Epidemiological perspective of drug resistant extrapulmonary tuberculosis

Table 1 Drug resistant-extrapulmonary tuberculosis: Reasons to worry

Drug resistance (including MDR) in cases of EPTB is increasing and now it cannot be considered as rare

Accurate and timely diagnosis and drug susceptibility testing are very difficult and may result into high morbidity and mortality

DR-EPTB is often difficult to treat due to poor penetration of some key anti-tubercular drugs into extra-pulmonary sites (especially in CSF)

HIV and young age are independent key risk factors

Although not contagious but it may co-exist with highly contagious pulmonary manifestation

MDR: Multi-drug resistant; DR-EPTB: Drug resistant-extrapulmonary tuberculosis; CSF: Cerebrospinal fluid; HIV: Human immunodeficiency virus.

Table 2 Drug resistant extrapulmonary tuberculosis in different parts of world

Region	Type of EPTB	Study period	Culture positive cases/total cases analyzed	Prevalence of drug resistant MTB	DST method	Concomitant Pulmonary TB cases/total cases analyzed	HIV positive cases/total cases tested1	Treatment outcomes	Ref.
Argentina	TBM	1996-2004	101	Any DR: 51.5%  MDR: 41.6%	E	Not stated	101/101	64/101 died during hospitalization	Cecchini et al[49]
Australia	Various sites (including pulmonary)	2007	8712 (culture proven PTB/EPTB cases with available DST result)	MDR: 25% (6/24) of all MDR-TB cases	E	Not stated	Not stated	Not stated	Lumb et al[50]
Bangladesh	Various sites	2011	152 (culture proven TB cases)	Any DR: 45.4% MDR: 11.2 %	C	Not stated	Not stated	All cured	Afroz et al[51]
Brazil	TBM	1999-2007	108 (DST result available for 90 cases)	Any DR: 40% MDR: 9%	D	Not stated	108/108	31/108 died during hospitalization	Croda et al [46]
Canada	Various sites	1995-2002	126/214	Any DR: 19% INH-R: 7.9%	G	0/214	4/126	Not stated	Yang et al[52]
China	Spinal TB	2005-2010	127/249 (35 DR cases studied in detail)	Any DR: 30.7%	A	9/35	0/35	No death;	Li et al[47]
								33/35 cases cured
	Spinal TB	2006-2011	76/152 (19 DR cases studied in detail)	Any DR: 30.3%	A	Not stated	Not stated	No death;	Xu et al[53]
								19/19 cases cured
	TBM	2009-2010	30 (culture proven TB cases)	Any DR: 66.7% MDR: 32.1%	B	20/30	0/30	Not stated	Duo et all[54]
Denmark	TBM	2000-2008	41/50	INH-R: 4%  MDR: 2%	D	23/50	5/50	9/50 cases died	Christensen et al[55]
Ethiopia	Tuberculosis lymphadenitis	2012	225/437	Any DR: 6.7%  MDR: 1.3%	D	Not stated	Not stated	Not stated	Biadglegne et al[56]
France	Various sites (including pulmonary)	1992-1999	264 MDR-TB cases (207 PTB cases, 19 EPTB cases and 38 EPTB cases with concomitant PTB)		D	38/264	55/224	Not stated	Robert et al[16]
India	Various EP sites	2007-2010	227/756 (165 isolates confirmed as MTB)	Any DR: 39.9% MDR: 13.5%	C	Not stated	3/165	Not stated	Maurya et al[18]
	TBM	Not stated	51/370	Any DR: 33.3% MDR: 1.9%	D	Not stated	Not stated	Not stated	Jain et al[57]
	Abdominal TB	2008-2013	31/61 (DST analyzed for 18 isolates)	Any DR: 14.3% MDR:5.4 %	A	0/61	0/61	Not stated	Samant et al[58]
	Various EP sites	2010	150/547 (14 cases excluded)	MDR: 33%	A	Not stated	16/547	Not stated	Vadwai et al[59]
	Various EP sites	2007-2011	125/419	Any DR: 20.8% MDR: 12%	A	Not stated	7/125	Not stated	Sankar et al[32]
	Various EP sites	2002-2006	338 (culture proven TB cases)	Any DR: 52.7% MDR: 11.8	D	Not stated	Not stated	Not stated	Sethi et al [19]
	Various EP sites	2010-2011	18 (culture proven TB cases)	MDR: 5%	D	Not stated	0/18	Not stated	Desikan et al[60]
	TBM	2004-2005	22/100	MDR: 18.2%	C	Not stated	1/4 MDR cases	All 4 MDR cases died	Baveja et al[61]
	TBM	2000-2003	256/2325 (DST analyzed for 205 isolates)	Any DR: 19% MDR: 1.5%	C	Not stated	Not stated	Not stated	Venkataswamy et al[22]
	TBM	2001-2005	366 (culture proven TB cases)	Any DR: 17.8% MDR: 2.4%	C	Not Stated	48/107	Not Stated	Nagarathna et al[62]
	Spine TB	2004-2007	25 (culture proven MDR-TB cases)		E	Not Stated	2/25 MDR cases	19/25 MDR-ETPB cases cured; rest 6 cases not concluded	Pawar et al[63]
Kazakhstan	Osteoarticular TB	2007-2009	76/285	MDR: 54.4%	I	Not stated	Not stated	Not stated	Tutkyshbaev and Amanzholova[64]
Korea	Various sites	2008-2010	168 (culture proven TB cases)	Any DR: 8.9%  MDR: 1.8%	E	52/168 (5 cases had DR-TB; 43 cases had disseminated TB)	4/168	Not stated	Cho et al[65]
Nepal	Various sites	2004	54/513 (48 isolates confirmed as MTB)	Any DR: 62.9% MDR: 12.6%	F	Not stated	Not stated	Not stated	Gurung et al[66]
Pakistan	Various sites	2000-2002	98/460 (88 isolates confirmed as MTB)	MDR: 21.4%	H	Not stated	Not stated	Not stated	Butt et al[67]
Russia	Tuberculous spondylitis	2008-2011	107 (culture proven TB cases)	DR: 75.7% MDR: 69.1%	I	66/107	25/107 (15 HIV cases had MDR)	Not stated	Vyazovaya et al[30]
South Africa	TBM (in children)	1992 -2003	362/6781	Any DR: 11.6% MDR: 2%	E	Not stated	6/8 MDR cases	7/8 MDR cases died	Padayatchi et al[68]
	TBM	1999 -2002	350/6762 (Only MDR cases studied)	MDR: 8.6%	E	14/30	18/30 MDR cases	17/30 MDR cases died (rest cases survived with disability)	Patel et al[20]
Taiwan	Various sites	2000-2010	798 (culture proven TB cases)	Any DR: 15.5%  INH-R: 9.4%  MDR: 2.5%	D	Not stated	Not Stated	Not stated	Lai et al[17]
Turkey	Various EP sites	2001-2007	103 (culture proven TB cases)	Any DR: 25.2%	A/C	Not stated	Unknown	Not stated	Gunal et al[69]
United States	Various sites	1993 -2006	31633/47293	MDR: 0.9%	E	Not stated	4179/16888	Not stated	Peto et al[13]
	Pleural TB	1993 -2003	4215/7549	Any DR: 9.9% INH-R: 6%; MDR: 1%	E	264/7549 (sputum positive by culture)	305/1378	679/7549 (9%) cases died during treatment	Baumann et al[15]
	Various sites	1993-2003	197/239 (in an ethnic group)	Any DR: 18% MDR: 3%	D	41/239	2/175	One MDR case died; 169/186 (91%) cases completed treatment	Rock et al[23]
	TBM	1993 -2005	1614/1896 (from CSF samples)	INH-R: 6%	E	468/777 (sputum positive by culture)	404/989	43/123 INH resistant cases died	Vinnard et al[24]
Vietnam	TBM	2004-2005	51/58 (DST result available for 46 cases)	Any DR: 54.3% MDR: 8.7%	D	Not stated	36/55	39/58 cases died; 11/58 cases survived; 8 cases lost to follow-up	Torok et al[27]
	TBM	2001-2003	222 (culture proven TB cases)	Any DR: 35.1% MDR: 4.1%	D	Not stated	35/222 (17 HIV cases had DR-TB)	24/35 TBM cases (HIV co-infected) died	Caws et all[28]
	TBM	2000-2003	180 (culture proven TB cases)	Any DR: 40% MDR: 5.6%	A	Not stated	40/178	60/180 cases (including 29 DR cases) died; 49/180 cases disabled; rest recovered well	Thwaites et al[70]
							(21 HIV cases had DR-TB)

