Characteristics of clinical practice guidelines

We included 38 guidelines (figure 1) published from 2002 to 2017. These guidelines focused on medical immunosuppression (19 guidelines),1 15–32 solid organ and stem cell transplantation (seven guidelines)3 33–38 and in HIV settings (three guidelines).9 39 40 Nine were general guidelines which were not specific to a particular patient group and covered the detection of LTBI and its management.10 41–46 These guidelines were published across 16 different countries from regions including North America, Western Europe, Asia, Australia and South Africa. A summary of the guideline characteristics is provided in table 1.

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Figure 1

Database search strategy The medical databases EMBASE, PsychINFO and Medline were searched for articles relevant to tuberculosis in an immunosuppressed setting, using the search strategy described in online supplementary appendix 1. A total of 9467 articles were found and compiled into the EndNote software (Clarivate Analytics 2017, V.X7), of which 1130 articles were duplicate articles. From the remaining articles, 6121 articles were excluded by abstract review, primarily because they were irrelevant. A further 2056 articles were removed during a second review of titles and abstracts. A total of 160 articles were reviewed in full of which 122 were excluded as they did not fulfil guideline or relevance criteria. A total of 38 articles were included in our final review.

Of the guidelines that discussed medical immunosuppression, nine provided recommendations for treatment across various medical specialties including dermatology, rheumatology, gastroenterology and respiratory medicine.15 16 18 21 24 26 28 29 31 Four were specific to patients with rheumatoid arthritis,20 23 25 27 of which one focused only on patients receiving infliximab,23 while two guidelines were specific to patients with psoriasis.18 30 One guideline focused on patients with rheumatological or gastroenterological disease.15 There were specific guidelines addressing inflammatory joint disease,19 rheumatological disease1 and autoimmune bullous diseases.22 One guideline discussed patients at risk due to methotrexate therapy.32 Of the transplantation guidelines, two guidelines were for kidney transplantation,34 36 one for stem cell transplantation,38 one for both solid organ and stem cell transplantation33 and three for all forms of solid organ transplantation.3 35 37

Three guidelines addressed LTBI in patients with HIV.9 39 40 There were nine other guidelines which discussed screening in all at risk populations.10 41–48 Six of these also included discussion on patients with HIV41–45 47 and four were IGRA specific guidelines, although these guidelines also used TST as part of their screening strategies.41 43 44 46 Three guidelines were developed in countries with a high prevalence of TB (South Africa and Philippines).20 24 40

Across the guidelines, the methods for literature review were not always specified. Literature review was conducted in 32 guidelines (84%),1 3 9 10 15–22 24 26–35 37–39 41–46 48 of which 12 based their recommendations on a combination of the literature review and expert consensus.3 9 10 15–18 20 21 26 29 34 37 43–46 Two guidelines were based on expert consensus alone.23 42 Twenty guidelines graded the level of evidence.3 9 10 17 18 24 27–30 32 34–39 42 46 48 Furthermore, 17 guidelines graded the strength of their recommendations.3 9 10 24 26 28–34 38 39 41 45 48 Where evidence was graded, it was often of low quality. Only nine (24%) guidelines were peer reviewed,9 10 17 19 20 24 29 30 48 with five (13%) made available for public consultation prior to publication.9 19 20 24 48 Only one guideline included a formal cost-effectiveness analysis48 which suggested that TST was more cost effective compared with the IGRA. The incremental cost-effectiveness ratio was influenced by prevalence of disease and age of the patients.

Methodological quality

Table 2 summarises the AGREE domain scores of each guideline. The mean AGREE score (and range) for all guidelines was 55% (0%–100%). In terms of scope and purpose, on average 80% (56%–100%) of criteria were met for all guidelines. The average score for stakeholder involvement was 51% (11%–97%), for rigour of development 47% (10%–93%), clarity and presentation 74% (50%–92%), applicability 47% (0%–92%) and editorial independence 35% (0%–92%). The overall domain mean score was 55% (35%–80%).

Weighted Kappa scores (κ) to assess inter-rater agreement ranged from a score between poor to very good, with the majority being moderate (0.41–0.60) to very good (0.81–1.00). The overall weighted score was 0.65 (95% CI 0.60–0.69), with good concordance between reviewers. The AGREE scores did not improve with later guidelines and over time.

