negative but TB culture from bronchoalveolar lavage was positive for M. Tuberculosis

affects about 50% of patients. The cavities are usually Bronchial stenosis occurs in 10–40% of patients with
multiple and typically have thick, irregular walls, which active tuberculosis [5, 22] and can lead to segmental or
become smooth and thin with successful treatment [10]. lobar atelectasis, lobar hyperinflation, mucoid impaction,
Cavities may demonstrate air-fluid levels which can also and post-obstructive pneumonia [4].
indicate superinfection [5] (Fig. 2), (Additional file 1: Fig. Miliary TB describes haematogenous dissemination,
S1). resulting in randomly distributed nodules which have
Bronchogenic spread manifests as multiple, 2–4 mm uniform size between 1 and 4 mm. They may have a slight
centrilobular nodules and sharply marginated linear lower lobe predominance, often associated with intra-
branching opacities, described as a “tree-in-bud” pat- and interlobular septal thickening [23], and may coalesce
tern [7] (Fig. 3). These have a tendency to coalesce in a to form focal or diffuse consolidation [5]. Chest radiogra-
segmental or lobar distribution, typically involving the phy is usually unremarkable at the onset of symptoms [5]
lower lung zones and the peripheral areas of consolida- and the nodules only become discernible after 4 weeks
tion or cavities [10]. Micronodules are difficult to iden- [8]. CT can reveal miliary disease before it becomes
tify on standard chest radiography [20], therefore CT is radiographically apparent [7]. Miliary TB may be seen in
the imaging technique of choice to reveal early broncho- association with typical parenchymal changes or may be
genic spread [7]. The term “tree-in-bud” was first used to the only pulmonary abnormality [11]. Miliary disease has
describe the characteristic appearance of the endobron- been reported to be associated with both childhood and
chial spread of TB [19], however, it is not pathognomonic immunocompromised adult infections [6, 7, 11] (Fig. 5a),
for active TB [4, 21]. Patchy areas of air trapping are also manifesting within 6 months of initial exposure [5]. This
seen in some patients with tuberculous bronchiolitis [6]. pattern’s diffuse random distribution distinguishes it
Characteristic findings of central airway TB include from the patchy centrilobular distribution of tree-in-bud
irregular circumferential wall thickening with luminal [23]. Other organs with high blood flow, such as the liver,
narrowing. Isolated tracheal disease is rare with most spleen, bone marrow, adrenals and kidneys, are also fre-
patients presenting with distal trachea, carina and proxi- quently affected [6].
mal main stem bronchi involvement [6, 11] (Fig. 4). The Lymphadenopathy is typically unilateral, involving the
coexistence of tracheobronchial disease and lymphad- right hilum and paratracheal region, but can be bilateral
enopathy is high in patients with active pulmonary TB in about one-third of cases. It may represent the only
[6]. In the pathophysiology of tracheobronchial TB, radiographic finding or can be associated with parenchy-
peribronchial lymphatic spread seems more common mal infiltrates on the same side as nodal enlargement,
than endobronchial spread from infected sputum [6]. especially in the subpleural areas [10]. On CT, nodes
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 4 of 13

Fig. 2 An 83-year-old male presented with pyrexia of unknown origin. CT (lung window) demonstrates extensive consolidation in the right
upper lobe (coronal plane—a), bilateral thick-walled cavities (axial planes—b, c, circled) and centrilobular nodules with a tree-in-bud appearance
(arrowheads)

greater than 2 cm in diameter may present with low- showing clusters of micronodules on CT and whose acid-
attenuation centres and peripheral rim enhancement [5, fast bacilli (AFB) smear test and PCR assay were negative,
6] (Fig. 5b). TB lymphadenopathy may be complicated demonstrated peribronchiolar granulomas [26]. Some
by obstructive consolidation, obstructive atelectasis or granulomas were confined to the peribronchiolar inter-
hyperinflation secondary to compression of a bronchus stitium with no caseation necrosis or invasion of the air-
by an adjacent enlarged node, perforation of a lymph way or alveolar space. Subpleural nodules have additional
node into a bronchus, typically at the level of a right lobar clinical significance, especially in young male patients,
bronchus or bronchus intermedius [7, 24], (Fig. 6). because they are thought to be responsible for the devel-
The incidence of lymphatic dissemination may be opment of paradoxical response—an unusual expan-
higher than initially thought [13]. Perilymphatic micro- sion or new formation of a TB lesion within the immune
nodules were detected in up to 58% of active TB cases, reconstitution inflammatory syndrome during TB treat-
with most of the nodules distributed along the broncho- ment [25]. This was described in 26% of patients with
vascular bundles, but also along the interlobular septa pleural TB [25]. Radiologically, lymphatic spread of TB is
and subpleural regions [13, 25]. A recent study failed to more common than bronchogenic spread in the lungs of
detect any evidence of lymphatic spread in the autopsied patients with pleural TB [25].
lungs of nine patients with advanced active PTB and the Pleural effusion may result from breakdown of sub-
authors suggested that “clusters of micronodules” on CT pleural foci and release of their contents into the pleu-
represent aggregated tree-in-bud lesions [19]. However, ral space directly or via pulmonary lymphatics followed
PTB can be a lymphatic disease. Lymphatic spread is a by acute inflammation and exudation caused by delayed
major route of primary TB, and it could also explain the hypersensitivity reaction to tuberculous protein [4, 25].
manifestation of TB resembling sarcoidosis and the nega- However, frank pleural infection and isolation of M.
tive sputum results despite extensive pulmonary lesions tuberculosis from pleural fluid is uncommon. Tubercu-
with micronodules on CT imaging [13, 25], (Fig. 7). Fur- lous empyema is typically loculated and associated with
thermore, lung biopsies in patients with early stage TB pleural thickening and enhancement [4] (Fig. 8).
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 5 of 13

