Chapter 1

INTRODUCTION

1.1 What is Tuberculosis (TB)

Tuberculosis is an infectious disease caused by the bacillus Mycobacterium

tuberculosis and occasionally by Mycobacterium bovis and Mycobacterium
africanum. Tuberculosis commonly affects the lungs, but it can affect any other organ
in the body.

1.2 How does tuberculosis spread?

The bacteria that cause tuberculosis usually spread through air. When a patient with
infectious pulmonary tuberculosis coughs, sneezes or laughs, bacilli are expelled into
the air in the form of tiny droplets. These droplets dry up rapidly to form droplet
nuclei and may remain in the air in suspension for several hours.
Adequate, “through and through ventilation” removes and dilutes these droplet
nuclei, and direct sunlight quickly kills the bacilli, but they can survive in darkness for
several days. When a healthy person inhales these droplet nuclei containing the
tubercle bacilli, he/she may become infected.

1.3 Risk of infection

An individual’s risk of infection depends on the extent of exposure to an infectious
source and susceptibility of the individual to infection. The risk of infection is therefore
high in a person who has close, prolonged exposure to a person with sputum smear
positive pulmonary TB. An untreated sputum positive patient has the potential risk of
infecting 10-15 persons per year. The risk of transmission of infection from sputum
negative pulmonary TB is low. While many forms of extra pulmonary TB have neglible
risk of transmission, others such as laryngeal TB are infectious.

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The risk of infection is equally there from MDR-TB patients and in fact, because of
their longer sputum positivity period even after being put on treatment, this risk may
be even more. Further, in the absence of uniform adoption of the Guidelines for
Programmatic Management of Drug-Resistant TB, these patients have high risk of
irregular and inappropriate treatment which increases the risk of transmission in the
community.

1.4 How does Tuberculosis develop BOX 1: Risk factors for Tuberculosis

Tuberculosis develops in two stages. • Period of exposure

The first stage occurs when the tubercle bacilli • Distance from infectious source

from an infectious source enter the body of an • Classified type of TB in source

case
individual but remain dormant without causing
• Immunity of the exposed
disease and is called tuberculosis infection. individual. E.g. HIV,DM

The second stage is when the infected individual

actually develops the disease; then it is called or tuberculous
tuberculosis or tuberculosis disease.
•

1.5 Risk of progression of tuberculosis infection to

tuberculosis disease

Once infected with M.tuberculosis, a person may remain infected for the whole life.
Approximately 10% of people infected will develop active disease during their life
time. The majority (90%) of people will not develop the disease and the only evidence
of infection in these individuals, may be a positive tuberculin skin test.
However the organisms may remain dormant within the body and the disease can
develop at any time. The chance of developing the disease is greatest shortly after
infection (within the first two years) and lessens as time goes by, but the risk probably
remains for life. Any weakening of the immune system will lead to progression of
infection to disease e.g. HIV infection, diabetes, malnutrition, prolonged steroid
therapy, chronic alcoholism, malignancies etc.

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1.6 Transmission

Certain procedures, for example, bronchoscopy, sputum induction, autopsy and even
irrigation or other manipulation of tuberculous abscesses, may also produce infectious
aerosols. The droplets have an extremely slow settling rate (0.5 mm per second or
less), which permits their transport by air currents for significant distances from the
source case. For practical purposes, only the droplet nuclei in the size range 1 to 5
microns reach the terminal air spaces or alveoli; each is understood to contain only a
few bacteria.

The risk of transmission is measured by ‘Annual Risk of TB Infection’ (ARTI) with the
help of tuberculin surveys.

1.6.1 Susceptibility of those exposed

Persons with no prior exposure to M. tuberculosis are at risk of becoming infected if

exposed. Prior infection, and especially prior infection giving rise to tuberculosis
disease, provides a measure of protection against reinfection, at least in immune
competent persons.
However this protection is not perfect. Epidemiological and autopsy data suggest that
BCG (Bacille Calmette-Guérin) vaccination does not prevent the establishment of
infection in an exposed subject.
Interferon-γ release assay data, however, indicate that BCG, while not preventing the
establishment of infection in everyone, will prevent it in some. If infection is
established, BCG limits the subsequent multiplication and dissemination of the
bacteria and the development of lesions.

1.6.2 Effect of treatment upon the contagiousness of the patient

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Effective treatment rapidly reduces cough frequency and sputum bacillary counts.
Moreover, the rate of decrease of bacillary counts in cough-generated aerosol cultures
is considerably more rapid than that in sputum cultures. Those bacteria that continue
to be expectorated may be less metabolically active and/ or are inhibited by
antituberculosis drugs, two effects that may be anticipated to decrease the chance of
the organism establishing an infection in a new host.

1.6.3 Measures to prevent transmission

The highest priority should be given to early diagnosis and prompt, effective treatment
of the source case and to the degree appropriate. The insidious development of
symptoms in most cases of TB commonly results in a delay of weeks or months before
the patient presents for diagnosis. Awareness regarding TB among health care
providers is critical to reduce transmission and initiate early prevention and treatment.
Administrative and engineering controls (e.g. isolation protocols, room ventilation
devices, ultraviolet light fixtures) that aim to reduce exposure in health care and other
congregate settings complement but cannot replace prompt diagnosis and
appropriate therapy.

1.6.3.1 Natural history of untreated PTB (Pulmonary Tuberculosis)

Without treatment, after 5 years,

• 50% of pulmonary TB patients die

• 25% remain asymptomatic (good immune response)

• 25% remain ill with chronic infectious TB

BOX 2: Preventive measures of Tuberculosis transmission

• Early diagnosis
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• Effective and prompt treatment

• Thorough awareness of the disease among healthcare workers

• Infrastructure development of health care and other congregate settings

1.7 Who is a tuberculosis suspect?

A TB suspect is a person who presents with symptoms or signs suggestive of TB;

particularly cough of two weeks or more.

1.8 Who is considered a ‘Case’ of tuberculosis?

A case of tuberculosis is a patient in whom TB has been bacteriologically confirmed or

diagnosed by a clinician.

1.9 Definite case of tuberculosis

A definite case of TB is a patient with positive culture for the Mycobacterium

tuberculosis complex. (In countries where culture is not routinely available, a patient
with two sputum smears positive for acid-fast bacilli (AFB) is considered a ‘definite’
case)

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1.10 Common symptoms of pulmonary tuberculosis

1.10.1 Respiratory symptoms:

This include, cough – usually more than two weeks, haemoptysis (blood stained
sputum), shortness of breath or chest pain

1.10.2 Constitutional symptoms:

Constitutional symptoms of pulmonary TB include, fever and night sweats, loss of

appetite, loss of weight and tiredness (fatigue)

1.11 Symptoms of Extra-pulmonary TB

The symptoms depend on the organ involved. Patients may present with
constitutional features of the disease: fever, night sweats, loss of weight, and loss of
appetite or local symptoms related to the site of the disease

1.12 Latent tuberculosis infection

M. tuberculosis bacteria are able to survive for years in the small granulomas or solid
caseous material of lymphohematogenously seeded foci. Presumably local conditions,
an intact cell medicated immunity or the presence of inhibitors, result in conditions
unfavourable to replication. Although rapid death and autolysis occur after abrupt

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depletion of oxygen, the organism can shift into a state of dormancy if allowed to
settle through an oxygen gradient.

BOX 3: Common symptoms of Pulmonary Tuberculosis

a) Respiratory symptoms

▪ Cough

▪ Haemoptysis

▪ Shortness of breath

▪ Chest pain

b) Constitutional symptoms

▪ Fever

▪ Night sweats

▪ Loss of appetite

▪ Loss of weight

▪ Tiredness (fatigue)

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Chapter 2

CLASSIFICATION OF TUBERCULOSIS
It is important to classify the cases of TB in order to determine the correct treatment
regimen and the duration of treatment and for recording and reporting purposes,
which will facilitate cohort analysis of treatment outcome.

Classification of tuberculosis is based on:

• Site of TB disease

• Results of sputum smear

• History of previous TB treatment

2.1 Classification by site of the disease and result of sputum smear

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2.1.1 Pulmonary tuberculosis (PTB)

Pulmonary tuberculosis refers to disease involving the lung parenchyma and

conduction airways.

1.1.1.1. Smear-positive pulmonary tuberculosis

A patient with at least two sputum smears positive for AFB by direct

smear microscopy

OR

A patient with at least one sputum smear positive for AFB by microscopy
and chest X Ray abnormalities consistent with active pulmonary TB as
determined by a clinician

OR

A patient with at least one sputum smear positive for AFB by microscopy
and sputum culture positive for M. tuberculosis

2.1.1.2 Smear-negative pulmonary TB

• A patient with at least two sputum smears negative for AFB by

microscopy and chest X-ray abnormalities consistent with active
pulmonary tuberculosis and no response to a course of broad-spectrum
antibiotics and a decision by a clinician to treat the patient with a full
course of anti-tuberculosis therapy. Any patient given anti-TB treatment

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 should be recorded as a case. Incomplete trials of anti-tuberculosis
treatment should not be considered a method of diagnosis.

OR

• A patient whose initial sputum smears were negative for AFB, but whose

sputum culture is positive for M. tuberculosis.

This group also includes cases without smear result, which should be

exceptional in adults but are relatively more frequent in children,

because children rarely produce a positive sputum smear.

BOX4:

A patient with pulmonary and co-existing extra-pulmonary tuberculosis should be

classified as a case of pulmonary TB.

2.1.2 Extra- pulmonary tuberculosis (EPTB)

This refers to tuberculosis of any organ of the body other than the lung parenchyma.
Diagnosis should be based on smear/culture positive specimen, OR histological OR
strong clinical evidence consistent with active extra-pulmonary tuberculosis, followed
by a decision by a clinician to treat with a full course of anti-tuberculosis
chemotherapy.

BOX 5:

Cases of pleural effusion and intra-thoracic lymphadenopathy (mediastinal and

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hilar) without X-ray abnormalities in the lung parenchyma are classified as extra-
pulmonary TB.
2.2 Classification by previous treatment

In order to identify those patients at increased risk of acquired drug resistance and

to prescribe appropriate treatment, a case should be defined according to whether or

not the patient has previously received TB treatment.

The following definitions are used:

New

A patient who has never taken treatment for TB

OR
who has taken anti-tuberculosis drugs for less than one month

Relapse

A patient previously treated for TB who has been declared cured or treatment
completed, and is diagnosed with bacteriologically positive (smear or culture)
tuberculosis.

2.2 Treatment after failure

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 A new smear positive pulmonary TB patient on treatment with the appropriate
regimen for such patients and who remains smear positive at the end of the
fifth month or later during the course of treatment or a smear negative patient
who converts to smear positive at two months or later during treatment.

2.3 Treatment after default

A patient who returns to treatment, with positive bacteriology, following

interruption of treatment for two months or more is called a default patient.

2.4 Transfer in

A patient already registered in one district and transferred to another district

for continuation of treatment is named a transfer-in patient.

2.5 Other

A patient who does not fit into any of the above definitions: e.g.

- A patient who has been taking treatment for TB for more than one month

with out being registered with the NTP.

- A patient with smear negative pulmonary TB or extra pulmonary TB who

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 may have relapsed (but without any bacteriological evidence) although this

may be rare.

Patints with extrapulmonary tuberculosis with treatment failure will

come to this category

2.6 Chronic

Patient remaining sputum smear positive after completing a fully supervised

re-treatment regimen.

Chapter 3

DIAGNOSIS

3.1 Diagnostic Considerations

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 A high index of suspicion is of paramount importance for the rapid diagnosis of
extrapulmonary TB. Delay in EPTB diagnosis may be related to the often nonspecific
(e.g. fever, night sweats, weight loss) or organ-specific presentation compounded by
the absence of an abnormal chest radiograph or positive sputum samples. When
evaluating at-risk patients with fever of unknown origin, with fever and site-specific
signs and symptoms of patients with biopsy-proven granulomatous inflammation,
appropriate steps should be taken to secure the diagnosis of TB.

With a diagnosis of EPTB established, confirmation of HIV status is imperative.

Whenever practical, every effort should be made to obtain clinical samples for both
mycobacteriological (acid fast bacteria [AFB] smear and culture) and histopathologic
tests. Histopathologic sample requires the specimen to be placed in formalin, which
destroys the mycobacteria and prevents further attempts to culture.

Biopsy material for mycobacterial culture should be submitted fresh or in a small

amount of sterile saline.

3.2 Investigations
In all cases of suspected EPTB diagnosis depends on organ involvement. In such
patients, every attempt must be looked for co-excisting PTB.

BOX 6

In suspected EPTB patients every attempt must be made to look for co-existing PTB

3.2.1. Microbiological investigations

3.2.1.1 The acid-fast smear and microscopy

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The early and rapid diagnosis of TB still relies on the traditional AFB smear in both PTB
and EPTB specimen. Overall, smears have a reported sensitivity of 22% - 65%. A
minimum of 5 000 to 10 000 bacteria/ml are needed in a sputum sample to obtain a
positive result from concentrated smear. Diagnostic yield of EPTB specimen from
direct smear depends on standard of laboratory procedure and expertise.

3.2.1.2 Mycobacterial culture

Culture, as the gold standard for a positive diagnosis, is highly recommended for
laboratory diagnosis. However culture result may take 2-6 weeks depending on the
culture method employed. Liquid culture can provide results in as early as two weeks.
Solid culture on Lowenstein-Jensen (LJ) conventional media, may take 4-6 weeks.
Decision to treat will have to be taken on clinical and available other supportive
evidence. However culture may provide retrospective confirmation of diagnosis and as
a guide for drug susceptibility pattern.

3.2.2 Biochemical investigations

Bio chemical markers such as adenosine deaminase, gamma interferon are dealt in
detail under relavent sections.

3.2.2.1 Baseline investigations

• ESR
• CRP
• HIV

• FBC
• FBS
• Liver profile

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 • Renal profile

The above investigations may be carried out as indicated.

3.2.2.2 Nucleic acid amplification testing

Positive smears can be tested by an amplification test. Nucleic Acid Amplification

(NAA) tests, which amplify target sequences of DNA or RNA from the M. tuberculosis
organisms, are complex and expensive tests but have several important advantages.
They are rapid, have excellent specificity and provide results within 3 to 24 hours.

3.2.3 Interferon-Gamma Release Assays (IGRA)

IGRA are new, in vitro T-cell based assays that measure interferon-gamma (IFN-γ)
production. They operate on the basis that T-cells previously sensitized to TB antigens
produce high levels of IFN-γ when re-exposed to the same mycobacterial antigens.
Two tests in commercial use are the Quantiferon TB Gold In-Tube® (Cellestis Ltd.) and
T-SPOT. TB® (Oxford Immunotec). Early IGRAs used PPD as the stimulating antigen,
newer assays use M.tuberculosis-specific proteins – the early secretory antigenic
target 6 (ESAT-6) and culture filtrate protein 10 (CFP10) – encoded by genes located
within the RD-1 segment of the M. tuberculosis genome. These antigens are not found
in BCG and many NTM species.

3.2.3.1 The tuberculin skin test (TST)

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TST is a supportive tool to diagnose tuberculosis (TB) infection. It is more useful in
diagnosing EPTB than PTB.

3.2.4 Radiological investigations

44

3.2.4.1 Chest x rays:

In EPTB CXR is mandatory. This may provide a clue to co-excistance of PTB or evidence
of previoue exposure.

3.2.4.2 Other radiological investigations

X ray of other affected sites may be useful in supporting diagnosis, mainly bone and
joint TB. Depending on site of involment, other radiological investigations such as ultra
sound, Echocardiography, computerized tomography, magnetic resonance imaging
and other specialized tools can be used as supportive investigations.

3.2.5 Pathology (Histology)

BOX 6:

▪ In EPTB Chest X-Ray is

The entire or part of tissue sample taken mandatory
from the affected organ can be used for ▪ In microbilogy for EPTB, tissue
histological examination and needs to be samples must always be sent in
normal saline
sent in formal saline.It is mandatory that,
tissue samples are sent for microbiological
investigations such as smears and culture
In normal saline.

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3.2.6 Invasive investigations

For the purpose of sampling of affected tissue, several invasive investigations areused
according to the site of involment. They include aspiration and true cut biopsies,
bronchoscopy, thorocoscophy, other endoscopic biopsies like colonoscophy,
laporoscophy and major procedures like laparatomy.

BOX 7: Investigations for Tuberculosis

1. Micribiological

▪ The acid-fast smear and microscopy

▪ Mycobacterial culture

2. Biochemical

▪ ESR
▪ CRP
▪ HIV

▪ NAA

3. Interferon gamma release assays

▪ The tuberculin skin test (TST)

4. Radiological tests

▪ Chest X Ray and 18

▪ X Ray other sites
▪ Ultra sound,
▪ Echo,
5. Histopathology

6. Invasive investigations

▪ True cut biopsies

▪ Bronchoscopy
▪ Thorocoscophy

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Chapter 4

DIFFERENT SITES OF EXTRAPULMONARY

TUBERCULOSIS

4.1 BONE AND JOINT TUBERCULOSIS

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Bone and joint tuberculosis made up approximately 3% of all reported cases of
Tuberculosis globally. However, in Sri Lanka, it accounts for less than that.

Bone tuberculosis is a secondary condition that results when a pulmonary focus

disseminates through the bloodstream. There is evidence of an active pulmonary
lesion in 30% to 50% of cases. The bone lesions result when the bacilli reach the bone
marrow, which represents approximately 20% of cases of extrapulmonary TB. It is
more commonly (> 50%) involves the vertebrae.

Most bone and joint tuberculosis is presumed to arise as osteomyelitis from

granulomatous foci in the growth plates of bones, where the blood supply is rich. Bone
TB may affect the epiphysis, metaphysis, and diaphysis. Because these growth plates
or metaphyses are typically near joints, the infection can then spread locally into joint
spaces, resulting in tuberculous arthritis. The lesion is typically destructive, evolves
slowly, and is eccentric. Local manifestations, such as pain, predominate, and soft
tissue collections (cold abscesses) may occur at or near the bone and joint focus.
Constitutional symptoms are relatively uncommon. The presence of multiple lytic
lesions in an asymptomatic patient with no demonstrable reactive changes should lead
to suspicion of TB. And also the lesions caused by bone TB are similar to those caused
by pyogenic osteomyelitis, but with less destruction and reactivity of the adjacent
bone.

