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A. Kumar and B. Dhingra
2.9 Osteoarticular TB
Depending on the site involved, it can be divided into three types [7, 8].
2.9.1 Pott’s Spine
This is the commonest among osteoarticular TB, almost 50% of osteoarticular TB
cases. Presenting features are insidious onset back pain (thoracic is the commonest,
followed by lumbar/cervical) for more than 6weeks and/or localised/referred root
pain. Constitutional symptoms of TB (fever/weight loss) may be associated with it.
Examination may be done to look for local tenderness or deformity. In advanced
disease, neurological complications like paraparesis (in 20–50 cases), cauda equina
syndrome or paraspinal muscle wasting may develop. X-ray spine is the rst line of
investigation that may show end plate erosions, joint space narrowing or collapse,
decreased vertebra height, and paravertebral soft tissue shadow. In the early stage,
the X-ray spine may be normal. The next imaging is MRI spine (preferable) and CT
scan (if MRI is not feasible). Imaging ndings may include marrow oedema, bony
destruction (intervertebral disc/adjacent vertebral bodies/opposing end plates),or
abscess in the prevertebral, paravertebral and/or epidural area. In cases of abnormal
chest X-ray, sputum or gastric aspirate (GA) samples is to be sent for NAAT.FNAC
for smear and NAAT are indicated in enlarged peripheral lymph nodes.
2.9.2 TB Dactylitis (Short Bones)
The swelling of the short tubular bones of the hands and feet is known as dactylitis.
The proximal phalanx or metacarpals of the index/middle/ring ngers are commonly affected. Multiple or consecutive bone involvement is common in children,
compared to a single bone in adults. It may present without pyrexia or signs of
inammation. X-ray of involved bones may show a diaphyseal expansile lesion.
Periosteal reaction is uncommon in contrast to pyogenic. Healing is by gradual
sclerosis. X-ray lm of the chest is also indicated to look for pulmonary focus.
Submit sputum or GA for NAAT if CXR is abnormal. FNAC for smear and NAAT
are indicated in enlarged peripheral lymph nodes.
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2.9.3 TB Arthritis
It commonly affects large joints. The hip/knee is the commonest weight-bearing
joint. Insidious onset joint pain and swelling is the presenting feature. TB arthritis is
characteristically mono-articular. Associated pulmonary or lymph node TB should
be looked for. Classical X-ray picture is a triad of peri-articular osteoporosis, peripherally located osseous erosion and gradual joint space narrowing, also known as
Phemister’s triad. In the early stages of synovitis and arthritis, radiographic features
may include joint space widening due to joint effusion. Bony ankylosis is uncommon in tubercular arthritis. USG/MRI of the joint is the next line of investigation.
X-ray lm of the chest is also indicated to look for pulmonary focus. In cases of
abnormal chest X-ray, sputum or GA for NAAT is to be sent. FNAC for smear and
NAAT are indicated in enlarged peripheral lymph nodes.
2.10 Summary ofImaging Findings
See Table2.1.
Table 2.1 Summary of imaging ndings of all forms of tuberculosis [10–17]
Thoracic
Primary TB
Lymphadenopathy Usually unilateral; commonly paratracheal, hilar or subcarinal; usually
Parenchymal
involvement
Miliary TB Pulmonary hematogenous dissemination: 1–4mm granulomata,
Pleural effusion Commonly on the side of the primary pulmonary focus, may be
Post-primary pulmonary TB
Parenchymal
involvement
Airway involvement Airway narrowing with irregular wall thickening; luminal obstruction
>2cm in diameter; can feature “rim-sign”: Enhancing the rim of
granulomatous tissue and a low-attenuation necrotic Centre
Ghon focus: Dense consolidation, preferentially in lower and middle
lobes, may heal with residual calcied granuloma, Ghon focus + hilar
lymphadenopathy=Ghon’s complex
randomly distributed throughout the lungs
complicated by broncho-pleural stula or empyema necessitans, can
result in pleural thickening and calcication, may lead to brothorax
Poorly dened consolidation; predominant in apical and posterior
segments of upper lobes and superior segments of lower lobes;
cavitations are common; endobronchial spread results in “tree-in-bud”
appearance; cavities can progress to TB empyema, broncho-pleural
stula, empyema necessitans and pulmonary arterial pseudoaneurysm
resulting in lobar collapse, hyperination, and/or tree-in-bud
conguration
(continued)
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Table 2.1 (continued)