Fig. 3 A 41-year-old male presented with chronic cough, weight loss and fevers. CT (lung window) demonstrates bilateral areas of centrilobular
and tree-in-bud nodules (coronal plane—a, circled; axial plane—c) and consolidation in the right upper lobe (axial plane—b). There are also
cavitating lesions with thick walls (arrow, a)

Known risk factors for development of active disease more likely to develop active tuberculosis compared
include conditions that are associated with defects in to HIV-negative patients [4]. The radiographic appear-
cell-mediated immunity: HIV infection, malignancy, mal- ance of HIV-associated PTB is dependent on the level of
nutrition, prior gastrectomy or jejunoileal bypass, drug immunodeficiency [7, 8, 11, 28] (Fig. 4 and 9). Patients
and alcohol abuse, end-stage renal disease, transplant with AIDS may present with extensive haematogenous
recipients (Additional file 1: Fig. S2), diabetes mellitus, dissemination following primary infection, and thus have
silicosis, corticosteroid or biological agents therapy, such a high risk of developing rapidly progressive primary TB
as tumour necrosis factor α inhibitors for autoimmune during the first year after infection [7]. Because of defi-
disorders [4, 11]. These immunodeficient, high risk cat- cient cell-mediated immunity, they are also prone to
egories can present with mixed type patterns of active reactivation TB. A paradoxical clinical and radiographic
infection including anterobasal infiltrates, miliary nod- worsening related to an increase in the CD4 counts and
ules, hilar/mediastinal lymphadenopathy and exudative a decrease in the viral loads was observed within 60 days
pleuritis, frequently combined with formation of cavities, after the initiation of highly active antiretroviral therapy,
as well as extrathoracic manifestations. This combina- known as immune reconstitution inflammatory syn-
tion of findings may pose diagnostic challenges and delay drome [4, 6] (Fig. 10). Typical imaging findings include
treatment [7, 11]. For example, atypical location of TB in intrathoracic or cervical lymphadenopathy in approxi-
the lower zone can lead to a misdiagnosis of pneumonia, mately 70% of patients, new or increasing areas of consol-
carcinoma, or lung abscess [27]. idation and pleural effusions, as well as intraabdominal
HIV infection is the strongest known risk factor and neurologic manifestations [6].
for developing active tuberculosis, with HIV-positive A pattern of noncavitary consolidation, pleural effusion
patients that have latent TB infection being 20–30 times and lymphadenopathy is most common in patients with
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 6 of 13

Fig. 4 A 35-year-old male presented with a 4-week history of productive cough, anorexia and weight loss. Initial CT demonstrates tracheal and left
main bronchus wall thickening with irregularity suggestive of ulcerations (lung window, coronal plane—a, arrow). There is also a thick-walled cavity
with surrounding nodularity (arrowheads). The appearances significantly improved following TB treatment as demonstrated on a follow-up CT
performed two months later (lung window, coronal plane—b)

Fig. 5 A 44-year-old female presented with symptoms of lethargy, loss of appetite, vomiting and fevers. She had been diagnosed with HIV two
months prior but was not compliant with antiretroviral therapy. Her CD4 count at the time of presentation was 110 cells/mm3. CT demonstrates
miliary nodules (lung window, coronal plane, maximum intensity projection—a) and an enlarged right paratracheal node with central low
attenuation (mediastinal window, coronal plane—b, arrow) consistent with necrosis

primary drug resistance, whereas cavitary disease is com- review article describes an advanced pattern of extensive
mon in patients who acquired multidrug-resistant TB consolidation with or without lymphadenopathy in AIDS
secondary to noncompliance with therapy [10, 29]. One patients with extensively-drug-resistant PTB [12].
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 7 of 13

