2. General diagnostic considerations

A high index of suspicion is paramount to the diagnosis of EPTB. Any delay in diagnosis could increase the risk of morbidity and mortality.¹⁸ In at-risk patients with fever of unknown origin and site-specific signs and symptoms, or patients with biopsy-proven granulomatous inflammation, appropriate steps should be taken to confirm the diagnosis of TB, including repeat sampling if mycobacterial cultures were not obtained.

Gold-standard phenotypic drug susceptibility testing can only proceed with a viable culture, the results of which can have important treatment implications.⁷^,¹⁹^,²⁰ This point cannot be overemphasized: with the rising incidence of drug-resistant TB, especially in foreign-born residents of Canada, it is difficult to provide appropriate treatment when mycobacterial cultures and drug susceptibility test results are not available.

The clinical specimens obtained for diagnostic purposes will depend upon the suspected anatomic site of involvement. In general, tissue biopsy yields positive nucleic acid amplification test (NAAT) and culture results more often than fluid aspiration; both are superior to swabs (see Table 1 for diagnostic yield estimates). Biopsy material for mycobacterial culture should be submitted fresh or in a small amount of sterile saline.¹⁹^,²⁰ Histopathologic examination requires the specimen to be placed in formalin, which kills the mycobacteria and prevents further culture confirmation.¹⁹^,²⁰ Common histopathologic findings include necrotizing and non-necrotizing granulomas (Table 1). Loss of host immune function can result in histopathologic findings demonstrating greater suppurative response and less well-formed granulomas.⁸⁸

Good practice statement

Every effort should be made to obtain clinical samples for both mycobacteriologic (acid-fast bacilli smear, culture, nucleic acid amplification test) and histopathologic tests. If the specimen is insufficient for all testing, mycobacterial culture should be prioritized given it has the highest diagnostic yield and allows for gold-standard phenotypic drug testing.

Anywhere from 10 to 50% of patients with EPTB also have pulmonary involvement; it may, therefore, be possible to confirm a diagnosis of TB (and obtain drug susceptibility testing) with sputa assessments, averting the need for more invasive sampling.²⁰

Good practice statement

Every person with presumed extra-pulmonary TB should be assessed for pulmonary TB to assess infectiousness and potentially assist with diagnosis.

Table 1. Sensitivity and specificity of diagnostic tests in extra-pulmonary tuberculosis compared to mycobacterial culture as gold standard unless otherwise stated.