Pleural effusion Less common than in primary TB; usually small, associated with
Cardiac Pericardial effusion and pericardial constriction
Abdominal
Lymphadenopathy Abdominal LN with central necrosis, conglomerate lymph nodes,
Peritoneal Loculated ascites, mesenteric thickening, caked omentum, multiple
Gastrointestinal Commonest at the ileo-cecal junction, may extend to terminal ileum and
Renal Parenchymal nodules or abscesses, urinary epithelial thickening or
Musculoskeletal
Tuberculous
spondylitis (Pott’s
disease)
Tuberculous arthritis Monoarticular, affecting large weight-bearing joints; imaging ndings:
Tuberculous
dactylitis
Central nervous system
Tuberculous
meningitis
CNS Parenchymal Tuberculomas: May be solitary, multiple or military; CT and MRI:
parenchymal disease
peripheral enhancement; abdominal lymphadenopathy (SAD >15mm)
with other abnormal ndings
spaces occupying lesions in the liver or spleen; peritoneal enhancement
common; brotic type: Omental and mesenteric masses
cecum, concentric thickening of the bowel in CECT
enhancement, urinary strictures, hydronephrosis, may lead to renal
cortical thinning, scarring and calcications
Most common in thoracic spine > lumbar spine; anterior vertebral body
adjacent to the end plate is the usual starting point, followed by an
intervertebral disc; associated paravertebral abscesses are common
Osteopenia, synovitis, soft-tissue swellings, marginal erosions, cartilage
destruction
The proximal phalanx or metacarpals of the index/middle/ring ngers are
commonly affected. Multiple or consecutive bone involvement is
common in children, compared to a single bone in adults. It may present
without pyrexia or signs of inammation. X-ray of involved bones may
show a diaphyseal expansile lesion. Periosteal reaction is uncommon in
contrast to pyogenic. Healing is by gradual sclerosis
Abnormal meningeal enhancement exudates predominantly in basal
cisterns, which may lead to deep infarcts, hydrocephalus, cranial nerve
involvement; spinal meningitis: Subarachnoid space obliteration, matting
of nerve roots, nodular and linear intradural enhancement
Round or lobulated masses with peripheral oedema, ring-like or
homogeneous enhancement, mid-line shift, lipid (cell wall) and lactate
(anaerobic glycolysis) pick in MRS
A. Kumar and B. Dhingra
2.11 Learning Points
1. Tuberculosis infection is not a tubercular disease. One-third of the world’s popu-
lation is infected, but only a few develop active diseases, depending on host
immunity and the virulence of the organism.
2. Transmission of tuberculosis is by droplet infection. Coughers are the most
infectious, especially patients with parenchymal cavitary disease. People with
close contact and immunodecient patients are at higher risk of infection.
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3. Diagnosis of tuberculosis is by identication of the organism. Radiology with
constitutional symptoms is supportive and very useful in diagnosing paucibacillary cases and in children where obtaining sputum is challenging.
4. Proper characterisation of constitutional symptoms results in an increased posi-
tive predictive value of this symptom complex in diagnosing tuberculosis.
5. Identifying tuberculosis-suggestive X-ray ndings is very important in diagnos-
ing smear-negative cases.
6. We are moving towards the upfront universal drug sensitivity testing strategy
(U-DST) to diagnose drug resistance at the beginning of treatment to prevent the
transmission of drug-resistant strains in the community and amplify drug resistance in index cases.
7. Pulmonary tuberculosis without treatment progresses to cause lung destruction
and death, but effective timely diagnosis and appropriate treatment can save
most of these cases with good outcomes.
References
1. Comstock GW, Cauthen GM.In: Reichman LB, Hersheld ES, editors. Tuberculosis. A comprehensive international approach, vol. 66. NewYork: Marcel Dekker; 1993. p.23–48.
2. Mohan AK, Cote TR, Block JA, etal. Tuberculosis following the use of etanercept, a tumour
necrosis factor inhibitor. Clin Infect Dis. 2004;39:295–9.
3. Centres for Disease Control and Prevention. Tuberculosis associated with blocking agents
against tumor necrosis factor- alpha– California, 2002–2003. MMWR Morb Mortal Wkly
Rep. 2004;53:683–6.
4. Keane J, Gershon S, Wise RP, etal. Tuberculosis associated with iniximab, a tumor necrosis
factor alpha-neutralizing agent. N Engl J Med. 2001;345:1098–104.
5. Okur E, Yilmaz A, Saygi A, et al. Patterns of delays in diagnosis amongst patients with
smear-positive pulmonary tuberculosis at a teaching hospital in Turkey. Clin Microbiol Infect.