Fig. 6 A 34-year-old male with Crohn’s disease presented with recurrent pyrexia and raised inflammatory markers. CT demonstrates a 29 mm
subcarinal node with central low attenuation (mediastinal window, axial plane—a, arrow) invading into the right main bronchus (lung window,
coronal plane—b, arrow). There is also right lower lobe consolidation and a small right pleural effusion (lung widow, axial plane—c). CT virtual
bronchoscopy demonstrates the node protruding into the lumen of the right main bronchus (d) with corresponding bronchoscopy image (e). The
patient underwent cryoprobe removal of the lymph node tissue successfully (bronchoscopy image—f)

Fig. 7 A 29-year-old male presented with cough and haemoptysis. CT (lung window, coronal planes—a, b) demonstrates a cluster of tiny nodules
within the apicoposterior segment of the left upper lobe with perilymphatic distribution

Something borrowed—unusual patterns characteristics of TB and may be considered an unusual

Some radiological features of TB may mimic those of appearance of perilymphatic micronodules.
other diseases in which they were initially described. The Fleischner Society defines the reversed-halo sign
These “borrowed” signs do not represent well-known (RHS) as “a focal, rounded area of ground-glass opacity
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 8 of 13

Fig. 8 A 37-year-old male presented with intermittent pyrexia, sweats, rigors, reduced appetite and weight loss. Post-contrast CT shows a moderate
volume left pleural effusion with pleural thickening and enhancement (mediastinal window, axial plane—a, arrowheads). There are also multifocal
areas of perilymphatic nodularity (lung window, axial plane—b) and bilateral paratracheal and mediastinal lymphadenopathy (arrows, a). Pleural
biopsy confirmed the presence of acid-fast bacilli

Fig. 9 A 47-year-old female with a known diagnosis of HIV presented with weight loss, night sweats and worsening dyspnoea. Her CD4 count at
presentation was 120 cells/mm3. CT (lung window) demonstrates thick-walled irregular cavities (coronal plane—a, arrow), extensive bilateral upper
lobe centrilobular and tree-in-bud nodules and nodular reversed halo sign in the apical segment of the right lower lobe (axial plane—c, arrowhead)
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 9 of 13

Fig. 10 A 74-year-old male with HIV and a CD4 count of 10 cells/mm3 was started on antiretroviral therapy. He developed immune reconstitution
inflammatory syndrome with worsening imaging findings in keeping with paradoxical reaction. Compared to the CT from three months prior
(mediastinal window, axial plane—a), there are enlarged centrally necrotic precarinal lymph nodes (mediastinal window, axial plane—b, arrow) and
necrotic nodules in the right upper lobe (arrowheads). These were avid on PET-CT (c)

surrounded by a more or less complete ring of consoli- the time interval for minimal radiologic progression of
dation” seen on CT images [30]. In 1999, Zompatori these lesions was greater than 6 months and their extent
et al. used the term “atoll sign” to describe a similar CT increased with disease progression, frequently accompa-
finding in a case of cryptogenic organising pneumonia nied by a pattern of bronchogenic spread and consolida-
(COP) [31]. COP is the most frequent cause of the RHS, tion [26].
but a wide spectrum of diseases can manifest with this
sign. Recently, the presence of RHS has been described Something blue—patterns associated with positivity
in patients with PTB [32]. Patients with TB present with of AFB smears
a nodular pattern of RHS characterised by the presence Establishing diagnosis and activity of PTB is usually
of micronodules representing granulomas within the wall based on the detection of AFB in sputum smears or cul-
and inside the reversed halo [9, 33] (Fig. 9c and 11a, c). ture [10]. WHO defines definitive sputum smear-positive
This morphological appearance of the ring and ground- active PTB as: 1 sputum smear examination positive for
glass component with presence of small nodules usually AFB, plus a sputum culture positive for M. tuberculosis,
indicates active TB, rather than organising pneumonia or 2 or more initial sputum smear examinations positive
[9] (Fig. 11). A recent study revealed an incidence of nod- for AFB [40]. The lipid-rich mycobacterial cell wall binds
ular RHS of 17% in a cohort of patient with active PTB basic fuchsin dyes, and the staining is acid and alcohol
[34]. The RHS in TB was described mainly in the right resistant; therefore, these mycobacteria are termed AFB.
upper lobe with one or two such lesions being identi- The most commonly used acid-fast staining technique
fied in most of the cases [9, 34]. Furthermore, RHS was is Ziehl–Neelsen. The frequency of transmission from
associated with perilymphatic-predominant nodularity patients with presence of AFB on Ziehl–Neelsen stain is
but not centrilobular-predominant nodularity in another 22% higher than that from patients with negative smear
recent study [13] (Fig. 11a). [20, 41]. The sensitivity of three successive expectorated
The galaxy sign (GS) is a large parenchymal nod- sputum smears for AFB ranges 68–72% in patients with
ule arising from the coalescence of small nodules with culture-positive tuberculosis and is approximately 62% in
many tiny surrounding satellite nodules (Additional HIV-positive patients [4]. Patients with sputum-negative
file 1: Fig. 3). The cluster sign (CS) is also characterised PTB are difficult to diagnose and may be missed at all
by clusters of multiple small nodules but the nodules points of care. There are several radiological signs that
do not tend to coalesce (Fig. 6 and 7a). While initially have been shown to correlate with smear-positive or neg-
defined in sarcoidosis [35, 36], these two signs were also ative samples, and radiologists should be aware of those
described in TB [37, 38]. Heo et al. suggested the term signs as they play an important role in guiding the need
“clusters of small nodules” instead of GS for better cor- for isolation and empirical anti-tuberculous therapy,
relation with pathological morphology [39]. Both GS while awaiting culture confirmation.
and CS seem to be post-primary in immunocompetent There is a significant correlation between radiologic
individuals and were described as associated with peri- extent of disease and the degree of smear positivity. Dif-
lymphatic-predominant nodularity rather than centrilob- ferent CT findings such as cavitation, ground glass opaci-
ular-predominant nodularity [13]. A recent study showed ties (GGO), consolidation, nodules and bronchial lesions
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 10 of 13