Textual synthesis

A summary of the guidelines and the recommendations are provided in table 3. Most guidelines recommended screening in all immunosuppressed patients, and treatment if there was clinical evidence of LTBI.

Screening for latent TB infection

Screening modalities and frequencies

A combination of TST and/or IGRA testing, chest X-ray, detailed background history (including previous exposure to other individuals with TB) and risk factor assessment (travel or migration from endemic areas) was the most frequent recommendation for LTBI screening in immunosuppressed individuals.1 17 18 21 23 24 26 29–32 47 The recommended choice of screening modalities and their frequency were reliant on test availability and costs. The TST is widely available and economical.10

In guidelines pertaining to medical immunosuppression, the recommendations for screening varied considerably between the use of TST and IGRA. Concurrent testing with both TST and IGRA was supported in six guidelines,16 18 20 22 26 32 however, three recommended the use of IGRA alone.15 28 30 Seven guidelines supported TST screening alone, but these recommendations were published prior to 2011.17 19 21 23 24 27 29 Two other guidelines recommended the use of either the TST or IGRA.1 22 In addition, two other guidelines recommended IGRA for BCG vaccinated individuals.16 17

In patients who require long-term maintenance medical immunosuppression, repeat testing at yearly intervals using IGRA was recommended by three guidelines,17 28 31 but two advocated against this, as the benefits of frequent IGRA screening was questionable.16 27 IGRA was recommended by one guideline in the presence of (any) skin disease due to difficulties in inoculating the TST in many of these cases.18

For transplant recipients, those with HIV and other immunosuppressed individuals, most guidelines acknowledged the added value of including TST and IGRA in the screening algorithm.9 10 33 35 37–39 41–46 48 Two guidelines specified the preference for IGRA over TST as the standard triage screening tool for LTBI, because of the high false positive rates associated with TST,34 particularly among those who had been vaccinated with BCG.47 However, across all guidelines, among BCG vaccinated individuals, two guidelines recommended a two-step strategy for screening LTBI.31 42 TST was often considered as the triage test. If negative, IGRA was recommended as the second test to confirm the diagnosis. This has also been recommended to increase case detection in five other guidelines.17 20 30 35 46

Costs were also considered as a key factor in determining the frequency and modality of screening in immunosuppressed individuals. The WHO have suggested IGRA and/or TST may be used in high-income and upper-middle-income countries.10 Given the anticipated costs of IGRA, and the general acceptance of TST by clinicians and patients, TST was preferred in low income countries, despite the lower test accuracies of TST.10 In the high prevalence settings of South Africa and the Philippines, there was no reliable testing method: a combined TST and IGRA approach was recommended in one guideline,20 treatment of all patients with HIV without screening was recommended in another40 and TST alone in one guideline.24

Defining screen positive and negative results

Criteria for TST positivity varied across guidelines. Some recommended a TST-induced reaction of at least 5 mm diameter in all populations, to allow for the treatment of patients in high-risk settings.17 19–21 26 35–37 40 48 Other recommendations for the threshold diameter ranged from 6 mm to 20 mm.18–21 23 24 26 27 31 33 Where the TST result was initially negative, two guidelines recommended repeat testing.23 45 In all guidelines, an individual was deemed to be at risk for LTBI if either the TST or IGRA was positive.

Are these recommendations valid?

There is a body of evidence assessing the test performance characteristics of TST and IGRA in the general population. However, these recommendations were sourced largely from observational studies performed in middle to high-income countries and did not include immunosuppressed patients from low-resource settings and with low certainty of the evidence. Given the low test sensitivity of TST in immunosuppressed patients, some guidelines suggested a two-stage screening, first using TST and then IGRA to increase the detection rates of LTBI.17 20 30 35 46 Among those who are immunosuppressed and had previously been vaccinated with BCG, IGRA generally performs better than TST. IGRA test sensitivity and specificity varies between 67%–75% and 93%–99%, respectively.33 43 However, given the concerns of spectrum bias, most guidelines suggested caution in the interpretation of test results among immunosuppressed hosts.