2006;12:90–2.
6. Ellis SM. The spectrum of tuberculosis and non-tuberculous mycobacterial infection. Eur
Radiol. 2004;14(Suppl. 3):E34–42.
7. Draft updated IAP RNTCP Ped TB guidelines 2019, Central TB division MOHFW, New
Delhi; 21.
8. Sharma SK, Ryan H, Khaparde S, Sachdeva KS, Singh AD, Mohan A, etal. Index-TB guidelines:
guidelines on extrapulmonary tuberculosis for India. Indian J Med Res. 2017;145(4):448–63.
9. World Gastroenterology Organisation (WGO). Practice guideline- digestive tract tuberculosis; 2021.
10. Geng E, Kreiswirth B, Burzynski J, et al. Clinical and radiographic correlates of primary and reactivation tuberculosis: a molecular epidemiology study. J Am Med Assoc.
2005;293:2740–5.
11. Skoura E, Zumla A, Bomanji J.Imaging in tuberculosis. Int J Infect Dis. 2015;32:87–93.
12. Burrill J, Williams CJ, Bain G, Conder G, Hine AL, Misra RR. Tuberculosis: a radiologic
review. RadioGraphics. 2007;27:1255–73.
13. Bhalla AS, Goyal A, Guleria R, Gupta AK.Chest tuberculosis: radiological review and imaging recommendations. Indian J Radiol Imaging. 2015;25:213–25.
14. Bomanji JB, Gupta N, Gulati P, Das CJ.Imaging in tuberculosis. Cold Spring Harb Perspect
Med. 2015;5:a017814.
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15. Van Dyck P, Vanhoenacker FM, Van den Brande P, De Schepper AM.Imaging of pulmonary
tuberculosis. Eur Radiol. 2003;13:1771–85.
16. Nachiappan AC, Rahbar K, Shi X, Guy ES, Barbosa EJM Jr, Shroff GS, et al. Pulmonary
tuberculosis: role of radiology in diagnosis and management. Radiographics. 2017;37:52–72.
17. Jeong YJ, Lee KS. Pulmonary tuberculosis: up-to-date imaging and management. Am J
Roentgenol. 2008;191:834–44.
A. Kumar and B. Dhingra
Chapter 3
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Pathology-Based Diagnosis ofTuberculosis
PrabhakarTiwari, AnjaliYadav, RekhaDwivedi, RekhaChaubey,
DaisyRaniRasaily, ManjariTripathi, SandeepR.Mathur, andRimaDada
Abstract Mycobacterium tuberculosis (Mtb) is a life-threatening infectious patho-
gen that causes tuberculosis (TB). The MTBC complex comprises eight species,
including Mtb, M. cannettii, M. bovis, M. africanum, Bacillus Calmette-Guerin
(BCG), M. caprae, M. microti, and M. pinnipedi. The methods used for TB labora-
tory diagnosis are constantly changing to produce more rapid, sensitive, less expensive, and accurate results. Currently, acid-fast staining remains a fundamental
component of the pathological diagnostic algorithm, enabling morphological diagnosis. Respiratory specimens like sputum, bronchial aspirates, bronchoalveolar
lavage uid (BALF), and biopsy samples are stained and examined under a microscope based on the clinical manifestation of tuberculosis. Mycobacteria staining
dyes include crystal violet, arylmethane dyes, carbolfuchsin dye, and Ziehl-Neelsen
staining. Also, these staining methods generally exhibit high sensitivity and specicity. Immunohistochemistry (IHC), which recognizes released mycobacterial antigens like MPT64 on formalin-xed tissue biopsies, is a technique for making an
etiological diagnosis of TB in a histological specimen. These antigens have been
detected primarily in Mtb and are not typically found in nontuberous mycobacteria.
TB can be differentiated by considering various factors, including endoscopy, clinical manifestations, and pathological examinations. In this chapter, we provide a
brief overview of the numerous diagnostic techniques used to evaluate pathological
and histological differential diagnoses based on pathology-driven examinations.
These techniques utilize a variety of specimens that have been extensively explored
for TB diagnosis thus far. Furthermore, we discuss into the future the prospects and
P. Tiwari (*) · A. Yadav · R. Dada
Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
R. Dwivedi · M. Tripathi
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
R. Chaubey · S. R. Mathur
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
D. R. Rasaily
Department of Pathology, Sikkim Manipal University of Medical Science,
Gangtok, Sikkim, India
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2023
A. Singh, D. Sharma (eds.), Diagnosis of Mycobacterium,
https://doi.org/10.1007/978-981-99-5624-1_3
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signicance of these histopathological techniques, which hold the potential to diagnose TB with increased accuracy and sensitivity.