Fig. 11 A 37-year-old male with active pulmonary TB presented with a 6-month history of weight loss and night sweats. CT (lung window)
demonstrates nodular reversed halo sign in the right lower and middle lobe (axial plane—a, coronal plane—c), and cavitating lesions in the left
upper lobe (coronal plane—b, circled). Image (d) is of a 25-year-old male with cryptogenic organising pneumonia who presented with cough and
night sweats. CT (lung window, coronal plane) demonstrates multiple areas of rim consolidation reversed halo sign

are significantly associated with smear-positive PTB and that opening and discharging into airways is easier for
increase in AFB smear grade [18, 42]. Multiple of such central cavities than for peripheral cavities, which further
lesions in the upper lobes and multiple lobe involvement explains smear negativity in some patients with periph-
are associated with smear-positive PTB [43, 44]. eral cavities on CT [18]. Cavitation is also associated with
Cavitation represents an independent predictive factor a prolonged time required for smear to turn negative
of smear-positive sputum results [41]. A significant rela- after 2 months of treatment [45].
tionship was reported between mycobacterial load and If consolidation involves multiple segments and lobes,
both volume and number of cavities [45]. The degree of positive AFB-smear results are likely [41, 43]. This is an
smear positivity was further found to be significantly cor- expected finding as caseous necrosis within the consoli-
related with cavity wall thickness and distance from cav- dation containing bacilli can drain through the airways.
ity to nearest airway [18]. The latter results from the fact It was found that consolidation score differs significantly
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 11 of 13

between smear-positive and smear-negative patients, of micronodules-predominant cases. Similarly, RHS was
while GGO score showed significant correlation with the reported in several smear-negative cases of PTB, prob-
degree of smear positivity [18]. ably due to a low rate of coexistent cavitation [9, 34]. The
On the other hand, centrilobular nodules may not be diagnosis of active PTB in these patients is usually based
associated with positive sputum smear results [41], due on culture positivity.
to a smaller affected volume containing less AFB-rich Further findings in smear-negative patients are consoli-
exudation and necrotic material, and a longer distance to dation in less than two lobes, absent cavitation or just in a
the central airway compared to consolidation and cavi- single pulmonary lobe [44], and presence of pleural effu-
tation [38]. This may explain the smear-negative cases sion [43, 49].
presenting with tuberculomas such as the one in Fig. 1. Similarly, in children with active TB there is an associa-
A more recent study showed that the numbers of AFB tion between cavitation, tree-in-bud changes, and upper
present on sputum smears and the frequency of positive lobe infiltrates with smear positivity. Whilst lymphad-
results for AFB in cases with centrilobular predominant enopathy and collapse were found to be associated with a
nodularity were significantly higher than in cases with negative smear [50]. These findings explain the false-neg-
perilymphatic predominant nodularity [13] (Fig. 12). ative sputum in up to 50% of AIDS patients with culture-
Several studies and case reports have demonstrated proven TB [6, 51].
that GS and CS were correlated with smear negative
results [26, 40, 46–48]. Clusters of nodules was found to Conclusion
be a positive predictor of initially smear-negative active We have presented the old, well-established findings in
PTB [40]. Cases with clusters of micronodules as the pulmonary TB, the new concepts in active pulmonary
predominant CT abnormality show significantly less TB with special focus on immune status, the borrowed
sputum smear positivity than those without this CT pre- appearances from other disease which may pose diagnos-
dominant pattern [26]. Moreover, in a subgroup analy- tic challenges, and the imaging findings which commonly
sis which solely included subjects without cavity, AFB correlate with sputum positivity. We hope this review
smear positivity was significantly lower in the clusters will help improve understanding and diagnostic value of