Spinal or vertebral TB (Pott’s disease) involvement is noted in approximately 50% of

the cases of bone and joint TB. When the incidence of TB is high, bone and joint TB
occur most commonly in childhood, usually within 1 year of primary infection. When
the incidence of TB is low, it is mainly a disease of adults and is associated with
reactivation.

As explained earlier, vertebral TB is the most common form of extrapulmonary

skeletal TB, and more frequently involves the lower part of the dorsal and lumbar
columns. This condition has been known as Pott’s disease for over 200 years.

Depending on the site involved, there are various types of vertebral TB such as disc,
paradiscal, somatic, ligamentous, and atypical etc. The purely disc form possibly
results from dissemination by contiguity from a vertebral focus that is not visible on a
radiograph. The paradiscal form is the most common and is manifested by
involvement of the discs, vertebral plates, and paravertebral soft tissue mass. The
somatic form, which is more common among children, is presented as a vertebral
osteomyelitis that leads to collapse of the body, occasionally accompanied by

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neurological lesions. Vertebral TB is accompanied by soft tissue mass, normally
symmetrically arranged in the paravertebral region.

These are the so-called “cold abscesses”, which later end up calcifying. When the
vertebrae are affected, it may not be certain if vertebral collapse was due to a
neoplastic or an infectious cause. The combination of loss of height in the disc and
badly defined contiguous vertebrae are very important signs of infectious aetiology,
since a reduction in height of a disc is an exceptional occurrence in neoplastic lesions.
The presence of paravertebral mass, in the phase when it has not yet calcified, is a
finding reflecting both a neoplastic and an infectious process.

Joint lesions are the most common after vertebral ones, and the larger joints are more
likely to be affected. In descending order of frequency, the joints involved are the hip,
knee, ankle, shoulder, wrist, and elbow. Joint TB has characteristics that differentiate
it from the pyogenic conditions. In pyogenic arthritis the inflammatory exudate has
many more proteolytic enzymes, which cause significant destruction, unlike what
happens in tuberculous arthritis. The location of the cartilaginous destruction is also
different, given that pyogenic arthrits occurs in cartilage in apposition, which supports
weight, whereas TB generally affects free surfaces. The exceptions to this are the hip,
ankle, and metacarpophalangeal joints, which generally show profuse damage as they
have little free surface. Another difference is progression time, which is quick in
pyogenic arthritis but slow in the case of TB.

4.1.1 DIAGNOSIS

4.1.1.1 Mycobacterial staining and Culture of affected tissue:

In order to diagnose joint TB with certainty, it is necessary to stain joint aspirate for
AFB and isolate colonies of M. tuberculosis in culture. Thus, biopsy samples and joint
fluid should be obtained from the affected area.

4.1.1.2 Imaging techniques:

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1. Simple radiology. This is useful for detecting alterations at an early stage and to
evaluate the effects of the therapy. The radiographic signs, include tumefaction or
blurring of the soft tissue, juxtaarticular osteoporosis, marginal erosions in the free
surfaces, a decrease in space, and, at times, joint destruction with calcification of the
soft tissue.
2. Techniques using isotopes. This estimates the physiological activity in the bones and
joints, detecting small increases and decreases. Findings are non-specific and thus
must be complemented with other methods in order to characterise the abnormal
areas. Scanning with technetium will yield signs of involvement early on in the initial
phases with a normal radiograph. In addition, it provides information on the whole
skeleton. Scanning with gallium, which is sensitive for the detection of inflammation, is
useful in detecting early disease. A decrease in the activity of gallium is a good
indicator of follow-up with regards to response to therapy, as well as of follow-up to
discern the presence of chronic osteomyelitis or its reactivation.
3. Computed tomography. This makes it possible to discriminate between contiguous
structures based on slight differences in density. The method provides information on
the extension of the process, the characteristics of the lesion, and the identification
and extension of the extra articular abscesses. It also guides percutaneous puncture
when diagnosis is uncertain.
4. Magnetic resonance imaging. Like computed tomography, this method provides
spatial resolution, showing better resolution in the contrast of the soft tissue. No
contrast injection is required and it is more sensitive than computed tomography
when detecting abnormalities, although this does not mean that it has higher
specificity. It provides a more precise anatomic delineation of all the structures in the
column.

4.1.2 MANAGEMENT

General management

Multidisciplinary approach with involment of Respiratory Physician, Orthopedic

surgeon, Neurosurgeon, Rheumatologist and Interventional radiologist is essential in
management of bone tuberculosis. Joint stabilizing manoeuvres and supervised
physiotheraphy with the basic proper nursing care are essential components of
management of bone TB.

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9-month to 12 regimens containing Rifampicin is effective because of the difficulties in
assessing response. Myelopathy with or without functional impairment most often
responds to chemotherapy. In some circumstances, however, surgery appears to be
beneficial and may be indicated. Such situations include failure to respond to
chemotherapy with evidence of ongoing infection, the relief of cord compression in
patients with persistence or recurrence of neurologic deficits, or instability of the
spine.

BOX 8:

Multidisciplinary approach with the involvement of several discleplines is essential in

management of bone tuberculosis.

2.2. TUBERCULOSIS OF THE CENTRAL NERVOUS

SYSTEM (CNS TUBERCULOSIS)

4.2.1 CNS Tuberculosis include

• TB meningitis

• Intracranial Tuberculomas
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 • Spinal TB (arachnoditis and TB myelitis)

CNS TB accounts for 1% of all TB and 6% of extra-pulmonary TB (EPTB). CNS

involvement is also seen in 15 – 20 % of patients with miliary TB.

TB meningitis with or without tuberculomas account for 75 % of CNS TB.

Tuberculomas alone account for the remaining 25 %. Tuberculomas are more common
in patients with HIV/AIDS.

TB meningitis is a medical emergency. It carries a mortality rate of around 15 – 40 %.

Fatality rates in miliary TB can be as high as 50%. 25 % of patients with TB meningitis
will end up with permanent neurological deficits inspite of treatment.

4.2.2 Pathology
CNS TB is the result of haematogenous dissemination of Mycobacterium tuberculosis
from a primary pulmonary infection and the formation of small subpial and
subependymel foci (Rich foci) in the brain and spinal cord. In some foci rupture and
release bacteria into the subarachnoid space causing meningitis while in others foci
enlarge to form tuberculomas. Granulomatous Basal exudates (proliferative
arachnoditis) may give rise to brain and cranial nerve damage, obstructive
hydrocephalus, cerebral oedema, periarteritis and thrombosis of blood vessels
especially of those supplying the basal ganglia and brainstem.

4.2.3 Clinical Features

4.2.3.1 TB meningitis

This is the most rapid form of tuberculosis, 50 % are ill for less than two weeks before
diagnosis.

4.2.3.2 Adults and older children

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Non-specific prodromal symptoms of headache, fever, vomiting and anorexia which is
followed by meningismus, cranial nerve palsies, confusion, seizures, coma and death.

4.2.3.3 Infants and younger children

A history of recent tuberculosis contact is common in children (50 -90 %). Failure to
thrive, loss of weight, irritability, poor appetite, sleep disturbance, vomiting and
abdominal pain are often seen. Seizures focal neurological deficits, cranial nerve
palsies and hemiplegia can be the presenting symptoms.

Atypical presentations in adults and children include subtle cognitive decline,

dementia and encephalitis like syndrome.

4.2.3.4 Complications
Cerebral oedema

Obstructive hydrochpelous

Cranial nerve palsies (V1, 111, V11)

Periarteritis and thrombosis of blood vessels especially of those supplying the basal
ganglia and brainstem.

Hemiparasis

SIADH

4.2.3.5 Presenting Clinical Features of TB meningitis in adults and older

children
Symptom Frequency

Headache 50 -80%
Fever 60-95%

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Vomiting 30- 60%

Photophobia 5- 10%
Anorexia/weight loss 60-80%

Clinical sign

Neck stiffness 40-80%

Confusion 10-30%

Coma 30-60%

Cranial nerve palsy 30-50%

VI 30-40%

III 5-15%
VII 10-20%

Hemiparesis 10- 20%

Paraparesis 5- 10%

Seizures in
Children 50%
Adults 5%

4.2.3.6 Cerebral tuberculomas without meningitis

Clinical features depends on anatomical location, but often asymptomatic. Most
patients complain of headache, fever and weight loss.Seizures either focal or
generalized are the commonest presenting feature in children and adults.
Focal neurological signs are common but motor and cerebellar abnormalities and
27
papilloedema are the most frequently reported in adults.
Unusual presentations include hypopituitarism, chorea and brainstem syndromes.

4.2.3 Diagnosis
Cerebrospinal fluid examination is essential for the diagnosis of central nervous
system tuberculosis.

Character of CSF

Clear appearance 80-90%

Opening pressure >25 cm H20 50%

Leucocyte count (10 3/ml) 5-1000

Neutrophils 10-70%
Lymphocytes 30-90%

Protein (g/L) 0.45-3.0

Lactate (mmol/L) 5.0-10.0

CSF glucose: blood glucose < 0.5(< 50%) 95%

Cerebrospinal protein can be >10 g/l in those with spinal block.

Atypical CSF findings can be seen particularly in the immune suppressed patients. CSF
can be acellular or contain a predominance of neutrophils.

4.2.3.1 Microbiology

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Acid fast staining and culture
The search for acid-fast bacilli is crucial for the rapid diagnosis of TB meningitis. A
positive CSF smear has been variably described in literature as 10-80% in adults and
15-20% in children.

Positive CSF smear and culture is independently associated with larger volumes of ( >
6ml) of CSF submitted for examination. Repeated lumber punctures also increase the
diagnostic yield.

MTB has been isolated in smaller CSF volumes in HIV positive patients.

Laboratory Protocol

• Centrifuge at high relative centrifugal force (3000 g) for 20 minutes.

• Remove all but 2 ml of supernatant (biochemical tests can be performed on the

supernatant if required) and vigorously re-suspend deposit.

• Dry two drops of deposit onto a microscope slide (the second directly on top of
the first) covering a diameter of less than 1 cm.

• Ziehl-Neelsen stain the dried deposit (auromine staining alone is not

recommended). Take great care the sample does not detach from the slide
when decolourising. Examine the slide carefully for at least 10 minutes.

• Search the areas of highest cellularity first. Extend the examination to at least
20 minutes if TBM strongly suspected.

MTB Culture

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Liquid culture media may recover more bacteria than solid media but is of limited use.

The diagnostic yield of CSF smear is critically dependent upon the volume of CSF
submitted and the care with which it is examined. When TB meningitis is suspected
at least 6ml of CSF should be taken exclusively for mycobacterial studies.

Repeated CSF examinations are strongly recommended particularly if clinical

suspicion is high.

Culture is too slow to help in initial treatment decisions but should be sent as this
may provide critical drug susceptibility information once treatment started.

Once anti-tuberculosis medication is commenced, the sensitivity of smear and culture

falls rapidly.

4.2.3.2 Nucleic Acid Amplification tests (NAA)

A recent meta-analysis has suggested that NAA assays for the diagnosis of TB
meningitis were 56% sensitive (95% CI 46-66%) and 98 % specific (95% CI 97-99%).

Most studies conclude that commercial NAA tests can confirm CNS TB but cannot rule
it out.

Comparrison of NAA tests with microscopy and culture of examining large volume
(>6ml) of CSF has shown similar sensitivities and repeated examinations have resulted
in the highest diagnostic yields.

The sensitivity of microscopy and culture falls rapidly after starting of anti-tuberculosis
treatment whereas mycobcaterial DNA may remain detectable even after one month
of treatment.
30
Quantitative real time PCR may enhance bacterial detection in CSF and may be a
promising tool.

4.2.3.3 CSF Adenosine Deaminases Activity (ADA)

ADA activity in CSF is elevated in patient with TB meningitis and has been evaluated as
a diagnostic assay.

High CSF ADA activity is seen in patients with lymphoma, malaria, brucellosis and
pyogenic meningitis. In HIV infected patients false positive results have been reported
in patients with Cytomegalovirus (CMV) infection, cryptococcal meningitis and
cerebral lymphomas.

ADA cannot distinguish between bacterial meningitis and TBM, but using ranges of
ADA values could be important to improve TB diagnosis, particularly after bacterial
meningitis has been ruled out.

4.2.3.4 Interferon-gamma assays (IGRA)

Two commercial assays (QuantiFERON-TB® gold and T-SPOT.TB®) are available. The
role of these assays as of present is in diagnosing latent infections. There role in
diagnosing active tuberculosis remains unproven.

Further studies have shown that CSF lymphocytes die rapidly out side the body and
the test fails to mount a response to stimulation by mycobactria specific antigens.

Recommendation

31
NAA tests are recommended in suspected CNS tuberculosis, however a negative test
does not rule out the diagnosis of CNS TB. Large volume (>6ml) and repeated
examinations increase the diagnostic yield.

NAA tests may remain positive even one month after starting anti-tuberculoses
treatment.

In suspected cases of drug resistance Rifampicine resistant genotypes can be detected

using NAA.

IGRAS in blood and CSF is not recommended.

ADA is not routinely recommended but may be useful if bacterial meningitis is

effectively ruled out.

4.2.3.5 Tuberculin Skin testing

This is influenced by BCG vaccination status, age, previous exposure to mycobacterial

infection (both tuberculosis and non-tuberculosis) nutritional status and HIV status.

The diagnostic utility is highly variable, studies have reported positivity ranging from
10 -50 % in patients with CNS TB. In high prevalence areas, a positive test may be
unrelated. False negative tests can be seen in disseminated disease and miliary TB.

4.2.3.6 Role of Imaging

32
4.2.3.6.1 Chest Radiography

About 50% of patients with TBM have chest X-rays suggesting active or previous
pulmonary tuberculosis. 10% have miliary disease, which strongly suggests CNS
involvement. Chest CT may reveal abnormalities missed by conventional X-ray.

Chest radiography should be followed up with sputum examination and / or

bronchoscopy if radiology is suggestive of active or healed pulmonary TB.

4.2. 3.6.2 Computarized Tormography of Brain

The commonest cerebral CT features of TBM are hydrocephalus and basal contrast
enhancing exudates. Both features are more common in children (80%) than adults
(40%) and may be absent in the elderly with TBM.

Infarctions as a result of ongoing vasculitis or tuberculoma are found in approximately

20% of patients at presentation.

More than 70% develop tuberculoma during treatment, although the majority is
asymptomatic. Infarctions most commonly involve the basal ganglia and the territories
of the medial striate and thalamoperforating arteries.

The combination of hydrocephalus, basal enhancement and infarction is thought to be

sensitive for the diagnosis of TB meningitis. Pre-contrast hyperdensity in the basal
cisterns has been suggested as a strong predictor.

4.2.3.6.3 Magnetic Resonance Imaging (MRI)

33
MRI provides high definition of infra-tentorial lesions and the early cerebral changes of
TBM, but data regarding the diagnostic sensitivity and specificity of these features are
limited. Cryptococcal meningitis, cytomegalovirus encephalitis, toxoplasmosis,
sarcoidosis, meningeal metastases, and lymphoma may all produce similar
radiographic findings.

Recommendation

The brain of every patient with TBM should be imaged with contrast enhanced CT
either before the start of treatment (as part of the diagnostic work-up), or within the
first 48 hours of treatment.

However delaying empirical treatment awaiting CT is strongly discouraged as this can

result in death or permanent neurological deficits of the patient.

Early brain CT can help diagnose TBM, and will provide important baseline information
particularly when considering surgical intervention for hydrocephalus.

4.2.3.6.4 Cerebral tuberculomas without meningitis

The clinical features of cerebral tuberculoma without meningitis are dependent on

their anatomical location, but are often asymptomatic. Constitutional symptoms vary,
but most patients complain of headache, fever, and weight loss. Seizures both focal
and generalised are the commonest presenting features in both adults and children.

Focal neurological signs are much less common, but motor and cerebellar
abnormalities and papilloedema are the most frequently reported in adults. Unusual
manifestations include hypopituitarism, chorea, and brain-stem syndromes.

34
Examination of the CSF reveals an elevated total protein in most patients and a
pleocytosis of 10 -100 cells/mm3 in 50% of cases. Tuberculomas cannot be
distinguished from other cerebral space-occupying lesions by clinical features alone.

Imaging of cerebral tuberculomas without meningitis

CT and MRI demonstrate the typical features of contrast enhancing ring lesions with
surrounding oedema; the latter being better able to demonstrate small lesions and
those in the posterior fossa and brain stem.

Increased use of MRI has shown that infra-tentorial tuberculomas are more common
than previously thought. Neither of these imaging modalities is able to reliably
distinguish tuberculoma from other causes of ring enhancing lesions, in particular
pyogenic bacterial abscess, neurocysticercosis (unless MRI reveals a parasitic scolex
within the lesion), toxoplasmosis, or neoplasia.

Advances in magnetic resonance spectroscopy (MRS) have shown most promise in

differentiating the causes of ring enhancing brain lesions: a large lipid CH2 peak has
been used to specifically identify tuberculomas , others have suggested tuberculomas
can be distinguished from neurocysticercosis on the basis of choline/creatine ratio >1
in tuberculoma.

4.2.3.6.5 Spinal tuberculosis

Tuberculosis can affect any part of the spinal cord, including the nerve roots, and
therefore can present with upper or lower motor neuron involvement, or a mixed
clinical picture. Around 10% of cases with TBM have some form of spinal tuberculosis.

35
Vertebral body tuberculosis (Pott’s disease) with cord impingement accounts for the
majority of all cases with spinal involvement and most commonly presents with pain, a
gibbus, and signs of extrinsic cord compression. Extra-dural cord tuberculomas cause
more than 60% of the cases of non-osseous paraparesis, although tuberculomas can
occur in any part of the cord. Tuberculous radiculomyelitis is a rare but well-reported
disease, characterised by subacute paraparesis, radicular pain and bladderdysfunction.
Syringomyelia is a rare complication of spinal tuberculosis.