Treatment for latent TB infection

Intervention and duration

Recommendations for the treatment of LTBI were largely similar across guidelines, regardless of the mode of immunosuppression. In most guidelines, isoniazid 300 mg daily with pyridoxine was recommended for a duration of 9 months.3 9 16–21 24–27 29 31 33–39 42 Six months of isoniazid therapy was considered less efficacious,18 but was recommended in one guideline.48 Three guidelines suggested a flexible treatment regimen of 6–9 months of the combined therapies.19 30 47 Four guidelines did not specify duration.15 23 32 45

Rifamycin-based therapy (10 mg/kg/day) either alone or for three10 or four1 3 9 10 15–18 24 26 27 31 33 35–39 42 months was the second most frequently reported treatment strategy among patients who tested positive for LTBI. This was thought to be useful when isoniazid was contraindicated or not tolerated,27 with one guideline describing the option as cheaper, but with more drug-drug interactions.18 Rifampicin plus isoniazid for three1 10 15–19 25 26 29–31 39 or 4 months10 24 was also an option. Rifampicin plus isoniazid for 3 months was stipulated as a primary alternative therapy to isoniazid in two guidelines.30 48 Other options included rifabutin for 4 months9 42 or 3 months of weekly rifapentine and isoniazid.9 10 Finally, rifampicin and pyrazinamide for a shorter 2-month regimen was considered as an option in eight guidelines,3 25 29 35–39 with most being in the transplantation setting. The shorter duration of treatment was considered advantageous for those maintained on the transplant waiting list.3 35–38 However, a biological therapy-based guideline advised against this option due to the increased risk of hepatotoxicity.24

In the transplantation and HIV settings, some guidelines specified avoidance of rifamycins, given the potential drug-drug interactions with calcineurin inhibitors and protease inhibitors.3 35 37 However, therapeutic drug monitoring may mitigate against the potential for such interactions.34 Several other non-rifamycin based alternatives were recommended and included ethambutol with levofloxacin or moxifloxacin for 6 months,3 3712 weeks of rifapentine and isoniazid and 6 months of isoniazid with ethambutol.24

Close monitoring with monthly liver function tests and for peripheral neuropathy was recommended while on treatment for all patients.3 9 10 17 18 26 31 35 37 40 47 Coadministration of vitamin B6 (pyridoxine) was suggested universally, to reduce the risk of peripheral neuropathy associated with isoniazid. If there were treatment interruptions for more than 2 months, one guideline recommended clinical and radiological reassessment for TB.42

Timing of preventive therapy

In patients who are medically immunosuppressed, most guidelines recommended delaying medical therapy for 1 month after commencement of LTBI treatment where possible, to reduce the risk of TB reactivation.15–18 20 24–28 Alternative waiting periods varied between 3 weeks25 47 to 2 months.30 One guideline preferred a prolonged delay, but did not provide a time frame.21 However, if the underlying disease was severe, earlier institution of immunosuppressive agents was accepted17 29 once active TB was excluded.28

In transplant setting, patients with LTBI are recommended to commence treatment on the waiting list where possible, with treatment ideally completed prior to transplantation.3 33 35 37 38 However, treatment interruption peritransplantation, with recommencement and completion of the treatment course once patients were clinically stable, may also be considered.33 35 37 LTBI treatment should not delay transplantation.38 In the setting of liver transplantation, the use of anti-TB medications has been associated with increased risk of hepatotoxicity. Thus, it was generally recommended that LTBI therapy be commenced after transplantation, to avoid drug-related fulminant hepatitis while waiting for a donor organ.3 35 37

In patients with HIV, the timing of commencement of antiretroviral therapy in relation to LTBI treatment was not specified by clinical practice guidelines. Unlike treatment for active TB, immune reconstitution related to LTBI treatment has not been documented.9 Generally, it was recommended to initiate or continue antiretroviral treatment concurrently with treatment for LTBI.39 40

Are these recommendations valid?

Overall, clinical practice guidelines recommended the use of isoniazid-based or rifamycin-based regimes for the treatment of LTBI. The evidence for recommendations was largely sourced from observational studies in high-income countries, thus limiting the ability to generalise recommendations to low-income countries. There was very little evidence about the exact time frame of delay before initiating treatment. In addition, side effects associated with the treatment of LTBI, such as hepatotoxicity, neuropathy, gastrointestinal toxicity and rash, were discussed in only 50% of the guidelines.1 3 9 10 18 19 21 24 29 31 33 35–37 39 40 42 47 48