Tuberculosis Control in India11

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EXTRAPULMONARY TUBERCULOSIS: MANAGEMENT AND CONTROL11

CHAPTER

11

Introduction

The goal of the RNTCP is to decrease mortality and morbidity due to TB, and to interrupt

the chain of transmission so that TB is no longer a major public health problem in India1.

To achieve this goal, the RNTCP has two objectives: to cure at least 85 percent of the new

smear-positive pulmonary TB (PTB) cases registered for treatment; and to detect at least

70 percent of the estimated new smear-positive pulmonary TB cases existing in the

community once the first objective has been reached2,3. Although the highest priority under

the RNTCP is thus given to the new sputum smear-positive PTB cases, all types of TB are

treated under the programme.

The clinical manifestations of TB are of two types: Pulmonary and Extrapulmonary

forms of TB (EPTB), the former being the commonest. In EPTB highly vascular areas such

as lymph nodes, meninges, kidney, spine and growing ends of the bones are commonly

affected. The other sites are pleura, pericardium, peritoneum, liver, gastro-intestinal tract,

genito-urinary tract and skin.

The definition of EPTB disease under the RNTCP follows the international classification4.

EPTB is defined as TB of organs other than the lungs, such as pleura, lymph nodes, abdomen,

genito-urinary tract, skin, joints, bones, tubercular meningitis, tuberculoma of the brain,

etc2,3. Diagnosis is based on one culture-positive specimen from the extrapulmonary site;orhistological evidence; orstrong clinical evidence consistent with active EPTB disease

followed by a medical officers decision to treat with a full course of anti-TB therapy.

Patients suspected of having EPTB should also have their sputum examined for AFB if

they have chest symptoms, irrespective of the duration of these symptoms. A patient

diagnosed with both pulmonary and EPTB is classified as a case of pulmonary TB.

The problem of EPTB is still high, both in developing and developed countries. In

India, EPTB forms 10 to 15 percent of all types of TB, in comparison to 25 percent in

France and 50 percent in Canada, partly due to the dual infection of TB with human

immunodeficiency virus (HIV)5,6. Since 1987, EPTB has been accepted as an AIDS defining

disease7. Lymph node TB (LNTB) is the commonest form of EPTB. Most studies inperipheral LNTB have described a female preponderance, while pulmonary TB is more

common in adult males8. In the era before the HIV pandemic, and in studies involving

immunocompetent adults, it was observed that EPTB constituted about 15 to 20 percent of

Extrapulmonary Tuberculosis:Management and Control

Fraser Wares, R. Balasubramanian, A. Mohan, S.K.Sharma


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TUBERCULOSIS CONTROL IN INDIA

all cases of TB in general practice. HIV infected persons are at markedly increased risk for

primary or reactivation TB and for second episodes of TB from exogenous re-infection. In

some settings, EPTB can account for up to 53 to 62 percent of cases of TB in HIV-positive

individuals9-12.

Diagnosis and Treatment of EPTB under the RNTCP

EPTB cases are diagnosed by attending physicians, and if required, referred to the District

TB Centre, Chest Clinic or the Medical Officer-TB Control for investigations.All

investigative procedures undertaken to arrive at the diagnosis of EPTB should be entered

in the patients RNTCP Treatment Card.

The treatment of extrapulmonary TB follows standard RNTCP treatment guidelines

depending on categorisation, and is consistent with international recommendations by WHO

and the International Union Against Tuberculosis and Lung Disease (IUATLD) 4,13.

Categorisation is done according to history, and clinical and diagnostic criteria. All RNTCP

regimens are given thrice weekly, and Rifampicin-containing regimens given for six to

eight months. If patients are seriously ill with extrapulmonary TB, they are treated with the

RNTCP Category I regimen consisting of, initially, two months Isoniazid (H), Rifampicin

(R), Pyrazinamide (Z) and Ethambutol (E) given thrice a week, with each dose given under

the direct observation of a DOT Provider (Table 1). This two-month intensive phase is

Category of Treatment Type of Patient Regimen*

Category I New sputum smear-positive pulmonary TB (PTB) 2H3R3Z3E3+ 4H3R3Seriously ill* * new sputum smear-negative PTB

Seriously ill* * new EPTB

Category II Sputum sm ear-positive relapse 2S3H

3R

3Z

3E

3+ 1H

3R

3Z

3E

3+

Sputum smear-positive failure 5H3R

3E

3

Sputum smear-positive treatment after default

Others* * *

Category III New sputum smear-negative PTB 2H3R

3Z

3+ 4H

3R

3

New EPTB, not seriously ill

Table 1 RNTCP treatment categories and regimens

* The number before the letters refers to the number of months o f treatment. The subscript after the letters refers to

the number of doses per week. The dosage strengths are as follows : H: Isoniazid (60 0 m g), R: Rifampicin (45 0

mg), Z: Pyrazinamide (1500 mg), E: Ethambutol (1200 mg), S: Streptomyc in (750 m g). Patients who w eigh 60 kg

or m ore receive additional Rifampicin 1 50 gm. Patients w ho are mo re than 50 years old recieve Streptomy cin 50 0

mg. Patients who weigh less than 30 kg receive drugs per body weight. Patients in Categories I and II who have a

positive sputum smear at the end of the initial intensive phase receive an additional month of intensive phase

treatement.