Imaging in Spinal Tuberculosis

The MRI characteristics of vertebral body tuberculosis have been extensively reported.
The thoracic spine is most commonly affected; the radiological features include bone
marrow oedema (best seen in T 2 weighted films with fat suppression protocol) and
enhancement, posterior element involvement, canal stenosis, and spinal cord or nerve
root compression. Inter-vertebral disc enhancement, vertebral collapse and kyphosis
deformity are particularly suggestive of tuberculosis, but radiological investigations
cannot accurately distinguish tuberculosis from pyogenic bacterial infections, fungal
infections, and neoplasia.

Vertebral intra-osseous abscess, disc abscess, abnormal para-spinal signal intensity

and involvement of multiple vertebral bodies are common in tuberculosis but rare in
pyogenic bacterial disease. Brucellar spondylitis cannot be distinguished radiologically
from tuberculosis.

The imaging characteristics of cord tuberculosis are less well described. Small case
series suggest >90% of patients with intra-medullary cord tuberculosis have an extra-
neural focus of disease. Typical MRI findings include fusiform swelling of the cord with
ill-defined iso- to hyper- intense lesions with rim enhancement indicating
granulomatous inflammation.

Tuberculous radiculomyelitis involves more than one spinal region in >80%, with the
thoracic and cervical region being most commonly affected. The CSF usually shows
36
increased signal intensity on T1-weighted images, which may be associated with
complete loss of the cord-CSF interface and an irregular cord outline. Subarachnoid
nodules, clumping of the cauda equine nerve roots and CSF loculations may also be
seen. Contrast enhancement may be seen in the meninges (80%), cord (20%), and
nerve roots (30%).

Recommendations

All patients with suspected cerebral tuberculoma or spinal cord tuberculosis are best
investigated by MRI, as it is critical to demonstrate whether surgery is indicated and to
follow the subsequent response to therapy.

An extra-neural focus of tuberculosis should be sought clinically and radiologically in

all patients with CNS tuberculosis as it may indicate safer and more accessible sites for
diagnostic sampling. All patients should have a chest-X-ray as part of the diagnostic
assessment.

4.2.4 Chemotherapy of CNS Tuberculosis

Chemotherapy for CNS tuberculosis follows the model of short course chemotherapy
for pulmonary tuberculosis, an intensive phase of treatment, followed by a
continuation phase. However, the continuation period is prolonged upto 10 months.
Isoniazid and Rifampicin are the key components of the regimen. Isoniazid penetrates
the CSF freely and has potent early bactericidal activity. Rifampicin penetrates the CSF
less well (maximum concentrations around 30% of plasma), but the high mortality
from Rifampicin resistant TBM has confirmed its central role in the treatment of CNS
disease. There is no conclusive evidence to demonstrate that Pyrazinamide improves
outcome of CNS tuberculosis, although it is well absorbed orally and achieves high
concentrations in the CSF. Isonaizid, Rifampicin and Pyrazinamide are considered
mandatory at the beginning of TBM treatment.

37
There are no data from controlled trials to guide choice of the fourth drug. Most
authorities recommend either Streptomycin or Ethambutol, although neither
penetrates the CSF well in the absence of inflammation, and both can produce
significant adverse reactions.

Streptomycin is preferred over Ethambutol and is should be added to the intensive

phase regimen. Streptomycin not be given to those who are pregnant or have renal
impairment and resistance is relatively common worldwide. Ethambutol induced optic
neuropathy is a concern, especially when treating comatose patients, although at the
standard dose of 15-20 mg/kg the incidence is less than 3%.

The fluoroquinolones may represent an effective agent, although data concerning

their CSF pharmacokinetics and safety during prolonged therapy are limited.
Fluoroquinolones should be avoided in women who are pregnant or breastfeeding and
prolonged fluoroquinolone therapy is not advised for children.

Recommendation

38
The recommended first-line treatment regimen for all forms of CNS tuberculosis is;

Drug Daily dose Route Duration

DRUG DOSE / DAY ROUTE DURATION

1)Isoniazid 5-10 mg/kg Oral 12 Months

300 mg
2) Rifampicin 10 - 20 mg/kg Oral 12 Months
if < 50 Kg 450 mg
if > 50 kg 600 mg

3) Pyrazinamide 30-35 mg/kg

Oral 2 Months
if < 50 Kg 1.5 g

if >50 Kg 2.0 g

4) Ethambutol 15- 20 mg/kg

Oral
(max 1 g)
15 mg/kg

2 Months

Streptomycine should be added to or could be replaced Ethambutol during the first 2

months of treatment.

Patients should be treated for a minimum of 12 months. Intensive phase of 2 months

and continuation phase of 10 months.

39
Communicating hydrocephalus may be treated initially with frusemide (40 mg/24 h
adults; 1 mg/kg children) and acetazolamide (10-20 mg/kg adults; 30 -50 mg/kg
children) (B,II) or repeated lumbar punctures.

Thalidomide should not be used for the routine treatment of TBM, but may be helpful
in patients with tuberculomas that are not responding to anti-tuberculosis drugs and
high dose corticosteroids.

Recomendation of steroids

It is recommended that all patients with TB meningites receive adjunctive

corticosteroids regardless of disease severity at presentation.

Adults (>14 years) should start treatment with prednisolone 20-40 mg if on rifampicin
and 10-20 mg if not on rifampicin (equalent doses of dexamethasone can be given as
an alternative), as a reducing course over 6-8 weeks.

Children (<14 years) should be given prednisolone 1-2 mg/kg/24 hr (maximum 40 mg

per day or equivalent dose dexamethasone) for 4 weeks, followed by a reducing
course over 4 weeks.

There is insufficient evidence to recommend routine adjunctive corticosteroids for all

patients with tuberculomas without meningitis, or with spinal cord tuberculosis.
However, they may be helpful in those patients whose symptoms are not controlled,
or are worsening, on anti-tuberculosis therapy, or who have acute spinal cord
compression secondary to vertebral tuberculosis.

4.2.4.1 When are surgical interventions indicated?

Hydrocephalus is the most common reason for neurosurgical referral in patients with
TBM; most authorities suggest early ventriculo-peritoneal shunting should be
40
considered in all patients with noncommunicating hydrocephalus. Response to
external ventricular drainage has failed to predict those who benefit from early
shunting. Endoscopic third ventriculostomy is advocated by some centres as an
alternative to shunt surgery.

Rarely, tuberculomas coalesce and liquify to cause tuberculous cerebral abscess which
may necessitate surgery.
There are various treatment options, including aspiration, repeated aspiration through
a burr hole, stereotactic aspiration and total excision, but there is no consensus as to
which is best.

The role of surgery in the management of all forms of vertebral body tuberculosis is
controversial. Anecdotal evidence suggests vertebral body tuberculosis associated
with paraparesis responds well to medical treatment (which may include
Corticosteroids) if the MRI shows relatively preserved cord size and oedema with
predominantly fluid compression.

Patients with extra-dural compression, but with little fluid component compressing or
constricting the cord, need early surgical decompression. Some centres advocate
microsurgical dissection of intra-medullary tuberculomas, but it is uncertain which
patients should be selected for surgery.

Recommendation

Hydrocephalus, tuberculous cerebral abscess, and vertebral tuberculosis with

paraparesis are all indications for neurosurgical referral. Early ventriculo-peritoneal
shunting should be considered in those with non-communicating hydrocephalus and in
those with communicating hydrocephalus failing medical management.

Communicating hydrocephalus may be treated initially with Frusemide (40 mg/24 h

adults; 1 mg/kg children) and Acetazolamide (10-20 mg/kg adults; 30-50 mg/kg
children) or repeated lumbar punctures.

41
Urgent surgical decompression should be considered in all those with extra-dural
lesions causing paraparesis.

4.2.4.2 Empirical treatment: when to start, when to stop?

Many patients with CNS tuberculosis require empirical therapy; inevitably, some will
receive unnecessary treatment.
There are no published studies that help determine when empirical therapy should be
stopped.

Mycobacterial culture results may give additional information, but culture is not
sufficiently sensitive to rule out tuberculosis and should not influence treatment
decisions if prior probability of CNS tuberculosis is high.

Response to treatment is a poor diagnostic aid: symptoms often worsen after starting
treatment for TBM, cerebral tuberculomas take months to resolve, and corticosteroids
cause symptomatic improvement in many other cerebral diseases.

Recommendation

Delayed anti-tuberculosis treatment of CNS tuberculosis is strongly associated with

death and neurological sequele. The low sensitivity of all currently available rapid
diagnostic tests mean empirical therapy may need to be started in many patients with
suspected CNS tuberculosis, although it is difficult to stop treatment once started.

Therapeutic response (either lack of response or rapid recovery) should not be used to
determine when to stop treatment. It is recommended that the safest approach is to

42
give a complete course of treatment in all patients given empirical therapy unless an
alternative diagnosis is made.

4.2.4.3 Common complications of treatment

Hydrocephalus, cerebral infarction, and the expansion of tuberculoma are the

commonest reasons for neurological deterioration during the treatment of TBM.
Severe hyponatraemia (<120 mmol/l) may cause deepening coma and seizures. The
syndrome of inappropriate anti-diuretic hormone may cause some cases, but reduced
plasma volumes and persistent natriuresis despite normal concentrations of anti-
diuretic hormone suggest other mechanisms.
The best way of correcting the sodium is uncertain. There is anecdotal evidence that
fludrocortisone replacement therapy and demeclocycline may be useful treatments.

Clinical deterioration secondary to the expansion of intra-cerebral tuberculoma

following the start of antituberculosis drugs, paradoxical reactions are a well-described
complication of all forms of cerebral tuberculosis. They may also be seen in HIV
infected patients in the context of IRD (immune-reconstitution disorder).Intra-cerebral
tuberculomas develop during treatment in nearly all patients with TBM, but the
majority is clinically silent. A few cause persistent symptoms that, dependent on their
size, location, and number, can be difficult to manage.

Corticosteroids may reduce peri-lesional oedema and control symptoms, but can be
ineffectual. In these circumstances, small case series support the use of thalidomide;
case reports suggest interferon-gamma and infliximab (TNF antibody) may be helpful.

Recommendation

New or worsening neurological signs in patients on treatment for CNS tuberculosis

should prompt immediate imaging and neurosurgical review. Hyponatraemia should
be considered as a cause of coma and seizures. Correct the sodium slowly, either by
sodium and water replacement if the patient is hypovolaemic, or by fluid restriction if
they are euvoleamic.
43
4.2.4.4 Role of repated lumber puncture in assessing response to treatment

Examining the serial CSF changes in patients with TBM on treatment have emphasised
the following:

(i) CSF normalises with time; the rate of change is very variable and is often very slow.
(ii)The different parameters change at different rates, with glucose usually normalising
faster than protein and the white cell count.
(iii)In studies, the lymphocyte and PMN counts are usually grouped together, and no
study has assessed the rate of change for lymphocytes and PMNs individually.

(iv) CSF can temporarily worsen after anti-TB treatment is started.

(v) TB PCR may remain positive for months.

There is no correlation between the rate of change in CSF and the patient's clinical
response to treatment or to the stage of the disease.

The differential rate of change between the lymphocyte and PMN cells, together with
the rapid change in the glucose, is the most useful guide.
In the clinical setting of a patient with a presumptive diagnosis of TBM who is
deteriorating despite treatment, a repeat LP may be of value as the PMNs and glucose
should be changing in a rapid and predictable fashion.

If these two parameters show no definite improvement on repeat LP, it should be

considered atypical for TBM and an alternative diagnosis or drug resistance should be
considered.

Recommendations
44
CSF normalises over time, however, the slow change in lymphocyte count and protein
concentration limits their clinical use. The rapid change in PMN cells and glucose
concentration allows making reasonable clinical decisions.

If a repeat LP does not show definite improvement in these two parameters, it should
be considered atypical for TBM.

4.2.4.5 Drug induced hepatitis in CNS TB.

Hepatic toxicity is the commonest serious drug-related event and is associated with
old age, malnutrition, alcoholism, HIV infection, and chronic hepatitis B and C
infections.

Recommendations

When drug-induced hepatitis occurs, the threshold for stopping Rifampicin and
Isoniazid should be higher in those with CNS tuberculosis compared with pulmonary
tuberculosis, since alternative bridging drugs, such as Strptomycin and Ethambutol
enter the CSF poorly.

If serum transaminases rise above five times normal it is recommended stopping

pyrazinamide, continuing Isoniazid, Rifampicin, Ethambutol, and performing daily liver
function tests. If serum albumin falls, the prothrombin time rises, or the transaminases
continue to rise, Isoniazid and Rifampicin should be withdrawn.

Streptomycin and Ethambutol should be given, and the addition of Moxifloxacin or

Levofloxacin should be considered in those with severe disease, (N.B. Moxifloxacin can
cause hepatitis).

45
Rifampicin and isoniazid should be restarted immediately the liver function tests are
normal. It is recommended to gradually increasing the dose of both drugs over 5-7
days, with regular (3x/week) liver function tests.

Pyrazinamide should only be re-started once full dose rifampicin and isoniazid has
been safely re-introduced and it must be given at a gradually increasing dose under
close supervision (3x/week liver function tests). If pyrazinamide is not given or
tolerated, ethambutol should be given throughout therapy, which should be extended
to 18 months. Streptomycin can be stopped once the full dose of Rifampicin and
Isoniazid are tolerated.

Suggested regimen for the reintroduction of anti-tuberculosis drugs following drug-

induced hepatitis in adults

Isoniazid Rifampicin
Pyrazinamide

Day 1 150 mg Omit

Omit
Day 2 150 mg Omit
Omit
Day 3 300 mg Omit
Omit
Day 4 300 mg 150 mg
Omit
Day 5 300 mg 300 mg
Omit
Day 6 300 mg 450 mg
Omit
Day 7 300 mg 50 mg (< 50 kg)
600mg ( >50 kg)

46
Consider gradual reintroduction if normal liver function after 14 days of full-
dose rifampicin and isoniazid. If pyrazinamide not used, treat for 18 months.

4.3 GENITOURINARY TUBERCULOSIS

4.3.1 Introduction
The National programme for TB control and chest diseases (NPTCCD), has reported a
very low rate of GUTB in Sri Lanka. In 2007 there had been 1966 cases of extra-
pulmonary TB, but only 4 cases of GUTB were reported. This may be due to
deficiencies in diagnosisng, reporting and documentation. Genito Urinary Tuberculosis
(GUTB) has been reported as the second most common form of extra-pulmonary TB in
some countries.

4.3.2 Historical background

In 1883, Babes and Rosentein identified Mycobacterium in urine. Surgical treatment
for GUTB was introduced in the latter part of nineteenth century. In 1870 Bryant
performed the first nephrectomy for a pyelonephritic kidney. Initial high mortality
following nephrectomy was reduced to about 10% around 1910. The occurrences of
fistulae from the residual ureteric stumps lead to the first nephroureterectomy in
1895 by Howard Kelly.

4.3.3 Pathology

47
GUTB results from blood stream spread of M. tuberculosis from the lungs. This
happens about 10-15 years after the initial pulmonary inoculation. Therefore GUTB is
rare in children and adults under the age of twenty five. These patients are more likely
to have a family history of TB. Generally the bacillus infects one kidney and the disease
progresses slowly. There is slow destruction of renal parenchyma with cavitation,
abscess formation, fibrosis and calcification. Fibrosis leads to calyceal deformities,
obstruction and tissue loss. Rarely, it produces a diffuse glomerulonephritis with acute
renal functional impairment. Generally the symptoms of renal involvement are
minimal. If not identified and treated, the disease would spread down along the ureter
into the bladder. The ureteric involvement and fibrosis leads to ureteric stenosis and
stricture formation particularly at the vesico-ureteric junction and pelvi-ureteric
junction. Once the bacilli enter the bladder the inflammatory process starts and leads
to storage (irritative) urinary symptoms (e.g. frequency, nocturia, and urgency),
lumbar pain and haematuria. If it is still not treated, the bacilli ascend the contralateral
ureter up to the other kidney.

Epididymal tuberculosis is almost a separate entity and the organisms reach the
epididymis via the blood stream. Therefore in most instances, epididymal TB is an
isolated finding without urinary tract involvement. Few cases of epididymal TB have
been reported where the infection occurred by direct retrograde spread of the
organism or via lymphatics from the urinary tract. But these modes of spread are rare.
Though epididymal TB is common, testicular involvement is rare. Most patients with
epididymal TB have a normal testis. Therefore even after the vasal involvement and
blockage causing subfertility, sperms can be retrieved from the testis for purpose of
artificial insemination. Since the obstruction is close to the epididymis, reconstruction
is difficult and results are poor. In India about 2% of subfertile men have vasal
obstruction due to TB.

Tuberculous involvement of the prostate is rare in Sri Lanka. Spread of the organism to
the prostate is also via the blood stream in most patients. Direct spread from the
urinary tract is possible but rare. The transmission of genital TB from male to female is
very rare. Occasional reports of pelvic tuberculosis in the sexual partner of patients
with epididymal TB suggest the possibility of female to male sexual transmission. TB of
the penis is extremely rare.

48
4.3.4 Clinical features
The symptoms of GUTB are non-specific. Hence a clinical diagnosis is almost
impossible. Any symptom related to urinary tract can be due to GUTB! Tuberculous
infection in the past as primary pulmonary TB or extra-pulmonary TB gives an
important clue. Storage symptoms not responding to antibacterial treatment
associated with haematuria, occurring from time to time is a common presentation of
GUTB.

Tuberculous involvement of the epididymis presents as a solid mass in the scrotum.

The commonest lump related to the epididymis in clinical practice is the epididymal
cyst which is soft, fluctuant and transilluminant. It can be differentiated from a solid
mass of TB easily by clinical means. In most cases the testis can be felt separately and
is normal. If longstanding, tuberculous epididymitis may rarely progress to sinus
formation.