Keywords Tuberculosis · Pathology · Diagnosis · Mycobacterium tuberculosis
(Mtb) · Microscopy · Staining
P. Tiwari et al.
3.1 Introduction
Mycobacterium tuberculosis (Mtb) is estimated to infect approximately one-third of
the global population. The histological diagnosis of tuberculosis (TB) has been an
important area in the eld of anatomical pathology for an extended period. Currently,
approximately 10–15% of Mtb infections are classied as extrapulmonary TB
(EPTB). The rates are increasing in parallel with the rise in HIV incidence. Globally,
It has been estimated that there were around 4,50,000 incident cases of multidrugresistant tuberculosis (MDR-TB) or rifampicin-resistant TB (RR-TB) in 2021, representing a 3.1% increase from the 4,37,000 cases reported in 2020 [1]. Due to the
limitations of TB diagnosis using staining methods or other approaches, the sensitivity and specicity of different diagnosis techniques vary. Different lab methods
used for the diagnosis of Tuberculosis included Ziel-Neelson staining for mycobacterial assessment, mycobacterial culture, and molecular and serological techniques,
histomorphological analysis emerges as the most feasible and viable tool for the
diagnosis of tuberculosis (TB) [2–4]. Histopathological investigation appears to be
an efcient approach to diagnosing TB for certain individuals in specic cases.
Granulomatous and nongranulomatous reactions like foamy macrophages or mycobacterial spindle cell pseudotumors can be observed in mycobacterial infections,
including TB.The presence of TB bacilli has been conrmed in mycobacterial culture using molecular and serological techniques [5]. ZN staining can be employed
to establish the relationship between tissue reaction and mycobacterial infection as
beaded bacilli are frequently detected in the necrotic zone of tissue specimens. The
ZN stain, with a sensitivity ranging from 0 to 44% for this infection, exhibits a relatively low sensitivity for detecting Mtb. In addition, a diagnosis usually required the
presence of at least ~104 bacilli per slide [6, 7]. Furthermore, this stain has limited
diagnostic relevance and is inadequate for the pathological evaluation of Mtb antigens in the tissue due to its mechanism and relatively low sensitivity and specicity,
as mentioned earlier. Therefore, current approaches such as immunohistochemistry
(IHC) are well-established methods for detecting mycobacterial antigens and have
found particular use in research initiatives. This method relies on the generation of
various polyclonal and monoclonal antibodies in response to tissue antigens. It has
been shown that this approach can detect mycobacterial antigens with a sensitivity
range of 64–100%. The positive tissue staining technique for Mtb has been examined in only a limited number of research studies [8]. While recent textbooks do not
offer a standardized approach for morphological evaluation concerning the IHC
staining or ZN staining of granulomatous reactions, pathology reference books only
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provide brief discussions on these procedures. Recent studies on the variable morphology of tuberculosis bacteria emphasize the signicance of differentiating various morphological attributions associated with TB antigens in tissue using different
staining techniques. Considering the limitations and available tools, in this chapter,
we discuss the details of pathological tissue staining methods and their microscopic
examinations, immunohistochemistry (IHC), and microbial culturing approaches.
Also, we discuss the clinical manifestations of tuberculosis in the pulmonary and
extrapulmonary regions. Subsequently, we delve into the differential diagnosis of
tuberculosis and the scope of these approaches for future investigations.
3.2 Histopathological Techniques fortheDiagnosis ofTB
Mtb has the ability to mimic numerous infectious diseases. It is imperative to identify and use the proper diagnostic tools. Also, patients who have latent tuberculosis,
HIV, and alcoholism comprise a large pool, which signicantly hinders efforts to
manage the disease. The common histological techniques utilized for the pathological diagnosis of TB are depicted in Fig. 3.1. However, detailed descriptions of each
method are provided below.
Fig. 3.1 Methods utilizing histopathology for the detection of active TB: this gure depicts the
various pathological techniques for the diagnosis of TB using different staining and detection methods
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P. Tiwari et al.