* * Seriously ill includes any patient, pulmonary or extra-pulmonary, who is HIV positive and declares his sero-

status to the categorising/treating medical officer. For the purpose of categorisation, HIV testing should not be

done.

* * * In rare and exceptional cases, patients w ho are sputum sm ear-positive or who have extra-pulmonary d isease

can have relapse or failure. The diagnosis in all such cases should be made by the MO and should be supportedby culture or histological evidence of current active TB. In these cases, the patient should be categorised as

Others and given Category II treatment.


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followed by a four-month continuation phase of Isoniazid and Rifampicin, given thrice a

week, with at least the first of the thrice-weekly doses given under the direct observation of

the DOT Provider. In patients with TB meningitis (TBM), Streptomycin is given instead of

Ethambutol. In addition, the continuation phase of treatment in TBM should be given forsix to seven months, extending the total duration of treatment to eight-nine months.

Steroids should be used initially in hospitalised cases of TBM and TB pericarditis, and

reduced gradually over six to eight weeks. If patients are not seriously ill with

extrapulmonary TB, they are treated with the RNTCP Category III regimen consisting of,

initially, two months Isoniazid, Rifampicin and Pyrazinamide given thrice a week, with

each dose given under the direct observation of a DOT Provider. As in the Category I

regimen, the two-month Category III intensive phase is followed by a four-month

continuation phase of Isoniazid and Rifampicin, given thrice a week, with at least the first

of the thrice-weekly doses

given under the direct

observation of the DOT

Provider.

Whether the EPTB is

classified as seriously ill or

not seriously ill is dependent

on the site of the disease. For

example, TB meningitis is

classified as seriously ill and

would be treated with aRNTCP Category I regimen.

Lymph node TB, however, is

classified as not seriously ill

and will be treated with a

Category III regimen (Table 2).

Review of Case Finding, Diagnostic Practices and Treatment Outcomesof EPTB Cases in the RNTCP

In 2002, the Central TB Division (CTD), Directorate General of Health Services, Ministry

of Health and Family Welfare, Government of India, undertook a review of case management

of EPTB patients under the RNTCP. The aims of the review were:

To provide an overview of case finding patterns for a one-year period of extrapulmonary

TB cases under RNTCP nationally and in 16 selected districts;

To provide an overview of diagnostic practices amongst extrapulmonary TB cases

registered under the RNTCP in 16 selected districts;

To provide an overview of treatment outcomes of extrapulmonary TB cases under the

RNTCP nationally and in 16 selected districts; and

To identify the challenges faced by the RNTCP with regard to extrapulmonary TB cases.

Data were collected from both national and district levels. The national data came from

the central level EpiCentre dataset of the RNTCP held by the CTD. This central-level

dataset contains the routine quarterly report data that is submitted from all districts that are

Seriously i l l Not seriously i l l

TB meningitis Lymph node TB

Disseminated TB Pleural effusion (unilateral)

TB pericarditis Bone (excluding spine)

TB peritonitis & intestinal TB Peripheral joint(s)

Bilateral or extensive pleurisy

Spinal TB with neurological

complications Genito-urinary tract

Table 2 RNTCP classification of extrapulmonary TB


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National 16 Distr icts

Total new cases 290,005 33,999

New smear positive PTB 140,279 17,017

New smear negative PTB 109,530 14,166

Extrapulmonary TB 40,196 (13.9 percent) 2,816 (8.3 percent)

Treatment Category III 33,563 (83.5 percent) 2,467 (88 percent)

Male : Female 46.8 percent : 53.2 percent 49 percent : 51 percent

EPTB treatment outcome

Treatment complete 36,337 (91 percent) 2,553 (90.9 percent)

Died 814 (2 percent) 43 (1.5 percent)

Default 2,541 (6.4 percent) 206 (7.3 percent)

Table 3 RNTCP case finding, Q3 2000 -Q2 2001. Source: RNTCP central dataset

Figure 1 Study districts (n=16)

Haryana

Gujarat

Karnataka

Rajasthan

Orissa

West Bengal

Madhya Pradesh

HimachalPradesh

Maharashtra

Sonipat

Dohad, Mahesana

Raichur

Dausa, Sikar, Nagaur,Alwar, Ajmer, SawaiMadhepur

Jharsuguda

Murshidabad, Malda

Rajgarh

Solan

Raigarh

DistrictsState

implementing the RNTCP14. Data were collected and analysed for a period of one year

from July 1, 2000 to June 30, 2001 (i.e. from Quarter 3, 2000 to Quarter 2, 2001). Data

available from this routine dataset included a total of different TB types, the gender of the

patient, treatment category and treatment outcomes (Table 3).