Constitutional symptoms like night sweats, evening pyrexia and malaise are rare in
GUTB. The commonest age group where GUTB is seen is 20-55 years. In this age group
presence of vague, longstanding urinary symptoms for which there is no obvious cause
should raise the suspicion of GUTB. It is important to realise that GUTB is not a disease
of the very old, frail people who are cachectic and severely ill.

Persistent pyuria is characteristic of GUTB. But GUTB is not the commonest cause of
sterile pyuria. Partially treated urinary tract infections with or without bladder outlet
obstruction and urolithiasis are the common causes of sterile pyuria. However once
bladder outlet obstruction leading to recurrent urine infections and urolithiasis are
excluded, one has to think of GUTB if the pyuria continues. At the same time it is
important to remember that up to 20% of patients with GUTB may not have any
leucocytes in the urine.

It is important to remember that GUTB is non-infective if there is no concomitant lung

infection.

49
4.3.5 Investigations
4.3.5.1 Microbiology and laboratory diagnosis

A microbiologic diagnosis of TB is made by isolation of the organism from urine or

biopsy material on conventional solid media. Detection of acid-fast bacilli from urine
samples by Ziehl-Neelsen stain is not reliable to make a definitive diagnosis due to the
possible presence of M. smegmatis which are acid-fast bacilli too. However it helps to
screen suspected cases. At least three (some even suggest five) early morning full
voided urine samples, should be sent for examination. For the acid-fast bacilli to be
positive at least 10,000 bacilli/ ml should be present in urine. Since GUTB is a pauci-
bacillary disease, false negatives with urine microscopy are common.

Culture of M. tuberculosis from urine or biopsied tissues is the gold standard in

diagnosis of GUTB. The traditional methods take 6 weeks to yield results (Lowenstein-
Jensen or Dubos media). However there are newer automated techniques which are
capable of giving the results within hours (BD ProbeTec ET System). These are
expensive and use specialised techniques (e.g. radiometry) to identify tiny colonies
which cannot be seen by the naked eye. Quinolones (e.g. ciprofloxacin) can destroy
the M. tuberculosis and should be avoided during the period when urine samples are
collected for diagnostic purposes.

Nucleic acid replication techniques such as polymerase chain reaction (PCR) are used
commonly to detect M tuberculosis in urine. Few studies done specifically to evaluate
the success of PCR in detecting mycobacterial DNA in urine have shown satisfactory
sensitivity and specificity. Though the reported sensitivity and specificity rates of
around 60% are good enough when compared with other tests to diagnose GUTB,
clinicians who have to take decisions on individual patients may not be happy with
these rates.

Utilisation of serum interferon (IFN) assays provides immunological evidence for

tuberculosis exposure. This is useful in immunocompromised patients (e.g. end-stage
renal disease, post-transplant patients) where tuberculin skin test is not useful.
Positive IFN-gamma assay results (QuantiFERON TB Gold test and ELISPOT) may help
the diagnosis of GUTB in such patients.

50
4.3.5.2 Tuberculin test

A strongly positive (more than 20mm) test is very useful in the diagnosis of GUTB. If
the Mantoux test is over 15 mm, one has to pursue for TB. However a normal
tuberculin test should not exclude a diagnosis of GUTB, especially epididymal TB.
Mantoux test is negative in most patients with epididymal TB.

4.3.5.3 Radiology

Plain X-ray KUB is useful in patients with calcifications. Any unusual pattern of
calcification should raise the suspicion of GUTB. Calcification of the renal parenchyma
develops in about 25% of patients with renal tuberculosis. Calcification due to
tuberculosis is ill-defined, diffuse and does not fit into any pattern. Calcification does
not mean inactive infection and need proper evaluation and treatment.

In spite of newer radiological investigations like ultrasound, CT scan and MRI, IVU
continue to be the key investigation in the diagnosis of GUTB. Approximately 90% of
patients with urinary tract TB cause abnormalities in the IVU. Renal lesions may
appear as distortion of a calyx, as a calyx that is fibrosed and completely occluded (lost
calyx), as multiple calyceal deformities or as severe calyceal or parenchymal
destruction and non-visualised kidneys. The IVU will demonstrate ureteric strictures
when present. The cystogram is important in defining the changes in the bladder such
as small capacity, irregular outline or vesicoureteric reflux.

Ultrasonography may detect changes associated with parenchymal involvement

(e.g.calyceal dilation, cavities) but its main role is in percutaneous nephrostomy in
obstructed kidneys due to ureteric stenosis. CT is helpful in identifying small intrarenal
lesions (scarring, masses and cavities) and autonephrectomy. Retrograde uretero-
pyelography is useful to delineate the site and length of a ureteric stricture. Ureteral
cathetrisation can be used to collect urine samples for culture from each kidney and
the yield rates may be higher than ordinary voided samples.

4.3.5.4 Cystoscopy

Cystoscopy will show extensive inflammatory changes in the bladder in the presence
tuberculous cystitis. Late cases show the classical ‘golf hole’ ureteric orifice due to

51
scarring and contraction. However bladder biopsy is to be avoided in the presence of
tuberculous cystitis.

4.3.5.5 Biopsy and histopathology

Biopsy material should be sent for histology in formal saline and also in saline for
smear and culture.

4.3.5.6 Erythrocyte sedimentation rate

Traditionally ESR is considered a useful test in helping the diagnosis of TB. In GUTB
majority of patients will have an ESR less than 50 mm. This is especially true in
epididymal TB.

4.3.6 Treatment
4.3.6.1 Pharmacological treatment

Since GUTB is a pauci-bacillary form of TB, a six-month course of anti tuberculous

drugs is adequate. Isoniazid (INAH), Rifampicin, Ethambutol and Pyrazinamide are
given for the initial two months (intensive phase). Isoniazid and Rifampicin are given
for the next 4 months (continuation phase). In complicated cases (e.g. recurrence of
TB, HIV infection, immunosuppression) longer courses (9-12 months) are
recommended.

Special considerations apply to the treatment of TB in patients with renal impairment.

Rifampicin, isoniazid and pyrazinamide can be given in normal dosage. These are
eliminated in the bile or broken down to metabolites that are not excreted by the
kidney. Dose adjustment (according to the GFR) is required in the use of Ethambutol. It
is widely excreted by the kidneys.

Steroid Therapy

Indicatios for prescribing steroids include severe bladder symptoms, and tubular
structure involvement (e.g. - ureter, fallopian tubes, spermatic code).

52
High dose prednisolone (ie, at least twenty mg/8 hrly) for 4-6 weeks is recommended,
because Refampicin reduces effectiveness and bioavailability of prednisolne by 66%.

4.3.6.2 Surgical treatment

Although chemotherapy is the mainstay of treatment, about 50% of patients with

GUTB will require some form of surgical intervention at some stage of the disease. Half
of them would be ablative surgery while the half would require reconstructive surgery.
Ablative surgery may be necessary in the initial management of GUTB to control sepsis
or to treat abscesses. Nephrectomy is indicated if there is uncontrollable urinary tract
sepsis, expanding calcification and hypertension attributed to the diseased kidney.
Almost all these are non-functioning kidneys.

Main forms of reconstructive surgery are ureteric reimplantation (after excision of

stricture) and bladder augmentation (for a small fibrotic bladder). Both ablative and
reconstructive surgical procedures are recommended to be done after about 4 weeks
of drug treatment within the intensive phase. Early ureteric stenting or percutaneous
nephrostomy may be indicated if the kidney is obstructed and patient has not yet
completed 4 weeks of treatment.

The ureteric strictures are commonly situated in the lower end at the uretero-vesical
junction. It can occur in the upper end or in the mid ureter less commonly. Pelvi-
ureteric junction obstruction can be treated with usual techniques of pyeloplasty (e.g.
Anderson-Hynes or Culp). Lower end strictures require reimplantation, while the mid-
ureteric strictures can be reconstructed by direct end to end anastomosis if the
stricture is short. Otherwise it may be necessary to raise a Boari flap. Endoscopic
dilatation of strictures has very low success rates and may jeopardise the kidney
function. All TB strictures require reconstructive surgery.

4.3.7 Follow up
M. tuberculosis is an organism with very destructive capabilities. Its destructive nature
is slow but longstanding. Even after making the urine free of organisms, tissue fibrosis

53
and scarring may progress. Hence these patients with GUTB should be followed up
carefully to identify the complications secondary to persisting tissue fibrosis.

BOX 8: Investigations for genitourinary TB

➢ Microbiology

▪ Culture of urine or biopsied tissues

▪ Urine microscopy

▪ PCR technique

▪ serum interferon (IFN) assays

➢ Mantoux test

➢ Plain X-ray KUB

➢ Cystoscopy

➢ Histopathology

➢ ESR

54
 4.4 TUBERCULOUS LYMPHADENOPATHY

4.4.1 Introduction
Lymphadenitis is the most common form of extra-pulmonary tuberculosis (EPTB)
accounting for 35 % of all EPTB.

It is both a diagnostic and therapeutic challenge because it mimics other pathologic

processes, yields inconsistent laboratory findings and the peculiar behaviour of TB LN
during treatment. This is further compounded by the occurrence of TB LN due to
mycobacteria other than tuberculosis (MOTT) in children and HIV positive patients.
Most MOTT species are resistant to standard anti-tuberculous medication and
treatment approaches differ.

Mycobacterial lymphadenitis most frequently affects patients in their second decade

but may afflict patients of any age. There is a female preponderance (approximately
2:1) in most of the studies.

Cervical lymph nodes are the most common site of involvement and reported in 60%
to 90% patients with or without involvement of other lymphoid tissues. Cervical
lymphadenitis, which is also referred to as scrofula, may be manifestation of a
systemic tuberculous disease or a unique clinical entity localized to neck.

4.4.2 Pathogenesis

Tuberculous lymphadenitis is a local manifestation of the systemic disease. It may

occur during primary tuberculous infection or as a result of reactivation of dormant
foci or direct extension from a contiguous focus.

55
 Primary infection occurs on initial exposure to tubercle bacilli. Inhaled droplet nuclei
are small enough to pass muco-ciliary defences of bronchi and lodge in terminal alveoli
of lungs. The bacilli multiply in the lung which is called Ghon focus. The lymphatics
drain the bacilli to the hilar lymph nodes. The Ghon focus and related hilar
lymphadenopathy form the primary complex. The infection may spread from primary
focus to regional lymph nodes. From the regional nodes, organism may continue to
spread via the lymphatic system to other nodes or may pass through the nodes to
reach blood stream, from where it can spread to virtually all organs of the body.

Hilar, mediastinal and paratracheal lymphnodes are the first site of spread of infection
from the lung parenchyma. Supraclavicular lymph node involvement may reflect the
lymphatic drainage routes from the lung parenchyma.

Cervical tuberculous lymphadenitis may represent a spread from the primary focus of
infection in the tonsils, adenoids, sinonasal or osteomyelitis of the ethmoid bone. In
untreated primary tuberculosis of children, enlargement of hilar and paratracheal
lymph nodes (or both) become apparent on chest radiographs.

In initial stage of superficial lymph node involvement progressive multiplication of the

M. tuberculosis occurs, the onset of delayed hypersensitivity is accompanied by
marked hyperemia, swelling, necrosis and caseation of the centre of the nodes. This
can be followed by inflammation, progressive swelling and matting with other nodes
within a group. Adhesion to the adjacent skin may result in induration and purplish
discolouration. The centre of the enlarging gland becomes soft and caseous material
may rupture into surrounding tissue or through skin with sinus formation.
Tuberculous mediastinal lymphadenitis may enlarge and cause compression of major
blood vessels, phrenic or recurrent laryngeal nerves or cause erosion of bronchus.

Asymptomatic intestinal or hepatic tuberculosis may spread via lymphatic drainage to

the mesenteric, hepatic or peripancreatic lymphnodes.

The lymphadenitis due to non-tuberculous mycobacteria (NTM) is transmitted from

environment by ingestion, inhalation, inoculation etc. The portal of entry for NTM may
be the oral mucosa or gingiva. This is particularly important in children, because
56
deciduous teeth may harbour the NTM that may reach the neck sites around the
mandible through the lymphatics.

4.4.3 Clinical Presentation

Tuberculous lymphadenitis most frequently involves the cervical lymph nodes

followed in frequency by mediastinal, axillary, mesenteric, hepato- portal, perihepatic
and inguinal lymph nodes.

Mycobacterial infection should be considered in the differential diagnosis of a cervical

swelling, especially in endemic areas. The duration of symptoms before diagnosis may
range from few weeks to several months. It may present as a unilateral single or
multiple painless slow growing mass or masses developing over weeks to months,
mostly located in the posterior cervical and less commonly in supraclavicular region. A
single node especially in the jugulodigastric triangle is likely to be non-tuberculous
lymphadenitis.

There is a history of tuberculous contact in 21.8%, and tuberculous infection in 16.1%

of the cases. Fistula formation is seen in nearly 10% of the mycobacterial cervical
lymphadenitis.

Cervical nodes in the submandibular region are most commonly affected in children.
Young children more often present with only one lesion and the referring physician
more frequently suspects a neoplasm, bacterial adenitis or reactive adenopathy.

In M. tuberculosis lymphadenitis, upto 57% of patients have no systemic symptoms.

Some patients may present with low grade fever, weight loss and fatigue and less
frequently with night sweats. Cough is not a prominent feature of tuberculous
lymphadenitis.
57
Multiplicity, matting and caseation are three important findings of tuberculous
lymphadenitis

Tuberculous lymph nodes can be classified into following five stages.

Stage 1- Enlarged, firm, mobile, discrete nodes showing non-specific reactive

hyperplasia

Stage 2- Large rubbery nodes fixed to surrounding tissue owing to periadenitis.

Stage 3- Central softening due to abscess formation.

Stage 4- Collar-stud abscess formation

Stage 5- Sinus tract formation.

Clinical features depend upon the stage of the disease. The lymph nodes are usually
not tender unless (i) secondary bacterial infection, (ii) rapidly enlarging nodes or (iii)
coexisting HIV infection are evident.
The lymph node abscess may burst infrequently leading to a chronic non-healing sinus
and ulcer formation. Classically, tuberculous sinuses have thin, bluish, undermined
edges with scanty watery discharge. Scrofuloderma is a mycobacterial infection of the
skin caused by direct extension of tuberculosis into the skin from underlying
structures.

Tuberculous mediastinal lymphadenitis is more common in children. Rare

manifestations observed in patients with mediastinal lymph node involvement include
dysphagia, oesophagomediastinal fistula and tracheo-oesophageal fistula. Cardiac
tamponade has also been reported due to mediastinal lymph node tuberculosis.
Local symptoms are uncommon in adults.

58
Upper abdominal and mediastinal lymph nodes may cause thoracic duct obstruction
and chylothorax, chylous ascites or chyluria. Rarely, biliary obstruction due to enlarged
lymph nodes can result in obstructive jaundice.

4.4.4 Differential Diagnosis

The differential diagnosis of isolated peripheral lymphadenopathy is extensive and

includes malignancy (eg, Hodgkin lymphoma and non-Hodgkin lymphoma) and other
infections (eg, nontuberculous mycobacteria M. scrofulaceum, M. avium complex, M.
Kansasii], cat scratch disease, fungal infection, toxoplasmosis, sarcoidosis, and
bacterial adenitis. Kikuchi's disease can cause a necrotizing lymphadenitis and mimic
tuberculous cervical lymphadenopathy.

The most likely alternative diagnoses depend on the clinical setting including the
patient's age, immune status, and presenting clinical features.

4.4.5 Diagnosis

A high index of suspicion is needed for the diagnosis of mycobacterial cervical lymphadenitis.

4.4.5.1 FNAC Smears of lymphnodes

Smears can be obtained either from a draining sinus or by FNAC. Ziehl-Neelsen

staining of the smears may reveal mycobacteria in the fresh specimens. Chance of
finding AFB is higher in patients with cold abscess.

59
The sensitivity and specificity of FNA cytology in the diagnosis of tuberculous
lymphadenitis are 88% and 96%, respectively. Clusters of epitheloid cells (sometimes
called epitheloid histiocytes) give rise to formation of granulomas. TB granulomas are
usually large 400 µm in maximum dimension with caseation and a band of epithelioid
histiocytes (pallisading) in periphery . Epitheliod cells fuse to form Langhans giant cells
which are seen more towards the centre. A rim of lymphocytes is also seen.
Neutrophils and haemorrhage may also be seen.

Neumerous neutrophils favour an alternative diagnosis while neutrophils in areas of

necrosis, serpentine Langhans giant cells, micro-abcesss favour an infection with
mycobacteria other than TB (MOTT).

FNA patterns of tuberculous lymph nodes can be grouped as follows;

Group 1 - Epitheloid cell clusters with or without Langhans giant cells with necrotic
material

Group 2 - Epitheloid cell clusters with or without Langhans giant cells without necrotic
material

Group 3 - Epitheloid cell clusters with or without Langhans giant cells / necrosis.

Group 4 - Only necrotic material without epitheloid cells, or giant cells.

Cytomorpholgy of tuberculous lymphnode aspirate reveal caseous necrosis in 92 %

cases, epitheloid cells in 85 % cases and AFB positivity in 13 % cases

60
The incidence of AFB positivity in patients of tuberculous lymphadenitis was highest
with the cytological picture of necrosis, polymorphs and lymphocytes i.e. 29 %.

In group 1 and 2 cases, the diagnosis of tuberculosis is easier to make because of the
presence of characteristic epitheloid cell clusters with or without Langhan’s giant cells
and with or without necrotic material. Purulent aspirates do not show epitheloid
granuloma or Langhan’s giant cells, however the chances of AFB smear positivity are
higher in such aspirates. The relationship between the presence of granulomas and
AFB positivity is inverse.

4.4.5.2 Ultrasound scan guided FNA

Ultrasound of the neck can demonstrate single or multiple hypoechoic and

multiloculated cystic lesions that are surrounded with thick capsule. US guided FNA
has been shown to have an increased diagnostic yield.