Fig. 12 A 27-year-old male with Crohn’s disease on treatment with infliximab presented with a cough that was not resolving despite antibiotic
therapy. CT demonstrates extensive centrilobular and tree-in-bud nodules with a mid-upper zone predominance (lung window, coronal plane—a).
There are also small volume mediastinal and hilar lymph nodes (mediastinal window, axial plane—b). Ziehl–Neelsen stain was positive for AFB (c)
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 12 of 13

imaging in pulmonary TB and contribute to the continu- Author details

1
Department of Radiology, Addenbrooke’s Hospital, Cambridge University
ous efforts led by WHO within the End TB strategy. Hospitals NHS Foundation Trust, Hills Rd, Cambridge CB2 0QQ, UK. 2 Depart-
ment of Pneumology, Iuliu Hatieganu University of Medicine and Pharmacy, 8
Victor Babeș Street, 400000 Cluj‑Napoca, Romania.
Abbreviations
AFB: Acid-fast bacilli; AIDS: Acquired immunodeficiency syndrome; COP: Cryp- Received: 14 August 2021 Accepted: 1 December 2021
togenic organising pneumonia; CS: Cluster sign; CT: Computed tomography;
GGO: Ground glass opacities; GS: Galaxy sign; HIV: Human immunodeficiency
virus; PCR: Polymerase chain reaction; PTB: Pulmonary tuberculosis; RHS:
Reversed-halo sign; TB: Tuberculosis; WHO: World Health Organisation.
References
Supplementary Information 1. World Health Organization (2020) Global tuberculosis report 2020,
Geneva. Available via https://​apps.​who.​int/​iris/​bitst​ream/​handle/​10665/​
The online version contains supplementary material available at https://​doi.​ 336069/​97892​40013​131-​eng.​pdf Accessed 24 April 2021
org/​10.​1186/​s13244-​021-​01138-8. 2. Rozenshtein A, Hao F, Starc MT, Pearson GDN (2015) Radiographic
appearance of pulmonary tuberculosis: dogma disproved. AJR Am J
Roentgenol 204:974–978. https://​doi.​org/​10.​2214/​AJR.​14.​13483
Additional file 1. Figure 1. A 57-year-old male presented with shortness
3. Marais BJ, Parker SK, Verver S, Warren RM (2009) Primary and postprimary
of breath, fevers, productive cough, haemoptysis, weight loss and night
or reactivation tuberculosis: time to revise confusing terminology? AJR
sweats. CT demonstrates multiple thick-walled cavities within areas of
Am J Roentgenol 192:W198; author reply W199–200. https://​doi.​org/​10.​
consolidation and centrilobular nodules (lung window, coronal plane – a,
2214/​AJR.​08.​1726
c, axial plane - b). There are also enlarged right paratracheal lymph nodes
4. Nachiappan AC, Rahbar K, Shi X (2017) Pulmonary tuberculosis: role
(mediastinal window, axial plane – d, arrow). Figure 2. A 39-year-old male
of radiology in diagnosis and management. Radiographics 37:52–72.
with recent pancreas kidney transplant presented with fatigue, drenching
https://​doi.​org/​10.​1148/​rg.​20171​60032
night sweats and a mild cough. CT shows patchy consolidation in the left
5. Burrill J, Williams CJ, Bain G, Conder G, Hine AL, Misra RR (2007) Tubercu-
upper lobe with a large thick-walled cavity (lung window, coronal plane
losis: a radiologic review. Radiographics 27:1255–1273. https://​doi.​org/​10.​
– a, axial plane - b) and an enlarged left lymph node with central low
1148/​rg.​27506​5176
attenuation in the aortopulmonary window (mediastinal window, axial
6. Restrepo CS, Katre R, Mumbower A (2016) Imaging manifestations of
plane - c). Figure 3. A 26-year-old female with incidental lung changes
thoracic tuberculosis. Radiol Clin North Am 54:453–473. https://​doi.​org/​
on cardiac MRI. CT shows clustering of perilymphatic nodules in the left
10.​1016/j.​rcl.​2015.​12.​007
upper lobe giving rise to the “sarcoid galaxy sign” (lung window, axial