District-level data came from 16 conveniently sampled districts with a combined

population of 32.6 million (Figure 1), out of the 124 districts implementing RNTCP on

July 1, 2000. Criteria for selection were that the: district had to be implementing RNTCP

on July 1, 2000 (i.e. at the start of Q3, 2000); the percentage of extrapulmonary TB cases


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amongst new cases was not outside a range of 5-20 percent; and the district had to be

electronically connected. Data were collected and analysed for a period of one year from

July 1, 2000 to June 30, 2001 (i.e. from Quarter 3, 2000 to Quarter 2, 2001). The analyses

included the data available from the central-level EpiCentre dataset and that collected viaa questionnaire sent by e-mail to the selected 16 districts. Information for the questionnaire

was gathered from the RNTCP Patient Treatment Cards of extrapulmonary TB cases

registered under the RNTCP during the study period and from the RNTCP TB Register.

Additional data available from the questionnaire included diagnostic and treatment outcome

details by site of extrapulmonary TB (Tables 4 to 8).

Results showed that EPTB cases comprised between 8.3 percent (16 districts) and 13.9

Site Total Percent

Lymph node 1630 57.3Pleural effusion 624 21.9

Bone 253 8.9

Abdominal 202 7.1

Others 134 4.7

Skin, eyes etc 42 1.5

TB meningitis 39 1.4

Renal/GUT 33 1.2

Miliary 12 0.4

Pericarditis 6 0.2

Tuberculoma 2 < 0.1

Table 4 Extrapulmonary TB case finding by disease site in the 16 districts,Q3 2000-Q2 2001 (n=2843)

Diagnostic examination Total Facil i ty where test per formed

Clinical gro0unds alone 696 Government Health Facility (GHF) 595

Governm ent M edic al College (GM C) 2 5Private Health Facility (PHF) 4

After antibiotic trial 341 GHF 202

GMC 2 Fine Needle Aspiration Cytology

and AFB smear 418

GHF 59

GMC 119

PHF 218

LN biopsy, AFB smear and histology 252 GHF 51

GMC 16

PHF 183

* Not all patients had all the relevant information reco rded in their RNTCP Treatment Cards. In addition, some patients had mo re than one of the abovediagnostic examinations performed. Hence the totals presented in the tables do not equal the total number of cases (n).

Table 5 Diagnostic practices in cases of lymph node TB (n=1630)*


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percent (national) of new cases registered under the RNTCP during the study period (Table

3). Overall 83.5 to 88 percent were treated with the Category III regimen and male (M) to

female (F) ratio was roughly 1:1, compared with a 2.3 male to 1 female ratio for PTB cases.

Paediatric cases (0-14 years) comprised almost 15 percent (n=412) of the EPTB cases in

the 16 districts. In these districts, lymph node (LN) TB comprised 57 percent of all the

EPTB cases (1M : 1.4F), pleural effusion (PE) 22 percent (2M : 1F), and bone/joint(s) 9

Diagnostic examination Total Facil ity where test per formed

Clinical grounds alone 10 GHF 5

Chest X-ray 610 GHF 272

GMC 78

PHF 249

Pleural aspirate, AFB smear, 153 GHF 55total lymphocyte count and differential, GMC 7and biochem istry PHF 65

Pleural biopsy and histology 2 PHF 2

Table 6 Diagnostic practices in cases of pleural effusion TB (n=624)*

Diagnostic examination Total Facil i ty where test per formed

Clinical grounds alone 19 GHF 16PHF 1

X-ray 224 GHF 82GMC 22PHF 112

Tissue and / or synovial biopsy, 17 GHF 4and histology GMC 3

PHF 10

Table 7 Diagnostic practices in cases of bone/joint(s) TB (n=253)*

* Not all patients had all the relevant information record ed in their RNTCP Treatment Cards. In addition, some patients had m ore than one of the abovediagnostic examinations performed. Hence the totals presented in the tables do not equal the total number of cases (n).

Table 8 Treatment outcomes of Category I and III EPTB cases by site (n=2809)

Site Treatment Died Treatment Default Transfer Out Totalcomplete fai lure

Lymph node 1498 (93) 6 1 103 (6.4) 3 1611

Pleural effusion 549 (89.6) 19 0 45 (7.3) 0 61

Bone / joint(s) 220 (88) 1 0 29 (11.6) 0 250

Abdom inal 174 (86.1) 12 0 15 (7.4) 1 202

Other 109 (82) 6 0 18 (13.5) 0 133

All sites 2550 (90.8) 44 (1.6) 1 (0) 210 (7.5) 4 (0.1) 2809


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percent (1M : 1F) (Table 4). Amongst the paediatric EPTB cases, LN TB made up almost

80 percent of the cases (324/412), with PE contributing about 8 percent (31/412) and bone/

joint(s) 7 percent (27/412).