Recommendations

Tuberculous lymphadenitis is suggested by the presence of lymphocytes , clusters of

epitheloid cells/ histiocytes ( granulomas) , Langhans giant cells, neutrophils, caseous
necrotic background (eosinophilic granular material without recognizable cellular
elements) and haemorrhage.
The chances of a positive AFB smear are highest on those with purulent cheesy
aspirates.

Granulomas and necrosis are of help in diagnosis of tuberculosis but with limitations.

61
In those whom FNA is inconclusive, a repeat FNA or betterstill FNA under US guidance
is recommended. FNAC is a sensitive, specific and cost-effective way to diagnose
mycobacterial cervical lymphadenitis, especially in children presenting with a
suspicious neck swelling.
Combination of FNA with culture or a Mantoux test further increases the diagnostic
yield in mycobacterial cervical lymphadenitis.

4.4.5.3 Histopathology of excision biopsy of lymphnodes

Lymph node biopsy — Excisional biopsy for histopathologic and microbiological

evaluations has the highest diagnostic yield and should be pursued, in cases where
fine needle aspiration is not diagnostic.
Histopathologic examination is diagnostic of mycobacterial cervical lymphadenitis.
Langerhans giant cells, caseating necrosis, granulomatous inflammation and
calcification can be seen.
The presence of microabscesses, ill-defined granulomas, noncaseating granulomas and
a small number of giant cells is more prominent in nontuberculous adenitis when
compared with tuberculous adenitis.
Biopsy material should always be sent in normal saline for mycobacterial culture.

Recommendation

Incision biopsy is not recommended, as this can result in sinus formation and poor
healing. Biopsies should always be excision in addition to histopathological
examination. Biopsy material should always be sent in normal saline for mycobacterial
culture.

4.4.5.4 Culture

62
Culture of mycobacterium is of diagnostic for mycobacterial cervical lymphadenitis.
However, a negative culture result should not exclude the diagnosis of mycobacterial
cervical lymphadenitis. The presence of 10–100 bacilli per cubic millimeter of the
specimen is enough for a positive culture result. Different media can be used to
culture the mycobacteria (L-J, Middlebrook, and Bactec TB). However, several weeks
are needed to obtain the culture result. Cultures are positive in 10–69% of the cases.

4.4.5.5 Tuberculin Test

False-negative reactions can occur in about 20% of all persons with active tuberculosis.
The tuberculin test is considered diagnostic in mycobacterial infections, though its
value in diagnosing disease is debated.

In mycobacterial cervical lymphadenitis cases the test may be positive (49%),

intermediate (36 %) or negative. (15%)

Recommendations

The tuberculin skin test (TST) is positive in the majority of patients with TB
lymphadenitis (in the absence of HIV infection), positive TST is not sufficient to
establish the diagnosis. A negative TST is not helpful in excluding the diagnosis,
especially in immunosuppressed individuals.

A positive reaction of > 10mm which would favour lymphadenitis due to MTB than due
to MOTT.

4.4.5.6 Molecular Testing with Polymerase chain reaction (PCR)

Molecular Testing Polymerase chain reaction (PCR) is a fast and useful technique for
the demonstration of mycobacterial DNA fragments in patients with clinically
suspected mycobacterial lymphadenitis. The presence of few dead or live

63
microorganisms is enough for PCR positivity. The PCR can be applied on the materials
obtained by FNA and can reduce the necessity for open biopsy.

Its sensitivity ranges between 43% and 84%, and its specificity between 75% and
100%. PCR can be applied when smears and cultures are negative. PCR is a
confirmatory and sensitive technique for the diagnosis of mycobacterial cervical
lymphadenitis. It can differentiate between lymphadenitis caused by Mycobacterium
tuberculosis and that caused by MOTT. It is used as an adjunct to conventional
techniques in the diagnosis of mycobacterial infections.

Recommendations
PCR has a sensitivity that ranges between 43% and 84%, and its specificity between
75% and 100%; it can differentiate between MTB and NTB infections. Presence of DNA
fragments from dead bacilli can give a positive result.It is done for problem cases.

The PCR should be reserved only for problematic cases

4.4.5.7 Radiology and imaging

Chest radiograph, ultrasound, CT and MRI of the neck can be performed in

mycobacterial lymphadenitis. In TB lymphadenopathy associated chest lesions on
chest radiography are commonly seen in children, but less common in adults.

Ultrasound of the neck can demonstrate singular or multiple hypoechoic and

multiloculated cystic lesions that are surrounded with a thick capsule.

In CT, the presence of conglomerated nodal masses with central hypodensity, a thick
irregular rim of contrast enhancement and inner nodularity, a varying degree of
homogeneous enhancement in smaller nodes, dermal and subcutaneous
manifestations of inflammation, such as thickening of the overlying skin, engorgement
of the lymphatics and thickening of the adjacent muscles, and a diffusely effaced
fascial plane may suggest mycobacterial cervical lymphadenitis. However, these

64
findings may also be seen in other diseases like lymphoma and metastatic
lymphadenopathy.

Computed tomography (CT) can be a useful tool to distinguish between TB

lymphadenitis and lymphoma. In patients with lymphoma, lower para aortic nodes
involvement is more common. TB more often involved upper para aortic, lesser
omental, mesenteric, and anterior para-renal lymph nodes . Peripheral enhancement
(often with a multilocular appearance) was also a feature of TB lymphadenopathy;
homogeneous attenuation was more common in the setting of lymphomatous
adenopathy.

MRI may reveal discrete, matted and confluent masses. Necrotic foci, when present,
are more frequently central than peripheral, and this together with the soft tissue
oedema may be of value in differentiating mycobacterial cervical lymphadenitis from
metastatic nodes. If the cervical mass is necrotic, there will be low and high signal
intensity in the center of the mass in T1- and T2-weighted images, respectively.

4.4.5.8 Bronchoscopy

In the setting of isolated intrathoracic lymphadenopathy, bronchoscopy may be useful

to establish a diagnosis of TB if sputum studies are negative.
Mediastionscopy with biopsy is indicated in assessing isolated mediastinal nodal
involvement.

4.4.5.9 HIV testing

Patients with suspected or proven TB should undergo HIV testing.

Recommendations

65
All patients with suspected TB LN should have a chest radiograph to rule out
concomitant pulmonary TB and to assess mediastinal nodes.

US is an inexpensive useful mode of imaging in patients with cervical lymhadenopathy.

It can also provide a guide for FNA and can assess nodes in follow up of patients or
those who develop complications. US should be used where available for assessment
of cervical lymphadenopathy.

CT or MRI is useful in assessing mediastinal and abdominal node involvement when

these are suspected.

4.4.6 Treatment

Antituberculosis treatment is the mainstay in the management of TB lymphadenitis.

First-line drugs are isoniazid (INH), rifampicine, ethambutol, pyrazinamide are given
daily during a 2 month intensive phase and isoniazid (INH), rifampicine for a further 4
months of continuation phase.

With treatment reduction of size of the lymph nodes swelling without complications
may occur in 70-90% of patients. Early institution of specific antituberculosis
treatment and close clinical monitoring for adverse drug reactions are the key to the
successful management.

Paradoxical reaction
Antimycobacterial therapy may prompt a paradoxical reaction or increase in lymph
node size and/or enlargement of additional lymph nodes during or after cessation of
treatment.This is attributable to an immune response to dying M. tuberculosis
organisms.

Clinical manifestations may include lymph node enlargement (12 %), fluctuance (11
%), overlying erythema and/or spontaneous discharge (7 %).

Repeated FNA with AFB smears and culture helps to differentiate true bacteriological
relapse from immunological reactions.TB PCR helps to differentiate MTB from MOTT.
66
In few cases even after treatment FNAC may remain positive for tuberculosis and even
for AFB because of dead bacilli. Therefore treatment in such cases should be given in
culture-positive cases only.

Corticosteroids

Systemic steroids have been shown to reduce inflammation during the early phase of
therapy for lymph node tuberculosis and may be considered if a node is compressing a
vital structure i.e. bronchus or in diseases involving a cosmetically sensitive areas.

Prednesolone, 0.5mg/kg per day for 4 weeks followed by gradual tapering over the
next 4 weeks, along with appropriate chemotherapy is adequate. However, the safety
and utility of this approach remains largely unproven except in intrathoracic disease
where it was found to relieve the pressure on the compressed bronchus.

4.4.7 Difficulties in managing lymph node TB

Apart from difficulties encountered in diagnosis of lymph node tuberculosis
mentioned earlier, certain problems may be encountered during its treatment.
These include;

1. Appearance of freshly involved nodes

2. Enlargement of the existing nodes

3. Development of fluctuation

4. Appearance of sinus tracts

5. Residual lymphadenopathy after completion of treatment

6. Relapses
67
Possible explanations of these responses to therapy in lymph node tuberculosis
include:

1. Enhanced delayed hypersensitivity reaction in response to mycobacterial antigens

released during medical treatment of the disease

2. Poor drug penetration into the lymph node

3. Unfavourable local milieu

4. Co- existence of additional pathology such as lymphomas and HIV etc.

5. Disease caused by MOTT

6. Unidentified drug resistance

4.4.8 How to overcome difficulties in managing lymph node

tuberculosis?
Proper care in diagnosis, evaluation and close monitoring of the case during treatment
are the keys to success in the management of lymph node tuberculosis.

A suggested management plan is as follows;

1. Record all the possible sites of involvement, nature and size of the involved
lymph nodes at the inception of treatment.

2. Identify any co-existing disease like HIV, lymphoma and manage appropriately.

3. Most nodes that enlarge during therapy or appear afresh will ultimately
respond to treatment. Only close follow up is required in these patients.

4. Appearance of fluctuation in one or more lymph nodes calls for aspiration

under aseptic precautions.

4.4.9 Indications for surgery

68
Surgical techniques include aspiration, incision and drainage, curettage, complete
surgical excision of the affected lymph nodes and the overlying skin and selective
nodal or functional neck dissection when required.
When lymph nodes are fluctuant and ready to drain, anti gravity aspiration should be
done.
Aspiration, which may result in 50% cure rate, can be performed when surgical
excision is limited. Curettage which may result in 70% cure rate, can also be made
when the lesion is in proximity to the nerve or there is extensive skin necrosis
Lymph node excision usually is not indicated. Surgery increases the cure rate with
excellent cosmetic results and a low complication rate. Antibiotics are used to
augment surgical therapy.
Simple incision and drainage are associated with prolonged postoperative wound
discharge and hypertrophic scarring. Excision of the skin overlying the mass can be
performed when there is a fistula, scar formation, or necrosis.
Residual lymph nodes after completion of treatment should be observed closely. Any
increase in size or appearance of symptoms calls for excisional biopsy for
histopathology and culture. Most of these patients will respond to retreatment with
the same regimen.
All efforts should be made to isolate the causative agent and to obtain prompt
sensitivity testing particularly in relapsed cases/nonresponders and chemotherapy
modified accordingly.

4.4.10 TB lymphadenitis in HIV infected patients

Among patients with TB lymphadenitis in the setting of HIV infection, there may be a
significant mycobacterial load with concomitant systemic findings including fever,
sweats, and weight loss. Abnormal chest radiography is frequently observed, and such
patients are more likely to have disseminated TB with lymphadenitis at more than one
site.

69
Diagnosis of TB lymphadenitis is established by histopathology examination along with
AFB smear and culture of lymph node material. The yield of FNA appears to be highest
in the setting of HIV infection and in regions where the prevalence of TB is high.

Specimens should be submitted for microscopy, culture, cytology and PCR testing
(where ever available).

PCR testing is especially usefull to exclude atpical mycobacterial infections in HIV

positive patients.

Excisional biopsy for histopathologic and microbiological evaluations has the highest
diagnostic yield and should be pursued in cases where fine needle aspiration is not
diagnostic.

Chest imaging should be pursued in the setting of suspected TB lymphadenitis. Many

patients with tuberculous lymphadenitis have no evidence of active pulmonary TB on
chest x-ray; abnormalities have been described more frequently among patients with
HIV infection in some series. (See 'Imaging' above.)

Those who are co-infected with HIV are more likely to develop paradoxical reactions
while on antitubercular drugs. A similar phenomenon is also seen in patients with HIV
infection who begin concurrent antiretroviral therapy is a result of immune
reconstitution.

4.4.11 Tuberculous lymphadenitis in children

As in adults tuberculous lymphadenitis in children has a wide differential diagnosis.

Infection with mycobacteria other than tuberculosis (MOTT) is commoner in children
than infection with mycobacterium tuberculosis. The initial focus of infection is
decidual teeth with harbour MOTT.
Multiple matted nodes, sinus formation favour MTB and Mantoux would not show a
positivity of more than 10 mm. Histologicaly non-caseating granuloma , stelatte
shaped Langerhan cells , micro-abscess and neutophilic infilteration favours MOTT
while caseation , palliasde of lymphocytes in periphery favour MTB.

70
4.5 TUBERCULOSIS OF SKIN
As the location is very unusual, this form of TB is frequently not diagnosed. Its clinical
presentation is very variable, which may range from small papules and erythemas to
large tuberculomas.
71
TB affecting the skin includes both cutaneous TB (direct infection of the skin) and
tuberculids (cutaneous reaction to non cutaneous TB infection)

Cutaneous TB is not common, as the organism prefers temperatures that are higher
than those at the surface of the body. Patients with skin involvement is about 1% of all
cases of extra pulmonary tuberculosis

4.5.1 Clinical manifestations

• Tuberculous chancre: result of direct inoculation into the skin. Patient presents
with chronic ulcer with regional lymphadenopathy. This occurs in patients with
no immunity to tuberculous bacilli.

• Warty Tuberculosis: Presents with a warty plaque, result from direct inoculation
to skin in a patient with good immunity to tuberculous bacilli.

• Scrofuloderma: Involvement and breakdown of the skin overlying a tuberculous

leision.

• Milliary tuberculosis: Acute haematogenous dissemination causes crops of

papules or pustules in a patient who is very ill.

• Lupus vulgaris: Progressive forms of cutaneous tuberculosis occur in a patient

with good immunity. Characteristic lesion is a progressive red plaque composed
of nodules of an apple – jelly colour. Mostly occur in head and neck region and
trunk.

• Tuberculides: This term is applied to any group of eruptions which occur in

response to an internal focus of tuberculosis and clear with anti tuberculous
therapy.

• Papulonecrotic tuberculides: Patient develops necrotizing papules.

• Erythema nodosum: Painful nodules usually over shins.

• Erythema induratum: Nodular lesion occur secondary to tuberculous focus

elsewhere in the body. Usually localized to legs of females.

72
TB should always be suspected when chronic, painless cutaneous lesions are observed.
Diagnosis will be based on presence of acid fast bacilli in the lesion histology, Positive
reaction to tuberculin, and presence of tuberculosis else where in the body.

Rarely infection with other mycobacteria is reported. Well known condition is fish tank
granuloma caused by M.marinum present in the fish tank water.

Treatment of skinTB

Treatment is as same as that for Pulmonary Tuberculosis.It is important to note that

lesions may evolve very slowly even when the treatment is correct.

4.6 TRACHEOBRONCHIAL AND UPPER AIRWAYS

TUBERCULOSIS
73
TB of the trachea and large bronchi in children is frequently a complication of the
primary disease. It may be associated with mediastinal adenopathies. Endobronchial
involvement is the result of rupturing of caseous material in the bronchial wall, or of
dissemination through the lymph vessels throughout the bronchial tree producing
ulcerations in the mucous membrane. This form is known as gangliobronchial TB.
These adenopathies do not only perforate the 341 bronchus but may also compress it.
For various reasons, residual stenotic lesions may form in the airway, possibly leading
to future repeated infections. In these cases, early diagnosis is of critical importance as
a high percentage of cases will need aggressive treatment if complications are to be
avoided.

Endobronchial involvement occurring via the direct implantation of tuberculous bacilli

from active parenchymatous lesions, which are transmitted through the air, is most
common in adults. The most common symptoms, apart from the general TB
symptoms, are a persistent cough and possible stridor. The epiglottis, larynx, and
pharynx are frequently affected and are usually an extension of pulmonary TB.

Clinical manifestations include hoarseness, earache, pain on swallowing, and

ulcerations on the tongue. This type of TB must be differentiated from cancer of the
larynx, although the latter condition is rarely painful. It is difficult to know how
prevalent these types of TB are since a smear microscopy and/or positive culture are
the principal diagnostic tests used in all cases. Nevertheless, in the case of pulmonary
TB, these results will aid in the diagnosis of the disease in the vast majority of cases,
considering that the upper airways, trachea, or large bronchi may also be affected.

The prevalence of tuberculous involvement of the trachea and large bronchi is

currently unknown. Before chemotherapy, it was traditionally considered a
complication of cavitary TB and was a fairly common presentation.

Various mechanisms are involved in these forms of TB. In children, this is frequently a
complication of primary TB. It is generally accepted that the incidence of bronchial TB
is increasing in the HIV-infected population, which may explain some cases in which a
smear-positive result and a normal chest radiograph have been observed. In the case
of pulmonary TB, these results will be true in the vast majority of cases and may lead
to a diagnosis of the disease, while considering the possibility that the upper airways,
trachea, or large bronchi may also be affected. For this reason, in order to determine if
74
there is extrapulmonary involvement, it is necessary to use endoscopic techniques,
such as laryngoscopy and bronchoscopy, which are capable of locating the lesions and
serving as a guide for a biopsy to confirm the diagnosis. In any event, treatment and
cure are the same as with pulmonary TB, although surgical intervention is sometimes
necessary in the case of gangliobronchial TB in children.

75
4.7 TUBERCULOSIS OF HEART

4.7.1 Tuberculous Pericarditis

The pathogenesis of pericardial TB has been attributed to hematogenous spread from
initial primary infection or later dissemination of reactivated disease, or contiguous
spread from adjacent organs, such as mediastinal nodes, lungs, spine, and sternum or
during military dissemination. It is usually accompanied by tuberculous disease at
another site.

76
The earliest clinical presentation of TB pericarditis is of a serosanguinous exudated
effusion that may resolve spontaneously over a few weeks, but may also heal with
constriction.