7. Van Dyck P, Vanhoenacker FM, Van den Brande P, De Schepper AM (2003)
plane -a). The coexistence of symmetrical mediastinal and hilar lymphad-
Imaging of pulmonary tuberculosis. Eur Radiol 13:1771–1785. https://​doi.​
enopathy (mediastinal window, axial plane - b) helps in the differentiation
org/​10.​1007/​s00330-​002-​1612-y
of TB and sarcoidosis in the presence of sarcoid galaxy sign. Endobronchial
8. Roy M, Ellis S (2010) Radiological diagnosis and follow-up of pulmonary
lymph node biopsy revealed granulomatous inflammation but no M.
tuberculosis. Postgrad Med J 86:663–674. https://​doi.​org/​10.​1136/​pgmj.​
Tuberculosis was identified on culture or PCR. Table 1. Computed tomog-
2009.​084418
raphy TB findings and underlying histopathology features.
9. Marchiori E, Zanetti G, Irion KL et al (2011) Reversed halo sign in active
pulmonary tuberculosis: criteria for differentiation from cryptogenic
Acknowledgements organizing pneumonia. AJR Am J Roentgenol 197:1324–1327. https://​doi.​
Figure 6 image (e) and (f ) courtesy of Dr Sian Stinchcombe, Respiratory org/​10.​2214/​AJR.​11.​6543
Medicine Department, Cambridge University Hospitals NHS Foundation Trust. 10. Buzan MTA, Coman MM, Duma MM et al (2015) Pulmonary tuberculosis:
Figure 12 image (b) courtesy of Dr Nick Brown, Clinical Microbiology and Pub- something old, something new, something borrowed, something blue.
lic Health Laboratory, Cambridge University Hospitals NHS Foundation Trust. ECR 2015. https://​doi.​org/​10.​1594/​ecr20​15/C-​1999
11. Jeong YJ, Lee KS (2008) Pulmonary tuberculosis: up-to-date imaging and
Authors’ contributions management. AJR Am J Roentgenol 191:834–844. https://​doi.​org/​10.​
Writing—original draft MTAW; Conceptualisation and Data curation: MTAW, 2214/​AJR.​07.​3896
TJS, JYJL, SK, JLB; Writing—review & editing: MTAW, TJS, JLB; Project administra- 12. Perez-Velez CM, Marais BJ (2012) Tuberculosis in children. N Engl J Med
tion: MTAW, Supervision: MTAW, JLB. All authors read and approved the final 367:348–361. https://​doi.​org/​10.​1056/​NEJMr​a1008​049
manuscript. 13. Ko JM, Park HJ, Kim CH (2015) Clinicoradiologic evidence of pulmonary
lymphatic spread in adult patients with tuberculosis. AJR Am J Roent-
Funding genol 204:38–43. https://​doi.​org/​10.​2214/​AJR.​14.​12908
Not applicable. 14. Mathur M, Badhan RK, Kumari S, Gupta S (2017) Radiological Manifes-
tations of Pulmonary Tuberculosis - A Comparative Study between
Availability of data and materials Immunocompromised and Immunocompetent Patients. J Clin Diagn Res
Not applicable. 11:TC06–TC09. DOI: https://​doi.​org/​10.​7860/​JCDR/​2017/​28183.​10535
15. Buzan MT, Pop CM, Raduta M, Eichinger M, Heussel CP (2015) Respira-
tory tuberculosis in children and adolescents: Assessment of radiological
Declarations severity pattern and age-related changes within two decades. Pneumo-
logia 64:8–12
Ethics approval and consent to participate 16. Jones BE, Ryu R, Yang Z et al (1997) Chest radiographic findings in
Not applicable. patients with tuberculosis with recent or remote infection. Am J Respir
Crit Care Med 156:1270–1273. https://​doi.​org/​10.​1164/​ajrccm.​156.4.​
Consent for publication 96091​43
Not applicable. 17. Geng E, Kreiswirth B, Burzynski J, Schluger NW (2005) Clinical and radio-
graphic correlates of primary and reactivation tuberculosis: a molecular
Competing interests epidemiology study. JAMA 293:2740–2745. https://​doi.​org/​10.​1001/​jama.​
The authors declare that they have no competing intersts. 293.​22.​2740
18. Ors F, Deniz O, Bozlar U et al (2007) High-resolution CT findings in
patients with pulmonary tuberculosis: correlation with the degree of
Wetscherek et al. Insights into Imaging (2022) 13:3 Page 13 of 13