Overall 28 percent of EPTB cases in the 16 districts were diagnosed on clinical grounds

alone, with no confirmatory laboratory or radiological examination being performed. In

lymph node TB cases, 43 percent were diagnosed on clinical grounds alone, with almost

identical figures seen for paediatric and adult cases separately (Table 5). Of those lymph

node cases that did have a confirmatory laboratory examination performed, including fine

needle aspirate (FNAC) and smear, and lymph node biopsy with smear and histology, 62

percent (401/646) had the test performed in a private health facility (Table 5). Twenty-one

percent (135) had the tests performed in a government medical college and 17 percent

(110) in a government health facility.

In contrast, over 97 percent of the pleural effusion patients had had at least one chest x-ray performed (Table 6). Similarly 88 percent of bone/joint(s) cases had had at least one x-

ray performed (Table 7). However 16 percent of abdominal TB cases had had no confirmatory

laboratory or radiological examination being performed prior to diagnosis and treatment

(data not shown). As seen in the lymph node TB cases, a significant proportion of the

laboratory or radiological examinations that were performed in these patients, were done

in private health facilities.

Overall 91 percent of EPTB patients under the RNTCP completed their treatment both

at the national and the study districts levels (Tables 3 and 8), while 1.5-2 percent of patients

died and 6-8 percent defaulted from treatment. Treatment completion rates ranged from

82-93 percent amongst lymph node, pleural effusion, bone/joint(s) and other cases, withno difference between the genders (Table 8). Default was the major problem, especially in

bone/joint(s) (11.6 percent) and other sites (13.5 percent).

It can thus be concluded that EPTB cases form a significant proportion (8-14 percent)

of the RNTCPs new case load. Amongst the EPTB cases, lymph node TB predominate

(>60 percent). Overall there were almost equal numbers of female and male cases, compared

with PTB where males outnumber females at least two-fold consistently. However, only

amongst lymph node cases did females actually outnumber male cases (1.4 to 1), whereas

in pleural effusion cases males outnumbered female cases 2 to 1.

Overall, 28 percent of cases were diagnosed on clinical grounds alone with noconfirmatory laboratory or radiological examination being performed. This rose to 43 percent

amongst the LNTB cases. The private sector performed a significant proportion of the

confirmatory laboratory or radiological examinations being done.

Treatment completion rates were high, with 91 percent of cases successfully completing

their treatment. The main problem was default (overall 6-7 percent), especially in bone/

joint(s) (11.6 percent) and other sites (13.5 percent).

The study recommended that despite the encouraging notification levels and high

treatment completion rates seen under the RNTCP for EPTB cases, there is need for a

review of the current diagnostic practices. The formation of an expert committee, to formulate

practical diagnostic algorithms for EPTB suspects under the RNTCP, should be considered.

Once the diagnostic algorithms have been laid out, they should be included in future revisions

of the RNTCP manuals and guidelines, and immediately disseminated to all staff involved

in RNTCP activities. There is an important role for medical colleges in the provision of


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diagnostic facilities for EPTB cases to offset the present reliance on the private sector for

diagnostic services in these cases. Research is needed to answer questions such as why

lymph node TB cases predominate amongst EPTB patients, and why female cases outnumber

male cases amongst lymph node TB cases in India.

Evidence-based Management of EPTB

The major pitfalls in the diagnosis of EPTB are atypical clinical presentations simulating

other inflammatory and neoplastic conditions, resulting in delay or deprivation of treatment.

Therefore a high index of suspicion is necessary to make an early diagnosis.

In developing countries, the lack of diagnostic resources adds to the problems.This

often leads to empirical treatment based on clinical grounds without pathological and/or

bacteriological confirmation, leading to over-diagnosis and unnecessary treatment. This

was shown in a study at TRC, Chennai, where only 34 percent of 373 biopsies done on

clinically diagnosed cases of LNTB, had histopathological confirmation15.

In clinical practice, the cutaneous reaction to PPD is used as an aid to the diagnosis. Its

value as a diagnostic tool is limited in adults in India, since about 40 percent of the adult

population is infected with TB2. However, it may be of use in children aged five years or

below.

The selection of the diagnostic procedures depends on the organ of involvement in

EPTB. Fine needle aspiration of lymph nodes and cytological examination plus AFB smear

and culture examination, appears to be the diagnostic procedure of choice in superficial TB

lymphadenitis16. However, if the FNAC examination results are inconclusive, excisionbiopsy may need to be done. Laparoscopy with target peritoneal biopsy is the current

investigation of choice in the diagnosis of peritoneal TB. Direct inspection of yellowish

white miliary tubercles or erythematous patches plus peritoneal adhesions and the

demonstration of acid-fast bacilli or characteristic caseating granulomas in biopsy specimens,

may confirm diagnosis in 80 to 95 percent of patients17.

Quite often, more than one procedure is necessary for the confirmation of diagnosis. By

undertaking relevant diagnostic procedures in different types of abdominal TB patients,

such as laparoscopic biopsy, liver biopsy, barium meal series, bacteriological and

biochemical examination of ascitic fluid, it was possible to establish the diagnosis in 138

(72 percent) of 193 patients in a study conducted by TRC18.