3.2.1 Tissue Staining Methods
In staining procedures, ZN staining is the most commonly used technique for the
detection of acid-fast bacteria, particularly mycobacteria. It plays an important role
in enhancing the accuracy of TB diagnosis. This approach is considered easy, rapid,
and cost-effective for the identication of mycobacteria. However, it is not entirely
specic as it can also bind and/or detect other nontuberculous mycobacteria. ZN
staining is commonly used in histological sections, contributing to the enhancement
of diagnostic accuracy. By utilizing ZN staining to recognize beaded bacilli in tissue
samples, it is possible to establish a connection between the tissue reaction and
mycobacterial infection. These beaded bacilli are more frequently found in the
necrotic zone. The sensitivity range of ZN staining for this infection is reported to
be between 0 and 44%, indicating its limited effectiveness for detecting Mtb for
diagnostic purposes in terms of both sensitivity and specicity [7].
3.2.2 Microscopic Examination
Typically, both ZN stain and mycobacterium culture are used under the microscope
for the clinical detection of Mtb. Histological examinations of specimens have
revealed the characteristic feature of TB lymphadenitis. The histological identication of TB has been a serious issue in anatomical pathology for a very long time.
Histological examinations of specimens have revealed the characteristic feature of
TB lymphadenitis which included a high prevalence of giant cells (88%), the presence of caseation (84%), an abundance of epithelioid cells (80%), and the occurrence of granulomas with caseation (68%), lymphocytes (31%), and a smaller
population of histiocytes (4%). Extrapulmonary Mtb infections account for approximately 10–15% of overall cases, around 15–20% in immunocompetent patients,
and approximately 50% in HIV patients [9–11]. Conventional ZN and uorescence
techniques are limited in their ability to diagnose TB due to their low sensitivity.
Histopathology remains the most accurate approach for detecting TB.However, in
cases of suspected tuberculous lymphadenitis, it is recommended to conrm negative histopathology results with a more sensitive and targeted method, such as polymerase chain reaction (PCR) or immunohistochemistry (IHC), before reporting
them [12, 13].
3.2.3 Immunohistochemistry (IHC)
Various staining techniques have limited diagnostic utility and a poor ability to
determine the pathophysiological nature of Mtb antigens in the tissue. This inadequacy is primarily attributed to their mechanism, as well as their comparatively low
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sensitivity and specicity [14]. IHC is a method that has gained widespread acceptance for its use in research projects looking for mycobacterial antigens. This
method is based on the staining of mycobacteria in tissue using various polyclonal
and monoclonal antibodies. According to numerous studies, its sensitivity ranges
from ~64 to 100% for the identication of mycobacterial antigen by IHC, proving
both the involvement of granulomatous tissue and the immunolocalization of Mtb
antigen. Although these techniques are more expensive and require more time, they
produce more accurate results than acid-fast staining [8]. In addition, polyclonal
antibodies can produce results that are not specic because of cross-reactions with
other nontuberculous mycobacteria. Also, due to their potential for cross-reaction
activity with other nontuberculous mycobacteria, polyclonal antibodies may provide less or nonspecic results [13].
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3.2.4 Mycobacterial Culturing
This method is considered a gold standard for conrming the presence of an active
TB infection. Also, it can effectively distinguish between different subspecies of
mycobacteria and assess their susceptibility to various antibiotics. In approximately
60–70% of respiratory specimens with positive cultures, acid-fast bacilli (AFBs)
can frequently be detected by microscopy. The sensitivity and specicity of TB
culture for pulmonary TB (PTB) forms are approximately 80–85% and around
98.5%, respectively [15]. However, culturing needs biosafety level-3 (BSL-3) labo-
ratories and is costly and time-consuming. Detecting pathogen excretion and determining the likelihood of transmission require the use of viable samples, which also
allows for ongoing research. It is essential to assess the infection rate both before
and after implementing additional precautions, like vaccination. It is also important
to evaluate the efcacy of vaccines in preventing TB infection. After culture isolation, the microbe can be identied using either colony traits, biochemical testing, or
nucleic acid recognition techniques [16].
3.3 Pathological Manifestations ofTB
The pathophysiology of TB is characterized by the formation of a lesion consisting
of inammatory cells, such as lymphocytes, macrophages, epithelioid cells, lymphocytes, and, in some cases, Langhans multinucleated giant cells. Necrosis in
caseating tubercles is also a hallmark feature of Tuberculosis. There may also be the
presence of nonnecrotizing granulomatous encapsulation [17]. According to international guidelines for TB management, individuals who have an unexplained
cough persisting for 2weeks or longer or unexplained abnormalities on chest radiographs are recommended to undergo a diagnostic evaluation of TB [1]. In addition,
the patient’s underlying medical conditions should be determined, especially
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