smear positivity. J Thorac Imaging 22:154–159. https://​doi.​org/​10.​1097/​ 39. Heo J-N, Choi YW, Jeon SC, Park CK (2005) Pulmonary tuberculosis:
01.​rti.​00002​13590.​29472.​ce another disease showing clusters of small nodules. AJR Am J Roentgenol
19. Im JG, Itoh H, Shim YS et al (1993) Pulmonary tuberculosis: CT findings– 184:639–642. https://​doi.​org/​10.​2214/​ajr.​184.2.​01840​639
early active disease and sequential change with antituberculous therapy. 40. Yeh J-J (2018) Validation of a model for predicting smear-positive active
Radiology 186:653–660. https://​doi.​org/​10.​1148/​radio​logy.​186.3.​84301​69 pulmonary tuberculosis in patients with initial acid-fast bacilli smear-
20. Lee JJ, Chong PY, Lin CB, Hsu AH, Lee CC (2008) High resolution chest CT negative sputum. Eur Radiol 28:243–256. https://​doi.​org/​10.​1007/​
in patients with pulmonary tuberculosis: characteristic findings before s00330-​017-​4959-9
and after antituberculous therapy. Eur J Radiol 67:100–104. https://​doi.​ 41. Yeh JJ, Chen SC-C, Teng W-B et al (2010) Identifying the most infectious
org/​10.​1016/j.​ejrad.​2007.​07.​009 lesions in pulmonary tuberculosis by high-resolution multi-detector
21. Rossi SE, Franquet T, Volpacchio M, Giménez A, Aguilar G (2005) Tree- computed tomography. Eur Radiol 20:2135–2145. https://​doi.​org/​10.​
in-bud pattern at thin-section CT of the lungs: radiologic-pathologic 1007/​s00330-​010-​1796-5
overview. Radiographics 25:789–801. https://​doi.​org/​10.​1148/​rg.​25304​ 42. Ko JM, Park HJ, Kim CH, Song SW (2015) The relation between CT findings
5115 and sputum microbiology studies in active pulmonary tuberculosis. Eur J