Attempts should always be made to confirm the diagnosis by histopathological and/or

bacteriological examinations. In TRC studies, all biopsy specimens were cultured in multiple

solid and liquid media, namely Lowenstein-Jenson medium with or without pyruvate,

Middlebrook 7H11 medium and Kirschner medium, and the culture positivity rates varied

from 33 to 62 percent in different forms of EPTB19. Since EPTB is essentially a paucibacillary

condition, smear and culture examination of specimens, including biopsy, sputum, urine

and other body fluids like ascitic and pleural fluid, are recommended. It was also observed

that atypical Mycobacteria were not commonly the pathogens leading to EPTB disease.

Even though a number of reports on molecular biological tests such as SAFA, Elisa,slide agglutination techniques and PCR are available in EPTB, the specificity and sensitivity

of these tests are variable20. The results need to be interpreted in the light of clinical findings.

Smith et alhad advocated the use of PCR in clinical specimens as the results were comparable


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to that of culture forM. tuberculosis21. It was also reported that the use of Adenosine De

Aminase (ADA) in ascitic fluid was a sensitive and specific marker approaching 100 percent

in the diagnosis of peritoneal TB22.It was recently reported that demonstration of

mycobacterial antigens in tissue specimens discriminate between an active and a resolvinggranuloma. This may be more sensitive than finding the bacilli23.

For the purpose of treatment, EPTB can be classified into severe and non-severe forms.

There has been some uncertainty regarding the most appropriate combination of drugs,

duration of chemotherapy and the role of surgery in the treatment of EPTB24. The difficulty

in evolving a clear cut end point in assessing the efficacy of treatment of EPTB led to

varying durations of treatment (6 to 24 months). Several randomised control trials (RCTs)

over the last two decades have established Short-Course Chemotherapy (SCC) as the

standard treatment for sputum positive TB. This has stimulated the research into shorter

regimens for the treatment of EPTB25. EPTB is usually paucibacillary and any treatment

regimen effective in PTB is likely to be effective as well in the treatment of EPTB.

TRC, with its rich experience in the conduct of RCTs, has undertaken several

collaborative studies on EPTB such as spinal TB, Potts paraplegia, TB meningitis, brain

tuberculoma, LNTB and abdominal TB15,18,19,26-31with the government teaching hospitals of

Chennai. The common objective of these studies was to assess the efficacy of SCC in

EPTB. The results, at the end of treatment and relapses over a varying period of three to 10

years, were assessed systematically. In studies on TB spine and abdominal TB, the role of

surgery was also addressed. Individual reports discuss the diagnostic criteria used, treatment

regimens tried and the outcomes in detail. For all patients, every dose of drugs was

administered under the direct supervision of a staff member at least for the intensive phaseof two months. Patients attended the clinic as out-patients and were hospitalised only if

they were sick.

Evidence of pulmonary TB on x-ray was variable, ranging from 9 to 55 percent. One-

third of abdominal TB patients had a disseminated form of TB. The mantoux induration

was 10 mm or more in 44 to 92 percent of the various forms of EPTB patients.

TRC studies have clearly established the efficacy of short-course treatment (six to nine

months) in both children and adults19. Intermittent regimens have been proven to be as

effective as daily regimens. Table 9 describes the efficacy of treatment regimens in different

forms of EPTB15, 18, 19, 26-30. The overall favourable response varied from 87 to 99 percent in

all forms of EPTB, except in TB meningitis where only one-third of patients responded to

treatment (Table 9).

Lymph nodes can enlarge, persist and become superinfected with bacteria in the course

of TB treatment, which are called paradoxical reactions. Generally, no modification or

prolongation in antituberculosis treatment regimen is indicated15.

Even though treatment gives good results in most forms of EPTB, there are a few

exceptions such as meningitis and spinal TB (Potts disease) in which the outcome greatly

depends on early diagnosis. In tuberculous meningitis, the outcome is related to the stage

of the disease at the time of the start of treatment; only a minority of patients with severe

disease recover completely. Predictors of poor outcome are younger age and advancedstage, neurological sequelae are directly related to the stage of the disease and the duration

of symptoms prior to admission31,32. Donald et alhad reported a mortality rate of 16 percent

and a relapse rate of 2 percent among 95 children diagnosed as tuberculous meningitis


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TB patients who might have overt involvement of liver, 17 percent developed hepatitis.

Hepatitis was more common with daily therapy with Rifampicin, Isoniazid and Pyrazinamide

and occurred within six weeks of treatment. However, hepatitis was not a problem when

the same drugs were given intermittently. During hepatitis, hepatotoxic drugs likeRifampicin, Isoniazid and Pyrazinamide should be withheld and substituted with

Streptomycin and Ethambutol. However after recovery from jaundice these drugs can be

resumed, eventfully in the majority of patients.