Site	Specimen type	Direct stain (ZN)	Culture	GeneXpert ^a		GeneXpert Ultra ^a		Histopathology and/or cytology	References
Site	Specimen type	Sensitivity	Sensitivity	Sensitivity ^b	Specificity ^b	Sensitivity ^b	Specificity ^b	Sensitivity	References
TB lymphadenitis	FNA	0.23-0.37	0.17-0.67	0.89	0.86	INS		0.62-0.80^d	^10–14
TB lymphadenitis	Excisional biopsy	0.35-0.53	0.71-0.80	0.82^c	0.80^c	INS		0.85-1.00^d	^10–14
Pleural TB	Pleural Fluid	0-0.10	0.10-0.63	0.50	0.99	0.75	0.87	N/A	^14–24
	Pleural Fluid	0-0.10	0.10-0.63	0.19^d	0.99^d	0.75	0.87	N/A
	Closed pleural biopsy	0.13-0.39	0.39-0.67	0.31	0.97	INS		0.69-0.97^d
	Thoracoscopic pleural biopsy	INS	0.41-0.76	0.52^e	1.0^e	INS		1.0^d ^, ^f
CNS – meningitis	CSF	0.05-0.83^g	0.40-0.87^g	0.71	0.97	0.89^h	0.91^h	N/A	²³ ^, ^25–35
CNS – meningitis	CSF	0.05-0.83^g	0.40-0.87^g	0.71	0.97	0.63^d ^, ^h	0.99^d ^, ^h	N/A
CNS – tuberculoma	FNA	INS	INS	INS		INS		0.85-0.92^d
CNS – tuberculoma	Biopsy (excisional/stereotactic)	0.17-0.38^f	0.5-0.8^f	0.87-1^f	0.89-0.96^f	INS		1^f
Abdominal TB	Feces	0-0.11ⁱ	0.44-0.5ⁱ	0.39^d	0.86^d	INS		INS	²³ ^, ^36–49
	Ascitic fluid	0.0-0.06	0.17-0.80	0.5	0.98	INS		INS
	Peritoneal biopsy	0.02-0.20	0.34-0.92	0.38-0.5^d ^, ^f	0.92-1.0^d ^, ^f	INS		0.76-1^d
	Intestinal biopsy	0.03-0.14	0.36-0.40	0.08-0.32^d ^, ^f	1.0^d ^, ^f	INS		0.16-0.7^d
GU TB – renal	Urine	0.15-0.30	0.80-0.90	0.83	0.98	1.00^j	1.00^j	N/A	²³ ^, ²⁵ ^, ^50–71
GU TB – renal	FNA/biopsy	0.29-0.44	0.95-1.0^b ^, ^j	INS		INS		0.88-0.95^j
GU TB – scrotal	Urine	0.20-0.24	0.63-0.93^b	0.83	0.98	INS		N/A
GU TB – scrotal	FNA/Biopsy	0.25-0.75	0.8^e	INS		INS		0.95^d ^, ^e
GU TB – female tract	Menstrual fluid	0.03-0.05	0.06-0.19	INS		INS		N/A
GU TB – female tract	Endometrial biopsy	0.05-0.57	0.06-0.46	INS		INS		0.07-0.71^d
Bone and Joint TB	FNA bone/synovial tissue	0.30-0.36	0.37-0.97	0.95	0.85	0.96^k	0.97^k	0.56-0.97	²³ ^, ^50–53 ^, ^72–80
	Synovial fluid	0.08-0.26	0.50-0.86	0.97	0.90	0.96^k	0.97^k	n/a
	Paraspinal fluid	0.52-0.59	0.9-0.93	0.97	0.90	0.96^k	0.97^k	n/a
Pericardial TB	Pericardial fluid	0-0.42^j	0.20-0.86	0.61	0.90	INS		N/A	¹³ ^, ¹⁴ ^, ²³ ^, ^81–88
Pericardial TB	Pericardial biopsy	0.38-0.40^j	0.22-1.0	0.71^e ^, ^j	1.0^e ^, ^j	INS		0.34-0.87^d	¹³ ^, ¹⁴ ^, ²³ ^, ^81–88
Disseminated TB^l	Sputum	0.31-0.37	0.32-0.90	INS		INS		INS	²³ ^, ^89–96
	Bronchial wash	0.20-0.55	0.07-0.71	INS		INS		INS
	Lung biopsy	0.25-0.43	0.42-0.54	INS		INS		0.63-0.95
	Liver biopsy	0.13-0.40	0.33-0.54	INS		INS		0.88-1.00
	Bone marrow	0.16-0.25	0.21-0.67	INS		INS		0.56-0.67
	Urine	0.00-0.18	0.33-0.67	INS		INS		INS
	Blood	INS	0.20-0.65	0.07-0.56	0.94-1.0	INS		INS

^{Abbreviations: TB, tuberculosis; ZN, Ziehl-Neelsen; SN, sensitivity; SP, specificity; FNA, fine-needle aspiration; INS, insufficient reported data; CNS, central nervous system; CSF, cerebrospinal fluid; GU, genitourinary; N/A, nonapplicable; HIV, human immunodeficiency virus.}

^{Reported data from single studies and meta-analyses included a minimum of 50 patients unless otherwise noted.}

^{Reported data from single studies come from HIV-negative cohorts or studies with a TB-HIV coinfection rate of less than 5% (where reported and if available). Data from meta-analyses that included studies with HIV prevalence greater than 5% and that reported a difference in diagnostics based on HIV status are noted.}

^{aGeneXpert and GeneXpert Ultra data provided as data from individual NAAT available in single site small studies.}

^{bPoint estimates used for data provided from meta-analyses.}

^{cData from Cochrane review does not define method of obtaining biopsy sample. 14}

^{dComposite reference standard definition: Positive result as the presence of granulomatous inflammation or a positive microbiologic result +/- clinical diagnosis of TB and/or improvement on TB treatment.}

^{eSingle study data.}

^{fData limited to two studies (combined n > 50).}

^{gHigher range sensitivity with larger volume (10 cc, 3 samples) concentrated samples (centrifuged at 3000 g).}

^{hMajority of people with HIV and from single study. 32}

^{iMajority of studies do not explicitly state if abdominal TB or intestinal TB present (many state disseminated disease). Presence of stool AFB and positive culture/Xpert documented in isolated pulmonary disease (primarily in children and HIV/AIDS studies).}

^{jLess than 50 patients.}

^{kBiopsy and fluid samples combined.}

^{lDisseminated TB includes miliary TB, as some included autopsy data did not allow differentiation.}

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TB Manual

Table 1. Sensitivity and specificity of diagnostic tests in extra-pulmonary tuberculosis compared to mycobacterial culture as gold standard unless otherwise stated.

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