Appropriateness Criteria® Imaging of Possible Tuberculosis. J Am Coll

22. Expert Panel on Thoracic Imaging: Ravenel JG, Chung JH et al (2017) ACR Radiol 84:2339–2344. https://​doi.​org/​10.​1016/j.​ejrad.​2015.​07.​032
43. Kim JH, Kim MJ, Ham S-Y (2019) Clinical characteristics and chest com-
Radiol 14:S160–S165. https://​doi.​org/​10.​1016/j.​jacr.​2017.​02.​022 puted tomography findings of smear-positive and smear-negative pul-
23. Andreu J, Cáceres J, Pallisa E, Martinez-Rodriguez M (2004) Radiologi- monary tuberculosis in hospitalized adult patients. Medicine (Baltimore)
cal manifestations of pulmonary tuberculosis. Eur J Radiol 51:139–149. 98:e16921. https://​doi.​org/​10.​1097/​MD.​00000​00000​016921
https://​doi.​org/​10.​1016/j.​ejrad.​2004.​03.​009 44. Matsuoka S, Uchiyama K, Shima H et al (2004) Relationship between CT
24. Lucas S, Andronikou S, Goussard P, Gie R (2012) CT features of lympho- findings of pulmonary tuberculosis and the number of acid-fast bacilli on
bronchial tuberculosis in children, including complications and associ- sputum smears. Clin Imaging 28:119–123. https://​doi.​org/​10.​1016/​S0899-​
ated abnormalities. Pediatr Radiol 42:923–931. https://​doi.​org/​10.​1007/​ 7071(03)​00148-7
s00247-​012-​2399-x 45. Perrin FMR, Woodward N, Phillips PPJ et al (2010) Radiological cavita-
25. Ko JM, Park HJ, Kim CH (2014) Pulmonary changes of pleural TB: up-to- tion, sputum mycobacterial load and treatment response in pulmonary
date CT imaging. Chest 146:1604–1611. https://​doi.​org/​10.​1378/​chest.​ tuberculosis. Int J Tuberc Lung Dis 14:1596–1602
14-​0196 46. Oda M, Saraya T, Shirai T, Ishikawa N, Fujiwara M, Takizawa H (2019) Mul-
26. Hong JH, Yoon SH, Goo JM, Yim JJ, Jeon YK (2020) Clustered micronod- tiple huge “cluster” and “galaxy” signs on chest radiography in a patient
ules as predominant manifestation on CT: A sign of active but indolently with pulmonary tuberculosis. Respirol Case Rep 7:e00398. https://​doi.​org/​
evolving pulmonary tuberculosis. PLoS One 15:e0231537. https://​doi.​org/​ 10.​1002/​rcr2.​398
10.​1371/​journ​al.​pone.​02315​37 47. Nakamoto K, Sasaki Y, Kokuto H, Okumura M, Yoshiyama T, Goto H (2018)
27. Kim J, Lee IJ, Kim JH (2017) CT findings of pulmonary tuberculosis and Multi-drug-resistant tuberculosis with galaxy and cluster signs on high-
tuberculous pleurisy in diabetes mellitus patients. Diagn Interv Radiol resolution computed tomography. Respirol Case Rep 6:e00369. https://​
Ank Turk 23:112–117. https://​doi.​org/​10.​5152/​dir.​2016.​16157 doi.​org/​10.​1002/​rcr2.​369
28. Kim JY, Jeong YJ, Kim K-I et al (2010) Miliary tuberculosis: a comparison of 48. Koide T, Saraya T, Tsukahara Y et al (2016) Clinical significance of the
CT findings in HIV-seropositive and HIV-seronegative patients. Br J Radiol “galaxy sign” in patients with pulmonary sarcoidosis in a Japanese single-
83:206–211. https://​doi.​org/​10.​1259/​bjr/​95169​618 center cohort. Sarcoidosis Vasc Diffuse Lung Dis 33:247–252
29. Kim H-C, Goo JM, Lee HJ et al (2004) Multidrug-resistant tuberculosis ver- 49. Wong K-S, Huang Y-C, Lai S-H, Chiu C-Y, Huang Y-H, Lin T-Y(2010) Validity
sus drug-sensitive tuberculosis in human immunodeficiency virus-neg- of symptoms and radiographic features in predicting positive AFB smears
ative patients: computed tomography features. J Comput Assist Tomogr in adolescents with tuberculosis. Int J Tuberc Lung Dis 14:155–159
28:366–371. https://​doi.​org/​10.​1097/​00004​728-​20040​5000-​00011 50. Hassanzad M, Bolursaz MR, Mehrian P, Aghahosseini F, Velayati AA (2016)
30. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J Relation between smear positivity and imaging findings in children with
(2008) Fleischner Society: glossary of terms for thoracic imaging. Radiol- pulmonary tuberculosis. Int J Mycobacteriology 5(Suppl 1):S163. https://​
ogy 246:697–722. https://​doi.​org/​10.​1148/​radiol.​24620​70712 doi.​org/​10.​1016/j.​ijmyco.​2016.​08.​007
31. Zompatori M, Poletti V, Battista G, Diegoli M (1999) Bronchiolitis obliterans 51. Pepper T, Joseph P, Mwenya C et al (2008) Normal chest radiography in
with organizing pneumonia (BOOP), presenting as a ring-shaped opacity pulmonary tuberculosis: implications for obtaining respiratory specimen
at HRCT (the atoll sign). A case report. Radiol Med 97:308–310 cultures. Int J Tuberc Lung Dis 12:397–403
32. Marchiori E, Grando RD, Simões Dos Santos CE et al (2010) Pulmonary
tuberculosis associated with the reversed halo sign on high-resolution
CT. Br J Radiol 83:e58-60. https://​doi.​org/​10.​1259/​bjr/​22699​201 Publisher’s Note
33. Marchiori E, Zanetti G, Hochhegger B et al (2012) Reversed halo sign Springer Nature remains neutral with regard to jurisdictional claims in pub-
on computed tomography: state-of-the-art review. Lung 190:389–394. lished maps and institutional affiliations.
https://​doi.​org/​10.​1007/​s00408-​012-​9392-x
34. Martini K, Loubet A, Bankier A et al (2020) Nodular reverse halo sign in
active pulmonary tuberculosis: A rare CT feature? Diagn Interv Imaging
101:281–287. https://​doi.​org/​10.​1016/j.​diii.​2020.​01.​013
35. Nakatsu M, Hatabu H, Morikawa K et al (2002) Large coalescent paren-
chymal nodules in pulmonary sarcoidosis: “sarcoid galaxy” sign. AJR Am J
Roentgenol 178:1389–1393. https://​doi.​org/​10.​2214/​ajr.​178.6.​17813​89
36. Herráez Ortega I, Alonso Orcajo N, López González L (2009) The “sarcoid
cluster sign”. A new sign in high resolution chest CT. Radiologia 51:495–
499. https://​doi.​org/​10.​1016/j.​rx.​2009.​05.​003
37. Marchiori E, Zanetti G, Barreto MM, Azeredo de Andrade FT, Rodrigues RS
(2011) Atypical distribution of small nodules on high resolution CT stud-
ies: patterns and differentials. Respir Med 105:1263–1267. https://​doi.​org/​
10.​1016/j.​rmed.​2011.​02.​010
38. Kosaka N, Sakai T, Uematsu H et al (2005) Specific high-resolution
computed tomography findings associated with sputum smear-positive
pulmonary tuberculosis. J Comput Assist Tomogr 29:801–804. https://​doi.​
org/​10.​1097/​01.​rct.​00001​84642.​19421.​a9