Clinical Picture and Management of Different Forms of EPTB

Patients with EPTB often present with constitutional symptoms such as fever, loss of

appetite, weight loss, malaise and fatigue. In addition, these patients manifest symptoms

and signs related to the organ system involved.

Lymph Node TB

Lymph Node TB (LNTB) is the commonest form of EPTB. LNTB is considered to be

the local manifestation of a systemic disease. Patients usually present with slowly enlarging

lymph nodes and may otherwise be asymptomatic. In HIV-negative patients, isolated cervical

lymphadenopathy is most often seen in about two-thirds of the patients. In HIV-positive

patients, multifocal involvement, intra-thoracic and intra-abdominal lymphadenopathy and

associated pulmonary disease are more common. Physical examination may be unremarkable

but for palpable lymphadenopathy. Occasionally, a lymph node abscess may burst leading

to a chronic non-healing TB sinus and ulcer formation10.

Pleural Effusion and Empyema Thoracis

TB pleural effusion usually presents as an acute illness and the symptom duration ranges

from a few days to a few weeks. Patients complain of fever, pleuritic chest pain, non-

productive cough and dyspnoea. Patients with TB empyema present with chest pain,

breathlessness, cough with expectoration, fever, and toxaemia. TB empyema may present

as a chest wall mass or draining sinus tract (TB empyema necessitatis)37.

Bone and Joint TB

Skeletal TB is a haematogenous infection and affects almost all bones. TB commonly

affects the spine and hip joint38,39. Other sites include knee joint, foot bones, elbow jointand hand bones. Rarely, it also affects the shoulder joint. Two basic types of disease patterns

have been observed: granular and exudative (caseous). Though both patterns have been

observed, one form may predominate.

Spinal TB is the most common form of skeletal TB. Constitutional symptoms generally

occur before the symptoms related to the spine manifest. Thoracic and lumbar vertebrae

are the most common sites of involvement followed by middle thoracic and cervical

vertebrae. Usually, two contiguous vertebrae are involved but several vertebrae may be

affected and skip lesions are also seen (Figures 2a and 2b). The infection begins in the

cancellous area of the vertebral body, commonly in the epiphyseal location and less

commonly in the central or anterior area of vertebral body. The infection spreads and

destroys the epiphyseal cortex, the intervertebral disc and the adjacent vertebrae. It may

spread beneath the anterior longitudinal ligament to reach the neighbouring vertebrae. The

vertebral body becomes soft and gets compressed to produce either wedging or total collapse.


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Anterior wedging is commonly seen in the thoracic spine where the normal kyphotic curve

accentuates the pressure on the anterior part of vertebrae.The exudate penetrates the

ligaments and follows the path of least resistance along fascial planes, blood vessels and

nerves, to distant sites from the original bony lesion as a cold abscess. In the cervicalregion, the exudate collects behind the prevertebral fascia and may protrude forward as a

retropharyngeal abscess. The abscess may track down to the mediastinum to enter into the

trachea, oesophagus or the pleural cavity. It may spread laterally into the sternomastoid

muscle and form an abscess in the neck.

In the thoracic spine, the exudate may remain confined locally for a long time and may

appear in the radiographs as a fusiform or bulbous paravertebral abscess and may compress

the spinal cord. Rarely, a thoracic cold abscess may follow the intercostal nerve to appear

anywhere along the course of nerve. It can also penetrate the anterior longitudinal ligament

to form a mediastinal abscess or pass downwards through medial arcuate ligament to form

a lumbar abscess. The exudate formed at lumbar vertebrae most commonly enters the psoas

sheath to manifest radiologically as a psoas abscess or clinically as a palpable abscess in

the iliac fossa. The abscess can gravitate beneath the inguinal ligament to appear on the

medial aspect of thigh or spread laterally beneath the iliac fascia to emerge at the iliac crest

near anterior superior iliac spine. Sometimes an abscess forms above the iliac crest

posteriorly. The collection can follow the vessels to form an abscess in Scarpas triangle or

the gluteal region if it follows femoral or gluteal vessels respectively.

A retropharyngeal abscess can present with local pressure effects such as dysphagia,

dyspnoea, or hoarseness of the voice. Further dysphagia may also occur due to a mediastinal

abscess. Flexion deformity of hip can develop due to a psoas abscess. The abscesses may

be visible and palpable if they are superficially located. Therefore, neck, chest wall, groin,

Figure 2a MRI scan of the dorsolumbar spine, (coronal view, T1 weighted image) showing centralhypointense lesion (arrow) with reduced vertical height of the vertebra and paraspinal coldabscess

Figure 2b MRI dorsolumbar spine of another patient (sagittal view, T2 weighted image) showing destructionof D10 and D11 vertebrae reduction in the intervening disc with anterior granulation tissue and

cord compression (arrow)


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inguinal areas and thighs where cold abscesses occur frequently, must be carefully examined

in addition to the location of a bony lesion.

Paraplegia (Potts paraplegia) is the most serious complication of spinal TB and itsoccurrence is reported to be as high as 30 percent in patients with spinal TB. Early onset

paraplegia develops during the active phase of infection. Paraplegia of late onset can appear

many years after the disease has become quiescent even without any evidence of reactivation.