Besides the reports tabulated here, some case studies as well as studies with very low sample size have also been reported from different countries but could not be addressed in this review.

¹Cases with unknown HIV status are excluded from total number of cases tested;

²Isolates recovered from both pulmonary and extra-pulmonary sites. DST methods: A: BACTEC MGIT 960 system; B: PCR and Genotype MTBDRplus line-probe assay; C: BACTEC 460 TB system; D: Conventional DST using proportion method; E: Method not specified; F: Conventional DST using minimum inhibitory concentration method; G: Middlebrook 7H10 agar using proportion method; H: BacT/AlerT 3D system; I: Conventional DST using absolute concentration method. DR: Drug resistance to any one first line anti-tuberculosis drugs; MDR: Multi-drug resistance; DST: Drug susceptibility test; MGIT: Mycobacterial growth indicator tube; MTB: Mycobacterium tuberculosis; EPTB: Extra-pulmonary tuberculosis; PTB: Pulmonary tuberculosis; INH: Isoniazid; HIV: Human immunodeficiency virus; R: Resistant; CSF: Cerebrospinal fluid; TBM: Tubercular meningitis; TB: Tuberculosis.

Table 3 Key issues in diagnosis of drug resistant-extrapulmonary tuberculosis

Issues in laboratory diagnosis

In general, the sensitivity of laboratory tests is often compromised

Due to pauci-bacillary nature of EPTB

Due to difficulty in obtaining an adequate sample

Risk associated with the sampling procedure (e.g., lumbar puncture, biopsy of deep lymph nodes, etc.)

Lack of accessibility of serial samples for monitoring the treatment response

Un-availability of reliable host biomarkers that can be analyzed in easily attainable specimens

Xpert-MTB-RIF test seems promising diagnostic tool but the negative test result does not rule out EPTB and it can only determine the resistance to rifampicin (not other crucial drugs)

Issues at programmatic/administrative level

Lack of focused programme (like pulmonary TB) in many high TB burden countries

Lack of reliable estimates on impact and magnitude of DR-EPTB

Although seeking microbiological, histopathological diagnosis and drug susceptibility testing is crucial, it is however not in routine practice (in many high TB burden countries)

Rapid molecular based diagnostic (Xpert-MTB-RIF) is still away from its accessibility at peripheral health care centers in many resource limited countries

Wide variation in diagnostic and treatment practices among health service providers (as reported in private sectors of India) that often do not comply with national or international standards

DR-EPTB: Drug resistant-extrapulmonary tuberculosis; MTB: Mycobacterium tuberculosis; RIF: Rifampicin; TB: Tuberculosis; EPTB: Extrapulmonary tuberculosis.