Clinical features are generally nonspecific and subtle. The onset may be abrupt or
insidious with symptoms such as chest pain, dyspnea, and ankle oedema.
Cardiomegaly, tachycardia, fever, pericardial rub, pulsus paradoxus, or distended neck
veins may be found on examination.

Imaging including radiographs and echocardiograms are non diagnostic. Diagnostic

yield is improved if pericardial fluid and tissue (pericardial biopsy) are sent for AFB
smear and culture (50% positive) as well as histopathologic analysis, especially in
symptomatic patients.

Antituberculosis treatment has reduced the incidence of constrictive pericarditis (10%

to 20% of treated cases) and morality associated with tuberculous pericarditis.
Empirical treatment should be considered, especially in the immune compromised.In
addition to antituberculous therapy, corticosteroids are recommended to hasten
resolution of symptoms and to reduce reaccumulation of fluid. The recommended
adult steroid dosage is 1mg/kg per day for 4 weeks, tapered slowly over the following
8 weeks.

In situations where the effusions reaccumilate or central venous pressure remains

persistently elevated despite removal of pericardial fluid and use of antituberculosis
drugs and steroids, early pericardiectomy is suggested.

4.8 ABDOMINAL TUBERCULOSIS

Abdominal TB includes disease of the intestines, peritoneum and mesenteric glands.
The intestines and peritoneum are involved with similar frequency. Genitourinary tract
and other organs such as liver, spleen, and adrenal glands usually are affected as a
consequence of miliary tuberculosis. The pathogenesis of abdominal TB has been
attributed to direct infection through swallowing of infected sputum or ingestion of
contaminated milk, hematogenous spread from initial primary foci in the lung or later

77
dissemination of reactivated disease or, rarely, contiguous spread from adjacent
organs.

Gastrointestinal involvement usually occurs in the ileocecal, jejunoileal or anorectal

area. A minority of cases are made up of mesenteric adenitis alone. A mass in the right
lower quadrant is palpable in 25% to 50 % of patients. In those with peritoneal
involvement, common presenting symptoms are abdominal swelling (particularly in
patients with coexisting alcoholic liver disease), abdominal pain, fever, weight loss and
diarrhoea. Patients with cirrhosis and those undergoing continuous ambulatory
peritoneal dialysis are at increased risk. The peritoneum becomes studded with
tubercles that leak proteinaceous fluid, clinically identified as ascites.

Late presentations of TB peritonitis can be “dry” with predominant fibro-adhesive

features (“doughy abdomen”). The macroscopic appearance of lesions may be
ulcerative (60%), hypertrophic (10%) or a combination of both (ulcero-hypertrophic,
30%).Patients with ileocecal TB may present with clinical and radiographic features
that are indistinguishable from those of Crohns disease, such as chronic abdominal
pain (up to 90%), constitutional symptoms and a right lower quadrant mass (25% to
50%). The differentiation of enteric TB from Crohn’s disease is difficult, though it
should be noted that patients with Crohns disease rarely have ascites or
circumferential ulcers, while cobblestoning”on colonoscopy is rarely seen with enteric
TB. Confirmation of the appropriate diagnosis is essential, given the implications of
immunosuppressing treatment for suspected Crohns disease that is, in fact, TB.

4.8.1 Investigations
1) Radiographic features of enteric TB are nonspecific, though the most common
finding on CT scan is concentric mural thickening of the ileocecal region (with or
without proximal dilation) and characteristic adjacent mesenteric lymphadenopathy
with hypodense centres.

2) Although colonoscopy and biopsy for histopathology and culture may be the
procedure of choice (up to 80% diagnostic yield), the diagnosis is frequently made only
after laparotomy. It should be noted that in Crohn’s disease, caseating granulomas are
rarely found. Empiric treatment is also an option prior to laparotomy, as the response
to antituberculosis treatment can be followed.

78
3) Ascitic fluid is exudative with a predominance of lymphocytes, although when TB
peritonitis complicates chronic peritoneal dialysis, neutrophils may predominate.

4) Culture yields of a large volume of ascitic fluid (1 L) after centrifugation are high (>
80%), though smears are often negative

5) Laparoscopy with peritoneal biopsy is the single best diagnostic procedure.

Targeted biopsies of the typical white nodules or tubercles seen in tuberculous
peritonitis lead to positive histopathologic and smear results in the majority of cases.

6) Radiologic features are nonspecific, though peritoneal thickening, omental caking

and septated ascites are suggestive of the diagnosis.

4.8.2 Tuberculous Peritonitis

The risk of tuberculous peritonitis is greater in patients with HIV infection or cirrhosis
and in those undergoing continuous ambulatory peritoneal dialysis. Tuberculous
peritonitis results from reactivation of latent foci in the peritoneum. Patients present
with the insidious onset of ascites, abdominal pain, and fever.

4.8.3 Investigations
4.8.3.1 Laborotary investigations

Peritoneal fluid is exudative, with a serum-ascites albumin gradient (SAAG) of less than
1.1 g per dL (11 g per litre). Peritoneal fluid leukocyte count varies from 150 to 4,000
per mm3 (0.15 to 4.00 × 109 per litre) with a lymphocytic predominance. However, a
neutrophilic pleocytosis may be seen with tuberculous peritonitis complicating
continuous ambulatory peritoneal dialysis.

Peritoneal fluid adenosine deaminase (ADA) level has a high sensitivity and specificity
if a cut off value greater than 33 U per litre is used.

Anaemia may be present, usually due to anaemia of chronic disease. Lymphocytosis is

usually evident. Inflammatory markers including ESR and CRP may be elevated.

Mantoux test is usually positive in 70% with TB peritonitis. However, a negative result
does not exclude the diagnosis.
79
TB-PCR has the capability of rapid detection of mycobacteria. However, utility of
ascitic fluid for PCR in detecting TB has not been well established.

4.8.3.2 Imaging

CXR is mandatory to exclude co-existing or previoius pulmonary TB. Plain X ray of

abdomen may reveal calcification or fluid levels due to bowel obstruction. USS and CT
of abdomen may reveal ascites with fine mobile septation, peritoneal thickening and
omental caking, bowel obstruction and lymphadenopathy.

In suspected coexisting intestinal tuberculosis, Barium meal and follow through (for
small bowel or ileo cecal TB), Barium enema (for colonic TB), Endoscopy and
Colonoscopy will be helpful.

4.8.3.3 Microbiology

Centrifugation of 1 L of peritoneal fluid enhances the yield of AFB smear and

mycobacterial culture.

4.8.3.4 Histology

Peritoneal biopsy guided by laparoscopy or mini-laparotomy is diagnostic in more than

95 % of patients and is strongly recommended.

4.8.4 Treatment of abdominal tuberculosis

Anti TB regimen for peritoneal tuberculosis is as for pulmonary disease. Place for
Steroid treatment in peritoneal TB is controversial, even though some studies have
shown beneficial effects.

Nutritional support is important to upgrade the immune status and general well being,
in this chronic illness.

4.8.4.1 Surgical Indications

80
Surgical interventions are reserved for diagnostic and therapeutic indications.

1. Diagnostic (Open/ Laparoscopic)

Laparoscopy may not be suitable in the presence of ascites or severe

adhesions.

1. Biopsy of the LN / Peritonium

2. Diagnostic laparotomy

B. Treatment

1. Intestinal obstruction / perforation in to peritoneal cavity

Surgery may be life saving in severe intestinal obstruction, where it is useful

for release of adhesions and strictures, necrotic bowel resection or bowel
anastomosis.

2. Confined Intestinal perforation with Intesinal / Anorectal fistula or

abscess formation

Fistulectomy or drainage may be needed in some cases.

2. Massive GI bleeding

81
BOX 8: Investigations for abdominal tuberculosis

➢ Microbiology

▪ PCR

▪ Microscopy

➢ Histology

➢ Lab investigations

▪ Heamatology

▪ Mantoux

➢ Imaging techniques

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4.9 OCULAR TUBERCULOSIS
Tuberculosis is a chronic granulomataus infection primarily affecting the lung but
other organs including the eye may get involved.

4.9.1 Pathogenetic Mechanism of Ocular Tuberculosis

It is now firmly believed that ocular tuberculocis results from the haematogenous
seeding from the primary complex or the secondary lesions that may develop, where
the bacilli remain latent for years before reactivation.

Clinical lesions develop depending upon the susceptibility of the host in terms of cell
mediated immunity. The clinical lesions depend on the availability of number and
virulence of the bacilli, the host resistance in the form of availability of sensitized T-
helper cells in the tissue.

4.9.2 Prevalence of the Ocular Tuberculosis

The lack of the diagnostic criteria coupled with difficulty in establizing tissue or
microbiological diagnosis has led to be believed that ocular tuberculosis was rare
However, recent report have shown that tuberculosis may indeed be a common
cause of uveitis.It has been shown that nearly 70% of infective uveitis was caused
by tuberculosis, which is approximately 10% of all the uveitis cases.

The clinical lesions of tuberculosis may affect any ocular tissue including sclera,
lacrimal sac, uvea, retinal vessels or the optic nerve head. The vision may also get
affected in patients of tuberculous meningitis and toxic drug reactions to the
antituberculous drug theraphy.

4.9.3 Tubercular Anterior Uveitis

The tuberculosis may present either as the anterior,intermediate,posterior or pan
uveitis in one eye or bilaterally,usually asymmetric,presenting as acute,subacute or
chronic uveitis.The patient may have symptoms such as pain,redness or decrease
in vision or seeing floaters.The most characteristic feature of the tubercular

83
anterior uveitis is the presence of multiple ;mutton fat,yellowish white
granulomatous keratic precipitateon the corneal endothelium .The cornea may
show mild oedema.Tthe iris may be thickened. The snow ball opacities are seen as
a string of pearls inferiorly in the vitreous cavity with or without vitreous haze.

4.9.4 Choroidal Tubercle

Choroidal tubercles are the most characteristic finding of ocular
tuberculosis.Nearly 25to30 percent patients of disseminated/milliary tuberculosis
and tubercular meningitis may show choroidal tubercle. The tubercles may be
unilateral or bilateral. The retinal detachment can occur overlying choroidal
tubercles. These lesions usually heal over several weeks with or without treatment
leaving behind atrophic, variably pigmented scars.In HIV patients choroidal
tubercles are asymptomatic and picked up only on routine examination.

4.9.5 Tubercular Retinal Vasculitis

The retinal vasculitis primarily affects the retinal veins but rarely the
arterioles.Whether the vasculitis represent a hypersensitivity reaction or may also
have an element of active infection in atleast some cases is not yet clear .It usually
affect small or large segments of retinal veis, appearing as fluffy grayish white
perivascular infiltrates with associated superficial haemorrages.The macula may
also affected with macular oedema and hard exudates.Over a period of several
weeks the vasculitis heals leaving behind residual haemorrage and exudates. The
retinal vasculitis can cause extensive ischaemia of the retina leading onto the
development of retinal neovascularization,which may result in either
preretinal/subhyaloid haemorrhages or frank vitreous haemorrhages.This can lead
to sudden loss of vision.Timely retinal ablation of the ischaemic retina by Laser
photocoagulation lead to regression of the new vessel over 3-4 weeks ,this can
prevent the occurrence of vitreous haemorrages.Some patients requires pars plana
Vitrectomy to clear the haemorrage.

84
4.9.6 Large Subretinal Abscess/Granuloma
Usually occur in patients with disseminated tuberculosis .The patient may present
with unilateral or bilateral large subretinal abscess like lesions Such lesions are
often accompaniedby exudative retinal detachment Such abscesses represent
rapidly multiplying tubercular bacilli .Rapidly progressive disease may cause
endophthalmitis.

4.9.7 Tubercular serpiginous like choroiditis

Most often it present as asingle or multifocal placoid lesion in the posterior pole. It
may be asymptomatic if the forvea is spared.

4.9.8 Diagnosis of Occular Tuberculosis

Diagnosis of the ocular tuberculosis is difficult, for obvious reasons, the
intraocular fluid for culture is scanty, organisms are too slow to grow in
cultures and a negative culture does not ruleout the diagnosis of ocular
tuberculosis. Similar presentation of ocular involment can be seen in other
medical conditions such as sarcoidosis, toxoplasma, shypilis, collagen
vascular diseases etc. hence appropriate investigation needs to be carried
out to exclude suspected causes.

4.9.9 Occular investigations

• Demonstration of AFB/culture of M.Tuberculosisfrom the ocular fluid

• Positive polymerase chain reaction from ocular fluid

4.9.10 Systemic Investigation

• Positive mantoux reaction

• Evidence of healed or active tubercular lesion on radiographyof chest

85
 • Exclusion of other infective uveitis in low incidence tuberculosis regions

• Evidence of extra pulmonary tuberculosis diagnosed by demonstration of

tubercular granuloma/culture of M.tuberculosis.

4.9.11 Positive Therapeutic response

A positive response to antituberculous theraphy over a period of 4-6 weeks

is highly suggestive of a possible tubercular aetiology.

4.9.12 Treatment of Ocular Tuberculosis

Medical Management

Drug treatment for ocular tuberculosis is same as pulmonary tuberculosis.

The role of concomitant use of corticosteroid therapy is controversial.Low
dose systemic corticosteroids for 4 to 6 weeks, along with multidrug
antituberculosis chemotherapy is helpful in limiting damage to the ocular
tissues from delayed type hypersensitivity.

86
4.10 TUBERCULOSIS PLEURAL EFFUSIONS
4.10.1 Introduction
Tuberculoous pleural effusions (TBPE) are second only to tuberculous lymhadenopathy
in terms of incidence of extr-pulmonary tuberculosis. The HIV/ AIDS pandemic has
resulted in doubling of the incidence of extra-pulmonary TB and the increasing
recognition of tuberculous pleural effusions.

4.10.2 Epidemiology
The frequency of pleural involvement has been variably reported ( 4% in the United
States to 23 % in Spain ) . The incidence of extrapulmonary TB (EPTB) has more than
doubled following the HIV pandemic. The incidence of TB pleural effusions (TBPE) in
HIV/ AIDS patients has been variably reported from 15 to 90 %.

87
In Sri Lanka lymphadenopathy is the commonest form of extra-pulmonary TB (EPTB)
accounting for 35 % while TBPE accounts for 20%. The number of extra-pulmonary
cases of TB reported over the years has been increasing in Sri Lanka.

4.10.3 Pathogenesis
TBPE can manifest as Primary or reactivated disease. Rupture of a subpleural caseous
focus in the lung and the consequent release of Mycobacterial antigens into the
pleural space is considered the initiating event in the pathogenesis of Primary TBPE.
This results in an interaction with predominantly CD4+ T –lymphocyte, mediated
delayed hypersensitivity reaction. This may occur during primary or reactivation TB
and may or may not involve viable bacilli entering the pleural space.

The CD4+ T-lymphocytes are of the T-helper type 1 (Th1) cells resulting, in an
interferon γ (INF γ) driven cytokine profile. INF γ is essential for macrophage activation
and killing and containment of mycobacteria Intercellular adhesion molecule-1 is also
over expressed resulting in increased capillary permeability and accumulation of fluid
in the pleural space. The protein rich exudates causes blockage and impaired drainage
of lymphatics also contribute to this. Reactivation disease is frequently associated
with paranchymal diseases and results from entry and active replication of
mycobacteria in the pleural space.

4.10.4 Clinical Features

Although tuberculosis is considered a chronic illness TB pleuritis most commonly
manifests as an acute illness. 1/3 rd of patients are symptomatic for < 1 week and the
remaining 2/3 are symptomatic for < 1 month.

Pleuratic chest pain (75 %) and non-productive cough (70 %) are the commonest
symptoms. Pain usually precedes the cough. Most patients are febrile but a normal
temperature does not rule out the diagnosis.

TBPE though considered a disease of the young (mean age 28 years) can present in the
elderly and in these instances is mostly due to reactivation disease.

TBPE are typically unilateral and small to moderate in size occupying less than 2/3 of
hemithorax .HIV positive patients with TBPE tend to be older, have a higher incidence
88
of fever, dyspnea, night sweats, hepato-splenomegally and lymphadenopathy. They
are more likely to have a pleural fluid smear and culture positive for M. tuberculosis, a
positive pleural biopsy result and /or a negative tuberculin test. Chronic TB empyema
represents active infection of the pleural space.

Chronic TB empyema can result in the development of a bronchopleural fistula or

empyema necessitasis (empyema fluid breaks out through the chest wall).

BOX 14: Clinical features of

TB pleural effusion

• Pleuratic chest pain

• Cough

• Fever

• Dyspnea

• Night sweats

4.10.5 Diagnosis
The definitive diagnosis of TBPE depends on the demonstration of M. tuberculosis
in sputum, pleural fluid and/ or culture of pleural biopsy specimens.

Classical granulomas on a pleural biopsy specimen, a positive tuberculin test, elevated

Adenosine Deaminase (ADA), positive nucleic acid amplification test and INF γ levels in
pleural fluid are supportive of the diagnosis.

4.10.5.1 Sputum examination

20 % of patients with TBPE have co-existing paranchymal lung involvement that is

radiologically visible; in these patients the yield of a positive sputum culture in an
induced sample of sputum approaches 55 %. Even in the absence of radiological
evidence of paranchymal involvement, 12 % will have a positive smear result in an
induced sample of sputum.
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RECCOMENDATION

Sputum induction with direct smear and culture should be perused in all patients with
suspected Tuberculosis pleural effusions.

4.10.5.2 Tuberculin Skin Testing (TST)

A positive TST (Mantoux) is supportive of TBPE in areas of low prevalence.

A negative result occurs in 1/3 rd of patients. A negative result can occur in the
following situations

1) Anergy secondary to immuno- suppression or malnutrition.

2) HIV positivity.

3) Sequestration of purified protein derived T-lymphocytes in pleural space.

In patients with TBPE TST will almost always become positive if repeated 6-8 weeks
later (unless immuno-compromised) and this can be used as supportive eviden

RECOMMENDATION

A TST should be part of the diagnostic work up of TBPE.