Most commonly, paraplegia develops due to mechanical pressure on the cord, but in a

small number of patients cord dysfunction may occur due to non-mechanical causes.

The clinical presentation of TB of the hip and knee joints depends on the

clinicopathological stage and each stage has a definite pattern of clinical deformity. Pain,

circumferential reduction of movements at the joint are evident. Night cries may develop

due to relaxation of muscle spasm and unguarded movements at the joint. TB osteomyelitis

may mimic chronic osteomyelitis of other causes.Poncets arthritis has been described inpatients with an active TB focus elsewhere40.

Neurological TB

TB Meningitis

TB meningitis (TBM) accounts for 70 to 80 percent of cases of neurological TB40-42.In

the bacteraemic phase of primary lung infection, metastatic foci can become established in

any organ, which can become active after a variable period of clinical latency. Rupture of

a subependymally located tubercle (Rich focus) results in the release of infectious material

into the subarachnoid space. Salient pathological features of TBM include: inflammatory

meningeal exudate; ependymitis; vasculitis; encephalitis; and disturbance of cerebrospinal

fluid (CSF) circulation and absorption.

In the developing world, TBM is still a disease of childhood with the highest incidence

in the first three years of life. The disease usually evolves gradually over two to six weeks.

The prodromal phase lasts for two to three weeks and is characterised by a history of vague

ill-health, apathy, irritability, anorexia and behavioural changes. With the onset of meningitis,

headache and vomiting become evident and fever develops. Focal neurological deficits

and features of raised intracranial tension may precede signs of meningeal irritation. Focal

or generalised seizures are encountered in 20 to 30 percent of patients. Cranial nerve palsies

can occur in 20 to 30 percent of patients, the sixth nerve involvement being the mostcommon.Complete or partial loss of vision is a major complication of TBM. In untreated

cases, progressive deterioration in the level of consciousness, pupillary abnormalities and

pyramidal signs may develop due to increasing hydrocephalus and tentorial herniation.

The terminal illness is characterised by deep coma and decerebrate or decorticate posturing.

Without treatment, death usually occurs in five to eight weeks.

Atypical presentations include acute meningitic syndrome simulating pyogenic

meningitis, progressive dementia, status epilepticus, psychosis, stroke syndrome, locked-

in-state, trigeminal neuralgia, infantile spasm and movement disorders.

Tuberculomas

Intracranial tuberculomas in patients under the age of 20 are usually infratentorial, but

supratentorial lesions predominate in adults. Solitary tuberculomas are more frequent than

multiple lesions. Tuberculomas still constitute about 5 to 10 percent of intracranial space

occupying lesions in the developing world. Patients with epilepsy who showed ring


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enhancing single CT lesions have

been described from India (Figure

3). TB has been implicated as one

of the causes for this form ofpresentation40-42.

Abdominal TB

Peritoneal TB

TB peritonitis may have an acute

onset and such patients may often

be subjected to emergency surgery.

Three varieties of chronic TB

peritonitis have been described.Ascitic form often has an insidious

onset. Abdominal distension, dilated

veins and transverse solid mass in

the abdomen due to greater

omentum which is rolled up and may

be infiltrated with tubercles, are

important clinical features. Patients

with encystedor loculatedform present with localised abdominal swelling. In thefibrous

form, widespread adhesions may cause coils of intestine to be matted together and distended

which may act as blind-loop and result in steatorrhoea, malabsorption syndrome and

abdominal pain. The disease may present as acute or subacute intestinal obstruction. The

adherent loops of intestine and the thickened mesentery may be felt as lump(s) in the

abdomen. Purulent form of TB peritonitis rarely develops secondary to TB salpingitis.

Cold abscess, entero-cutaneous and entero-enteric fistulae can develop.

Gastrointestinal TB

Gastrointestinal TB is usually secondary to a TB focus elsewhere in the body. With

widespread pasteurisation of milk, abdominal TB caused byM. bovisis now seldom seen,

andM. tuberculosisis the most frequently isolated pathogen. Gastrointestinal TB can be

of ulcerative, hypertrophic, ulcerohypertrophic, diffuse colitis and sclerotic forms.Gastrointestinal TB is a chronic illness with abdominal pain as the most common symptom.

Diarrhoea, anorexia, weight loss and fever are also common. Other symptoms include a

moving lump in the abdomen, nausea, vomiting, malaena, and constipation. A doughy feel

of the abdomen, mass in the right iliac fossa due to hyperplastic caecal TB, lymph node

enlargement and rolled up omentum, are often found. Abdominal distension with increased

peristaltic activity is generally associated with intestinal obstruction. When intestinal

perforation develops, signs of peritonitis may be apparent43,44.