A positive TST is supportive of a diagnosis of TBPE but should be interpreted along

with other evidence of pleural fluid examination. A negative test does not rule out
Tuberculosis pleural effusion.

4.10.5.3 Imaging

Chest radiography reveals a small-moderate pleural effusion. Paranchymal

involvement occurs in around 20 %. Contrast enhanced CT scans can increase this
diagnostic sensitivity by demonstrating lung paranchymal involvement (86%) and
lymphadenopathy.

Ultrasound scans (USS) are useful in demonstrating fibrin bands, septations, encysted
fluid, pleural thickening and occasionally pleural nodules. USS is also useful in
performing guided aspirations, intercostals (IC) tube placement and guided biopsy.
90
RECOMMENDATION

All patients should have an initial chest radiograph with documentation of changes so
that this could be used for comparison on follow up of these patients.

USS is useful guide for initial assessment, locating sites for aspiration/ biopsy and for
follow up. This should be used if the facilities are readily available.

CT scans are required in those with complicated Tuberculosis pleural effusion, who
may eventually require a surgical decortications procedure.

4.10.5.4 Pleural fluid analysis

A TBPE is typically clear and straw coloured, but can be turbid or serosanguinous and
never grossly bloody. It is important to document macroscopic appearance of the
fluid. It is always an exudate. PH is usually around 7.30 -7.40. In 20% it can be < 7.30
.Glucose is > 60 mg /dl in 80 – 85 % of cases though in 15 % it can be < 30 mg /dl.
Specimens for cytology must be sent in an EDTA bottle and a differential cell count
requested.

Older literature suggests that a pleural fluid mesothelial cell count of > 5% virtually
excludes TBPE. This is because uniform inflammation of pleural surface virtually
prevents exfoliation of mesothelial cells into pleural cavity. However, there have been
case reports of HIV positive patients with higher mesothelial cell counts in pleural
fluid. A pleural fluid eosinophil count of > 10 % virtually excludes TBPE unless there is a
pnemothorax or repeated thoracenteses has been performed.

In the first two weeks of illness cells may be predominantly neutrophillic, if serial
thoracentese is performed this shows a shift towards predominantly a lymphoctic
fluid.

RECOMMENDATION

All patients with undiagnosed pleural effusions will need a diagnostic pleural tap.
Utilization of ultra-sound scans for guided aspiration or marking of site for aspiration
will result in higher rate of successful pleural aspiration.

91
4.10.5.5 Microbiology

Direct examination of pleural fluid by Zeihil-Neelson staining detects acid-fast bacilli

(AFB) in < 10 % of case. In suspected TB empyema yields are higher. In HIV positive
patients yield is > 20 %. Culture for mycobacteria is positive in less than 40%. Bedside
inoculation of mycobacteria into culture media, use of liquid media, and BACTEC
system for culture has shown an increase diagnostic yield.

RECOMMENDATION

All patients should have pleural fluid sent for TB culture.

4.10.5.6 Adenosine Deaminase (ADA)

ADA is the enzyme that catalyzes the conversion of adenosine to ionosine. It is a

predominant T lymphocyte enzyme and its activity is increased in conditions which
cellular immunity is stimulated. There are two molecular forms of ADA. ADA1 and ADA
2. ADA1 is found in all cells but greatest activity is in lymphocytes and monocytes.
ADA 2 is found in monocytes and macrophages. The majority of ADA found in TBPE is
of ADA 2, ADA 1 is found in other pleural effusions also. ADA 1/ ADA 2 ratio of < 0.42
will only slightly increase the sensitivity and specificity of ADA in the diagnosis of TBPE
and is not needed in the vast majority of the cases as cost of test is higher.

An ADA level of > 70 IU / L is highly suggestive of TBPE and a level < 40 IU /L virtually
excludes the diagnosis. The specificity is increased when the lymphocyte / neurtrophil
ratio of > 0.75 and an ADA level of > 50 IU / L is considered. ADA measurement is a
rapid, minimally invasive, relatively inexpensive test which is gaining popularity
because of sensitivity of 95 % and specificity of 90 % respectively and could replace
pleural biopsy in high TB prevalence regions.

ADA levels in TBPE in HIV/ AIDS, renal transplant patients are comparable to those of
immuno – competent people.
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Other reported conditions in which pleural fluid ADA is increased include Rheumatoid
arthritis, pleural empyema (pleural fluid is neutrophilic in these two conditions),
mycoplasma, clamydia pneumonia, histoplamosis, brucellosis, bronchoalveolar
carcinoma. Most of these conditions can be differentiated on the basis of clinical
history and other investigations.

The specificity for discriminating TB from malignant effusions, an important

differential diagnosis in the elderly, remained high (95 %) but was disappointingly low
for parapneumonic effusions.

4.10.5.7 Neopterin

Neopterine is a marker of T-cell activation, is secreted by activated macrophages.

Levels in pleural fluid have been found to be higher than in patients with TB than
patients with malignancy or other conditions. However very high levels have been
reported in ureamic pleural effusions rising doubts about it’s specificity for TB.

In one study that used histopathology as the reference standard for TB, the sensitivity
and specificity for neopterin were 44 % and 85 % respectively.

4.10.5.8 Lysozyme

Lysozyme is present in epithelial cells of granulomas, macrophages and activated

granulocytes.

Lysozyme could discriminate malignant from tuberculous effusions with a sensitivity of

100% and a specificity of 83%, compared with culture and/or histopathology of pleural
tissue.

RECOMMENDATIONS

ADA measurement is a rapid, minimally invasive, relatively inexpensive test with a

sensitivity of 95 % and specificity of 90 % respectively and could replace pleural biopsy
in high TB prevalence regions.

93
A number of commercial tests are currently available in Sri Lanka with differing cut off
values. It is not possible to comment on this variety of tests and locally relevant cut off
values as there is insufficient data locally.

Estimation of neopterin and lysozyme levels is not commercially available in Sri Lanka
at present.

4.10.5.9 T-cell response to specific antigens

Recently, in vitro, T-cell-based IFN-γ release assays (IGRAs) have been developed and
licensed for diagnosis of latent TB infection. Normally, these tests use peripheral blood
mononuclear cells (PBMCs), but they can be used with pleural fluid mononuclear cells.
These assays detect IFN-γ secreted by mononuclear cells in response to in vitro
stimulation with the Mycobacterium tuberculosis-specific antigens early secreted
antigenic target-6 and culture filtrate protein-10. The genes that encode these
antigens are not present in any of the M. bovis bacille Calmette–Guerin (BCG) strains
or certain common nontuberculous (environmental) mycobacteria. Thus, in theory,
the test should not cross-react with antigens present due to BCG vaccination. This
hypothesis as yet remains unproven. Until this issue is settled, these assays may not
offer any additional value for the diagnosis of pleural effusion.

RECOMMENDATIONS

IGRAs, designed to detect latent TB infection and currently canot be recommended for
diagnosis of TBPE.

4.10.5.10 B-cell response (antibody detection)

Serologic tests using antibodies against mycobacterial protein and glycolipids show
some potential for the diagnosis of pleural TB because of their high specificity, but are
limited by very poor sensitivity.

4.10.5.11 Nucleic acid amplification tests (NAATs)

94
Several commercial and in-house assays exist for the amplification and detection of M.
tuberculosis nucleic acids from specimens such as sputum. These tests have also been
used with specimens such as pleural fluids. In a meta-analysis of 40 studies of nucleic
acid amplification tests (NAATs) for pleural TB, Pai et al. reported that commercial
nucleic NAATs have a potential role in confirming TB pleuritis because of high
specificity (98 (95% CI 96–98)%).

However, these tests had low and variable sensitivity 43–77% and, therefore, were not
useful in excluding the disease.

RECOMMENDATIONS

The evidence is consistent that NAATs have modest sensitivity but excellent specificity
for pulmonary and extrapulmonary TB. At present, no commercial kit has been
approved for the diagnosis of extrapulmonary TB, and NAATs cannot be used in
isolation to rule in or rule out pleural TB.

Disadvantages include the sophisticated technology involved, cost, false positives due
to contamination. The evidence for the use of PCR in the diagnosis of TBPE is not as
favorable for ADA.

4.10.5.12 Pleural Biopsy

Abram’s pleural biopsy is termed “blind” or “closed” biopsy because plural surface is
not directly visualized. In patient with TBPF biopsy reveals granuloma in 50 -97 % of
patients, culture reveals mycobacteria in 39 – 80 % patients. When both methods are
combined the diagnostic yield is 60 – 95 %.

4.10.5.13 Thorascopy

Thoracoscpy has been used extensively for the diagnosis of pleural TB and malignancy.
Thoracosopy may show yellow-white tubercles on parital pleura which are mostly
concentrated in the costovertebral angles. It also allows targeted biopsy of suspicious
lesions, under direct visualization.

95
In a study that compared various diagnostic modalities of TBPE, thoracoscopy was the
most accurate (100 % on histology) and 76% positivity on culture. However, the
procedure required expertise to perform and was expensive.

The advent of Vedio-assisted thoracoscopic Surgery has made available further

evaluation of pleural disease.

RECOMMENDATIONS

All patients with suspected TBPE (especially if cytology is lymphocyte predominant)

should have a pleural biopsy with histology and culture of pleural tissue.

Pleural tissue specimens for culture should be sent in normal saline.

In patients with undiagnosed pleural effusion in whom Abrahams Needle guided

pleural biopsy has not been of help, thoracoscopic pleural biopsy is recommended.

4.10.6 Treatment
The natural history of TBPE is characterized by spontaneous resolution in 4 – 16
weeks.Pulmonary TB can develops in 43 – 65 % of patients over the next several years
if TBPE not treated.

Treatment is INAH, Rifampicin, Ethambutol and pyrazinamide for 2 months (intensive

phase) with Rifampicin, INAH for 4 (continuation phase). Fixed dose combinations of
these medications are available in the National Program for Control of Tuberculosis
and Chest Diseases.

Patients with HIV/ AIDS with TBPE are treated similarly. Clinicians must be aware of
drug interactions with anti-TB drugs in patients on highly active antiretroviral therapy
(HAART) and the Immune reconstitution Syndrome.

4.10.6.1 Corticosteriods
96
Randomized studies have investigated the possible adjunctive role of oral
corticosteroids in TBPE. Doses of 0.75 – 1 mg / kg bd weight / day were use in periods
ranging from 4 – 12 weeks. Though early resolution of fever, chest pain and dyspnea
was observed there was no difference in the development of residual pleural
thickening or adhesions on follow up. Residual lung function was similar to the group
that did not receive steroids.

RECOMMENDATIONS

There is insufficient evidence to support the use of steroids in TBPE.

4.10.6.2 Surgical Procedures

Patients who are symptomatic with large pleural effusions will require intercostals
drainage.

In TBPE complicated by septations , multiple loculi and pleural thickening , Intra-

pleural instillations of streptokinase (250 ,000 IU in 100 ml normal saline via IC tube
after an initial test dose ) , tube is left clamped for 4 hours and patient is mobilized to

facilitate uniform distribution of streptokinase. Instillations are given twice daily up to

five days.

Tssue plasmnogen actvator (tPA) is an accepted alternative fibrinolytic agent.

Decortication surgery should not be considered until completion of 6 months of anti-

TB chemotherapy.

4.10.7 Complications of TBPE

4.10.7.1 Bronchpleural Fistula (BPF)

This complication is uncommon today because of the availability of anti-TB

chemotherapy. It is a complication in patients with reactivation of TB with chronically
diseased underlying lung. When such patients develop BPF their sputum production
increases and is at risk of invasion of pleural space by bacteria resulting in septicemia.

97
Also infected material enters the tracheobronchial tree from infected pleural space
resulting in a fulminant pneumonia.

The diagnosis is suggested by the presence of an air-fluid level in the pleural space,
particularly if the level fluctuates with serial chest radiographs. The fistula can be
confirmed by injection of methylene blue or a radiopaque dye into the pleural space.

Treatment is with standard regimens of anti –TB chemotherapy and IC tube drainage.
A surgical procedure should not be attempted until the patient is given 90 -120 days of
anti –TB chemotherapy or patients sputum tests are negative for AFB.

Definitive surgical treatment consists of decortication. This is sometimes combined

with thoracoplasty because underlying lung is damaged to such an extent that it
cannot expand to fill the chest cavity. Surgery carries a high morbidity and mortality.

4.11 TUBERCULOUS EMPYEMA

It is a less common complication of PTB. It is usually the result of the rupture of a
cavity, with spillage of a large number of organisms into the pleural space. Frequently
the underlying pleura are heavily calcified.

The patient has a sub-acute or chronic illness characterized by fatigue, low-grade fever
and weight loss. Patients with tuberculosis empyema present with chest pain,
breathlessness, cough with expectoration, fever, and toxaemia. Anaemia and
hypoproteinaemia are often present. Physical examiantion may reveal finger clubbing,
clinical findings suggestive of effusion and intercostal tenderness. Occasionally,
tuberculosis empyema may present as a chest wall mass or draining sinus tract
(tuberculosis empyema necessitatis).

Radiographically, there may be obvious pleural effusion, but frequently the chest
radiograph only shows pleural thickening. The chest CT demonstrates a thick, calcified

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pleural rind and rib thickening surrounding loculated pleural fluid .Thoracentesis yields
thick pus on which AFB smear is positive.

This process may create a bronchopleural fistula with evident air in the pleural space
where a chest radiograph will show a hydropneumothorax with an air-fluid level.

The pleural fluid is purulent and thick and contains large numbers of lymphocytes.
Acid-fast smears and mycobacterial cultures are often positive. Surgical drainage is
usually required as an adjunct to chemotherapy. Tuberculous empyema may result in
severe pleural fibrosis and restrictive lung disease. Removal of the thickened visceral
pleura (decortication) is occasionally necessary to improve lung function.

Treatment is with standard regimens of anti–TB chemotherapy. Intra-pleural

streptokinases via IC tube with chest physiotherapy and mobilization of patients have
often been used with success. Difficult cases will require surgical intervention.
Decortication at open surgery or as a VATS procedure will be the procedures of choice.

4.13 MILIARY TUBERCULOSIS

4.13.1 Introduction
Miliary tuberculosis (TB) is the widespread dissemination of Mycobacterium
tuberculosis via hematogenous spread. Classic miliary TB is defined as ‘millet like’
(mean diameter= 2 mm; range= 1-5 mm) seeding of TB bacilli in the lung, as evidenced
on chest radiography. This pattern is seen in 1-3% of all TB cases.

Miliary TB may occur in an individual organ (very rare, less than 5%), in several organs,
or throughout the entire body (more than 90%), including the brain. The infection is
characterized by a large amount of TB bacilli, although it may easily be missed and is
fatal if left untreated.

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Up to 25% of patients with miliary TB may have meningeal involvement. In addition,
miliary TB may mimic many diseases. In some case series, up to 50% of cases are
undiagnosed ante-mortem. Therefore, a high index of clinical suspicion is important to
obtain an early diagnosis and to ensure improved clinical outcomes.

Early empirical treatment for possible but not yet definitive miliary TB increases the
likelihood of survival and should never be withheld while test results are pending. On
autopsy, multiple TB lesions are detected throughout the body in organs such as the
lungs, liver, spleen, brain, and others.

Of all patients with TB, 1.5% is estimated to have miliary tuberculosis. No genetic
predisposition has been identified.

Miliary disease is more difficult to detect in patients who are very young or very old.
Children younger than 5 years who acquire miliary TB are more likely to develop life-
threatening miliary and/or meningeal TB. The disease usually follows primary
infection, with no or only a short latency period. Adults older than 65 years have a
higher risk of miliary TB. Clinically, it may be sub acute or may masquerade as a
malignancy. If undiagnosed, the disease is detected at autopsy.

4.13.2 Pathophysiology of Miliary TB

Following exposure and inhalation of TB bacilli in the lung, a primary pulmonary
complex is established, followed by development of pulmonary lymphangitis and hilar
lymphadenopathy. Mycobacteremia and hematogenous seeding occur after the
primary infection. After initial inhalation of TB bacilli, miliary tuberculosis may occur as
primary TB or may develop years after the initial infection. The disseminated nodules
consist of central caseating necrosis and peripheral epithelioid and fibrous tissue.
Radiographically they are not calcified. (as opposed to the initial Ghon focus, which is
often visible on chest radiographs as a small calcified nodule)

4.13.3 Aetiology of Miliary TB

Risk factors for miliary tuberculosis involve immunosuppression and include, but are
not limited to, the following:

• Cancer

• Transplantation

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 • HIV infection

• Malnutrition

• Diabetes

• Silicosis

• End-stage renal disease

• Major surgical procedures - Occasionally may trigger dissemination

4.13.4 Clinical Manifestations of Miliary TB

Patients with miliary tuberculosis may experience progressive symptoms over days to
weeks or occasionally over several months. Symptoms include the following:

• Weakness, fatigue (90%)

• Weight loss (80%)

• Headache (10%)

Signs of miliary TB include the following:

• Subtle signs, such as low-grade fever (20%)

• Fever (80%)

• Cough (60%)

• Generalized lymphadenopathy (40%)

• Hepatomegaly (40%)

• Splenomegaly (15%)

• Pancreatitis (< 5%)

• Multi organ dysfunction, adrenal insufficiency

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4.13.5 Differential Diagnosis of Miliary TB
A wide range of diseases including bacterial, fungal, and viral infections and some
neoplasms can mimic miliary shadows in a chest x ray.

BOX 15: Differential diagnosis of Miliary TB

• Mycobacteria • Parasitic

Mycobacterium tuberculosis Toxoplasmosis

Atypical mycobacteria Strongyloidiasis

• Fungal • Neoplastic diseases

Histoplasmosis Lymphoma

Coccidioiodomycosis Lymphangitic spread of carcinoma

Blastomycosis Mesothelioma

Paracoccidioiodomycosis • Other diseases

• Bacterial Sarcoidosis

Legionella Amyloidosis
Nocardiosis Hypersensitivity pneumonitis
Staphylococus aureus Pneumoconioses
Heamophilus influenza Foreign-body induced vasculitis related to injection
Psittacosis drug use

Brucellosis

Meliosis

• Viral

Varicella

Cytomegalovirus

Influenza

Measles

Complications of Miliary TB
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As miliary tuberculosis implies disseminated disease, any organ or system involvement
with dysfunction or failure of varying severity may be the presentation. Early diagnosis
of various patterns of organ involvement and complications is vital to avoid an adverse
outcome. Few of the commonest complications are listed below.

Pulmonary

• Acute respiratory distress syndrome

• Respiratory failure

• Pleural effusion

Extra pulmonary

• Addisions’ Disease

• SIADH

• Meningites and CNS tuberculoma

• Cholaestasis, Elevated liver enzymes, Acsites, Pancreatitis

• Pericarditis, Pericardial effusion, Mycotic aneurysms of ascending and

descending aorta

4.13.6 Investigations for Miliary TB

4.13.6.1 Laboratory Studies

A decrease in sodium levels may correlate with disease severity, and the syndrome of
inappropriate secretion of anti diuretic hormone (SIADH) or hypoadrenalism may
complicate tuberculosis (TB). In approximately 30% of cases, alkaline phosphatase
levels are elevated.

Elevated levels of transaminases suggest liver involvement or, if treatment has been
initiated, drug toxicity.

4.13.6.1.1 Full blood count

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Leucopenia / leucocytosis may be present in miliary tuberculosis. Leucemoid reactions
may occur; patients may develop anemia; and thrombocytopenia or, rarely,
thrombocytosis may be present.

4.13.6.1.2 Erythrocyte sedimentation rate (ESR)

The erythrocyte sedimentation rate is elevated in approximately 50% of patients.

4.13.6.1.3 Culture for Mycobacteria

Cultures, as available, may include those of the sputum, blood, urine, cerebral spinal
fluid, bone marrow and other tissue samples. Sensitivity testing is essential for all
positive isolates, and considers investigation for multidrug-resistant TB (MDR-TB) in all
cases. Negative sputum smear results (even 3 negatives) do not exclude the possibility
of TB.

For Mycobacterial blood cultures, findings are positive in approximately 5% of patients

who do not have HIV infection. Findings are positive in many patients who have HIV
infection. One study yielded an 85% positivity rate.

Lumbar puncture should be strongly considered, even with normal brain MRI findings,
and may reveal any of the following:

• Leukocytes: Approximately 65% of patients have WBC counts with 100-500

mononuclear cells / μl

Lymphocytic predominance (70%)

CSF lactic acid levels are mildly elevated.

• Elevated protein levels (90%)

• Low glucose levels (90%)

• RBCs are common

• Acid-fast bacilli (≥40% with serial spinal taps)

4.13.6.1.4 Coagulation studies

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Measure the prothrombin time/activated partial thromboplastin time (PT/aPTT) prior
to biopsy.

4.13.6.1.5 Tuberculin skin test

The tuberculin skin test with purified protein derivative (PPD) often yields negative
results in patients with miliary TB. This may be explained by the large number of TB
antigens throughout the body. Negative tuberculosis skin testing results do not
exclude the possibility of TB.

4.13.6.1.6 Nucleic acid amplification test

Polymerase chain reaction testing of the blood may yield positive results in most cases
of HIV-related disseminated TB; the yield is low in non-HIV miliary TB. Other tissue
sample can be used for PCR test such as bone marrow, liver and CSF.

4.13.6.1 Imaging Studies for Miliary TB

4.13.6.1.1 Chest radiography

Findings are typical in 50% of cases. A bright spotlight helps to reveal miliary nodules.
Bilateral pleural effusions indicate dissemination versus localized and unilateral pleural
TB. This may be a useful clinical clue. Nodules characteristic of miliary TB may be
better visualized on lateral chest radiography (especially in the retro cardiac space).

4.13.2 Chest CT scanning

Chest CT scanning has higher sensitivity and specificity than chest radiography in
displaying well-defined randomly distributed nodules. High-resolution CT scanning
with 1mm cuts may be even better. It is useful in the presence of suggestive and
inconclusive chest radiography findings.

4.13.3 Ultrasonography

Ultrasonography may reveal diffuse liver disease, hepatomegaly, splenomegaly, or

Para-aortic lymph nodes.

4.13.3 Head CT scanning with contrast and/or MRI of the brain

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This is useful to assess suspected TB lesions. Hydrocephalus or a cerebral mass lesion
(tuberculoma) may increase the risk of herniation if lumbar puncture is performed.

Abdominal CT scanning

Abdominal CT scanning may reveal para-aortic lymph nodes, hepatosplenomegaly, or

tuberculous abscess.

Echocardiography

Echocardiography is the most sensitive test for pericardial effusion.

Additional Tests and Procedures for Miliary TB

Additional tests and procedures for miliary tuberculosis include the following:

• Funduscopy may reveal retinal tubercles

• Electrocardiography helps evaluate for pericardial effusion; right ventricular

hypertrophy may indicate pulmonary hypertension prior to lung biopsy

• Miliary TB in a child indicates recent transmission, and contact investigation

could identify the source case and associated susceptibilities; contact
investigation of child index cases should be conducted quickly, and thoroughly
evaluate household contacts by means of tuberculin skin testing and, if the test
results are positive, chest radiography

• Sputum induction has low sensitivity, and findings are smear-negative and
culture-negative in 80% of patients because of hematogenous spread

• Fiberoptic bronchoscopy is the most effective procedure for obtaining cultures

(broncho-alveolar lavarge)

• The culture yield for transbronchial biopsies is 90%.

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 • Bone marrow biopsy yield is approximately 50%, without serious adverse effect

• In liver biopsy, liver bleeding is a serious and potentially life-threatening

complication estimated to occur in approximately 10% of cases

• For abdominal involvement, laparoscopy is useful to obtain tissue and material

for culture.

Histological Findings of Miliary TB

Caseating granulomas are the hallmark of TB, and staining for acid-fast bacilli reveals
rod like structures in approximately 80% of specimens. The disseminated nodules
consist of central caseating necrosis and peripheral epithelioid and fibrous tissue.

Treatment Overview for Miliary TB

Miliary TB with meningeal involvement may require prolonged treatment (up to 12
months). Early treatment of patients with suspected miliary tuberculosis decreases the
likelihood of mortality and improves outcome. Surgical treatment is rarely necessary.
Occasionally, a ventriculo-atrial shunt is indicated for hydrocephalus. Multi
discleplinary team may be required in the management.

Adequate attention to nutrition is important. Many patients with miliary TB are

debilitated by the disease, and malnutrition can contribute to a weakened immune
system.

Once several weeks of effective therapy is given, patient experiences significant

clinical improvement. Directly observed therapy is optimal for assuring compliance
and preventing relapse.

Paradoxical enlargement of the lymph nodes or intracerebral tuberculomas during

adequate treatment may require steroids. Hydrocephalus may require neurosurgical
decompression.

Pharmacological Therapy for Miliary TB

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Early empirical therapy for suspected miliary tuberculosis is prudent. A delay of even
1-8 days contributes to a high mortality rate. Steroids are warranted for hypotension
due to presumed adrenal insufficiency after an adreno corticotropic hormone (ACTH)
stimulation test.

For susceptible organisms, the treatment period is I year.

Miliary TB and Pregnancy

Miliary tuberculosis during pregnancy can be treated safely with standard treatment.

Placenta examination by the pathologist is imperative. In a newborn, 3 gastric

aspirates of the newborn are helpful, but tuberculin skin testing of the newborn during
the first 6 months is rarely helpful because of the limited immune response of the
newborn. Lumbar puncture is indicated if the newborn does not thrive.

Prognosis of Miliary TB
If left untreated, the mortality associated with miliary tuberculosis is assumed to be
close to 100%. With early and appropriate treatment, however, mortality is reduced to
less than 10%. The earlier the diagnosis, the better the likelihood of a positive
outcome. Early treatment for suspected TB has been shown to improve outcome.

Most deaths occur within the first 2 weeks of admission to the hospital. This may be
related to delayed onset of treatment. Up to 50% of all cases of disseminated TB
detected at autopsy were missed ante mortem in reported case series.

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4.13 NONREACTIVE MILLIARY TUBERCULOSIS

An acute septicemic form which occurs very rarely and is due to massive
hematogenous dissemination of tubercle bacilli. Pancytopenia is common in this
form of disease and rapidly fatal. At postmortem examination, multiple necrotic
but nongranulomatous ("nonreactive") lesions are detected.

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 4.14 CRYPTIC MILIARY TUBERCULOSIS

A rare presentation seen in the elderly. This has a chronic course characterized by mild
intermittent fever, anemia, and ultimately meningeal involvement preceding death.

Chapter 5

TREATMENT OF TUBERCULOSIS

5.1 Lymph node tuberculosis

A 6-month regimen is recommended for initial treatment of all patients with

tuberculous lymphadenitis caused by drug-susceptible organisms. Affected lymph
nodes may enlarge while patients are receiving appropriate therapy or after the end
of treatment without any evidence of bacteriological relapse. On occasion, new
nodes can appear during or after treatment as well. Therapeutic lymph node excision
is not indicated except in unusual circumstances. For large lymph nodes that are

110
 fluctuant and appear to be about to drain spontaneously, aspiration or incision and
drainage appears to be beneficial.

5.2 Pleural tuberculosis

A 6-month regimen is recommended for treating pleural tuberculosis.
Tuberculous empyema, a chronic, active infection of the pleural space containing a
large number of tubercle bacilli, usually occurs when a cavity ruptures into the pleural
space. Treatment consists of drainage (often requiring a surgical procedure) and
antituberculous chemotherapy. Surgery, when needed, should be undertaken by
experienced thoracic surgeons.

5.3 Tuberculous meningitis

Tuberculous meningitis remains a potentially devastating disease that is associated
with a high morbidity and mortality, despite prompt initiation of adequate
chemotherapy.Patients presenting with more severe neurologic impairment such as
drowsiness, obtundation, or coma have a greater risk of neurologic sequelae and a
higher mortality. Chemotherapy should be initiated with INH, RIF, PZA, and EMB or
streptomycin in an initial 2-month phase.
INH and RIF, as well as the aminoglycosides, and the fluoroquinolones are available in
parenteral forms for patients with altered mental status who may not be able to take
oral medications.
After 2 months of four-drug therapy for meningitis caused by susceptible strains, PZA
and EMB may be discontinued, and INH and RIF continued for an additional 10-12
months. Repeated lumbar punctures should be considered to monitor changes in CSF
cell count, glucose, and protein, especially in the early course of therapy.

On the basis of the available data, adjunctive corticosteroid therapy with

dexamethasone is recommended for all patients, particularly those with a decreased
level of consciousness, with tuberculous meningitis. The recommended regimen is
dexamethasone in an initial dose of 8 mg/day for children weighing less than 25 kg
and 12 ug /day for children weighing 25 kg or more and for adults. The initial dose is
given for 3 weeks and then decreased gradually during the following 3 weeks.

8.3.2. Bone and joint tuberculosis

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Standard regime for bone and joint tuberculosis include 2 months of induction with
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol/Streptomycin and continuation of
Isoniazid ,Rifampicin, for 7 to 10 months; i.e. a total duration of 9-12 months.

Myelopathy with or without functional impairment most often responds to

chemotherapy.

In some circumstances, however, surgery appears to be beneficial and may be

indicated. Such situations include failure to respond to chemotherapy with evidence of
ongoing infection, the relief of cord compression in patients with persistence or
recurrence of neurologic deficits, or instability of the spine.

8.3.3. Pericardial tuberculosis

For patients with pericardial tuberculosis, a 6-month regimen is recommended. That is
2 months of induction with Isoniazid, Rifampicin, Pyrazinamide, Ethambutol/
Streptomycin and continuation of Isoniazid, Rifampicin, for 4 months. Corticosteroids
are recommended as adjunctive therapy for tuberculous pericarditis during the first 11
weeks of antituberculosis therapy.

On the basis of studies, it is recommended that daily adjunctive prednisolone or

prednisone treatment be given to adults and children with tuberculous pericarditis.
For adults the prednisone dose is 60 mg/day (or the equivalent dose of prednisolone)
given for 4 weeks, followed by 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and
finally 5 mg/day for week 11 (the final week). Children should be treated with doses
proportionate to their weight, beginning with about 1 mg/kg body weight and
decreasing the dose as described for adults.

8.3.4. Pleural tuberculosis

A 6-month regimen is recommended for treating pleural tuberculosis. Isoniazid,
Rifampicin, Pyrazinamide, Ethambutol/Streptomycin for 2 months and continuation of
Isoniazid and Rifampicin for 4 months.

The surgical drainage is indicated, in a case of moderate to large effusion for symptom
relief and to minimize chronic complications like pleural thickening, adhesions and
restricition to lung expansion, particularly in paediatric age group.

112
Tuberculous empyema, a chronic, active infection of the pleural space containing a
large number of tubercle bacilli, usually occurs when a cavity ruptures into the pleural
space. Treatment consists of drainage (often requiring a surgical procedure) and
antituberculous chemotherapy. Surgery, when needed, should be undertaken by
experienced thoracic surgeons.

8.3.5. Tuberculous meningitis

Treatment regime includes 2 months of induction with Isoniazid, Rifampicin,
Pyrazinamide, Ethambutol/Streptomycin and continuation of Isoniazid ,Rifampicin, for
10 months .

It is recommended that all patients with TB meningites receive adjunctive

corticosteroids regardless of disease severity at presentation.

Adults (>14 years) should start treatment with prednisolone 20-40 mg if on rifampicin
and 10-20 mg if not on rifampicin (equalent doses of dexamethasone can be given as
an alternative), as a reducing course over 6-8 weeks.

Children (<14 years) should be given prednisolone 1-2 mg/kg/24 hr (maximum 40 mg

per day or equivalent dose dexamethasone) for 4 weeks, followed by a reducing
course over 4 weeks.

8.3.6. Disseminated tuberculosis

This includes generalized multiorgan involvement due to blood borne spread.
Disseminated TB with Miliary TB with meningeal involvement may require prolonged
treatment (up to 12 months). Early treatment of patients with suspected miliary
tuberculosis decreases the likelihood of mortality and improves outcome.

Surgical treatment is rarely necessary. Occasionally, a ventriculo-atrial shunt is

indicated for hydrocephalus. Multi discleplinary team may be required in the
management.

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Adequate attention to nutrition is important. Many patients with miliary TB are
debilitated by the disease, and malnutrition can contribute to a weakened immune
system.

Once several weeks of effective therapy is given, patient experiences significant

clinical improvement. Directly observed therapy is optimal for assuring compliance
and preventing relapse.

Paradoxical enlargement of the lymph nodes or intracerebral tuberculomas during

adequate treatment may require steroids. Hydrocephalus may require neurosurgical
decompression.

Early empirical therapy for suspected miliary tuberculosis is prudent. A delay of even
1-8 days contributes to a high mortality rate. Steroids are warranted for hypotension
due to presumed adrenal insufficiency after an adreno corticotropic hormone (ACTH)
stimulation test.

For susceptible organisms, the treatment period is I year.

8.3.7. Genitourinary tuberculosis

Renal tuberculosis is treated primarily with medical therapy and a 6-month regimen is
recommended.That is 2 months of induction with Isoniazid, Rifampicin, Pyrazinamide,
Ethambutol/Streptomycin and continuation of Isoniazid, Rifampicin, for 4 months.

If ureteral obstruction occurs, procedures to relieve the obstruction are indicated. In

cases of hydronephrosis and progressive renal insufficiency due to obstruction, renal
drainage by stenting or nephrostomy is recommended. Nephrectomy is not usually
indicated for the treatment of uncomplicated renal tuberculosis but should be
considered when there is a nonfunctioning or poorly functioning kidney, particularly if
hypertension or continuous flank pain is present. Tuberculosis of either the female or
male genital tract responds well to standard chemotherapy, and surgery is needed
only for residual large tubo-ovarian abscesses.

A positive urine culture for M. tuberculosis occurs relatively commonly as an incidental

finding among patients with pulmonary or disseminated disease, especially those with
HIV infection. The positive culture may occur in the absence of any abnormalities on
urinalysis and does not necessarily represent genitourinary tract involvement.

114
8.3.8. Abdominal tuberculosis
A 6-month regimen is recommended for patients with peritoneal or intestinal
tuberculosis. That is 2 months of induction with Isoniazid, Rifampicin, Pyrazinamide,
Ethambutol/Streptomycin and continuation of Isoniazid, Rifampicin, for 4 months.

8.3.9. Other sites of involvement

Tuberculosis can involve any organ or tissue. In treating tuberculosis in sites other
than those mentioned, the basic principles of therapy apply, but experts should be
consulted for specific advice concerning individual patients.

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 Chapter 6
Treatment summary of EPTB

TYPE OF TB INDUCTION CONTINUATION Remarks

(Months) (Months)

1 2 3 4 5 6 7 8 9 10 11 12

1.TB Lymph node HRZE HRZE HR HR HR HR

2. TB Meningites HRZE/S HRZE/S HR HR HR HR HR HR HR HR HR HR Standard Rx

for all CNS
TB

4.Pleural TB HRZE HRZE HR HR HR HR May need IC

tube/aspirat
ion

4.GU TB HRZE HRZE HR HR HR HR Some need

surgery

5.Bone & Joint TB HRZE HRZE HR HR HR HR HR HR HR HR HR HR Multidiscpli

nary
approach

6.TB HRZE HRZE HR HR HR HR Steroids in

lymphadenitis special
Situations

7.TB Skin HRZE HRZE HR HR HR HR

116
8.TB of the HRZE HRZE HR HR HR HR
trachea

9.TB HRZE HRZE HR HR HR HR Corticoste

Pericardites roids as
adjunctive

10.Pleural HRZE HRZE HR HR HR HR

tuberculosis

11.Disseminated HRZE HRZE HR HR HR HR HR HR HR HR HR HR 09 month

TB for child

117
Co-ordinator-
Extra-pulmonary TB guidline -

118