Other Gastrointestinal Sites

TB at other gastrointestinal sites such as hepatobiliary and pancreatic TB are rare, oftenassociated with disseminated/miliary TB (DTB/MTB) and occur more often in

immunocompromised patients. The clinical manifestations are non-specific and depend on

the site and extent of disease. Anorexia, malaise, low grade fever, weight loss, night sweats,

Figure 3 Contrast enhanced MRI of the brain

(sagittal view, T1 weighted image)

showing solitary enhancing ring lesion


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Ocular TB

In ocular TB, the choroid is the most commonly affected structure. Primary ocular TB is

extremely rare and ocular TB is usually secondary to a TB focus elsewhere in the body.Lupus vulgaris may spread to the face and involve the eyelid. Conjunctival TB and lupus

vulgaris are the common manifestations of primary TB while tuberculids and phlyctenulosis

occur in post-primary TB. Phlyctenulosis can involve conjunctiva, cornea or the lid margin.

TB has also been implicated in the causation of Parinauds oculoglandular syndrome and

Eales disease. TB uveitis can present as pan uveitis or as chronic granulomatous iridocyclitis.

Choroidal tubercles when present can provide valuable diagnostic clues to the diagnosis of

DTB/MTB.

Disseminated/Miliary TB

DTB refers to the involvement of two or more non-contiguous sites by TB disease.

Dissemination can occur during primary infection or after reactivation of a latent focus/re-

infection. In the post-primary period, acute MTB can occur when these foci fail to heal and

progress. Later in life, re-activation of these latent foci, caseation and erosion into blood

vessels can result in haematogenous embolisation and the development of MTB47,48.

Clinical manifestations of DTB/MTB are protean. Though the association of MTB and

acute lung injury (ALI) and acute respiratory distress sydnrome (ARDS) is well known,

only a few cases of this association have been published48,49. Even in areas where TB is

highly endemic, the diagnosis of MTB can be difficult as the clinical symptoms are non-

specific.

Principles of Diagnosis of EPTB

When EPTB is suspected as a possible diagnosis, every attempt should be made to

obtain samples of tissue/relevant body fluid for diagnostic testing. The most easily accessible

tissue should be obtained for histopathological, cytopathological and microbiological

diagnosis. For example, when working up a patient with suspected LNTB, the most easily

accessible representative peripheral lymph node should be aspirated, biopsied or excised

and subjected to diagnostic testing. Similarly cerebrospinal fluid (CSF) and ascitic fluid

examination can provide valuable diagnostic clues in patients with neurological and

peritoneal TB respectively.

With the advent of ultrasound scanning, and subsequently CT scan and magneticresonance imaging (MRI), and widespread availability of thoracoscopy, upper

gastrointestinal endoscopy, colonoscopy, laparoscopy, cystoscopy and biopsy under visual

guidance and other invasive investigations such as hysterosalpingography and colposcopy,

tremendous progress has been achieved in precise anatomical localisation of the lesions in

EPTB antemortem43,50. If no accessible tissue/fluid is available for analysis, radiologically

guided fine needle aspiration and cytopathology (FNAC) or biopsy may be required to

secure tissue for diagnosis.

Treatment of EPTB

Antituberculosis treatment is the mainstay in the management of EPTB. However, theissue of the ideal regimen and duration of treatment have not yet fully been resolved. The

RNTCP which follows the WHO-recommended DOTS strategy, advocates the use of short-

course intermittent chemotherapy for patients with EPTB also1-4. According to the DOTS


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guidelines, patients with less severe forms of EPTB are categorised under the treatment

Category III and those with severe form of EPTB under the treatment Category I (Tables 1

and 2). While the six-month treatment is sufficient for the vast majority of patients, each

patient should be individually assessed and, where appropriate, treatment duration may beextended for a given patient51. The treatment outcome of patients with EPTB receiving

DOTS under the RNTCP has been good (Table 8). Patients receiving antituberculosis

treatment should be carefully monitored for adverse drug reactions, especially drug induced

hepatotoxicity52,53.

The usefulness of corticosteroids in the treatment of EPTB is controversial and not well

established54. When the diagnosis of TB is established with certainty, additional oral

corticosteroid treatment may be helpful in selected patients with life-threatening forms of

EPTB.

Published evidence suggests that a majority of the TB patients with HIV infection respondwell to DOTS55. In EPTB patients known to have co-existent HIV infection, Category I

regimen is to be used under the DOTS strategy. All HIV co-infected TB patients should

receive a Rifampicin-containing regimen. To address the problem of drug interaction between

Rifampicin and some of the anti-retroviral (ARV) drugs, such as Nevirapine, antiretroviral

treatment can be initiated after DOTS treatment is completed. In HIV co-infected TB patients

in the later stages of immunosuppression, concomitant anti-retroviral and antituberculosis

treatment may be required and in such cases the ARV regimen needs to be suitably modified,

e.g. Nevirapine replaced with Efavirenz56.

A high index of clinical suspicion, timely and judicious use of invasive diagnostic methods

and confirmation of the diagnosis, early institution of DOTS and close clinical monitoringfor adverse drug reactions, are the key to the successful management of EPTB.


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