The effect of surgery on the outcome of treatment for multidrug-resistant tuberculosis: a systematic review and meta-analysis

It is estimated that 20 % of previously treated TB cases and 3.3 % of new TB cases worldwide have multidrug-resistant tuberculosis (MDR-TB), which is caused by bacterial strains resistant to both the two major anti-tuberculosis drugs, isoniazid and rifampicin [1]. In 2014, there were an estimated 480,000 incident cases of MDR-TB and 190,000 people died of MDR-TB [1]. Extensively drug-resistant TB (XDR-TB) is defined as MDR-TB with additional resistance to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, kanamycin). Individuals with XDR-TB have been reported by 105 countries to-date, and are estimated to account for 9.7 % of those with MDR-TB [1].

Treatment for MDR- and XDR-TB currently entails therapeutic regimens with much lower efficacy and much greater toxicity than those used for drug-susceptible TB. Recommended treatment requires at least 20 months of therapy and in 2014 only 50 % of MDR-TB patients globally had a successful treatment outcome compared to 86 % for newly diagnosed drug susceptible disease. Even with the discovery of bedaquiline and delamanid, the first anti-tuberculosis drugs with new mechanisms of action to be approved in over 40 years and the first drugs to be introduced specifically for MDR-TB combination therapy [2‐4], access is limited and regimen effectiveness still remains below that of drug susceptible disease [4, 5]. Increasing drug resistance further limits the treatment options available to MDR-TB patients.

In the pre-chemotherapeutic era surgical procedures were commonly used for management of tuberculosis. Collapsing the lung by creation of an artificial pneumothorax or by plombage was regarded as an effective way to deal with lobes of affected, non-functioning lung. With the advent of effective chemotherapy however it soon became clear that medical therapy offered a superior option and enthusiasm for surgical approaches waned. In the current context of increasing drug resistant TB with far less effective medical therapy there has been an understandable resurgence of interest in the use of surgery as an adjuvant therapeutic strategy. In contrast to earlier techniques, the dominant procedures in the 21^st century are resection of segments, lobes or whole lungs, with collapse therapy much less used. Surgical resection can debulk disease, reducing bacillary load, and removing devitalised lung that acts as a sanctuary site for resistant organisms, poorly penetrated by drug therapies. However, removal of lung tissue reduces pulmonary capacity and thus it is crucial that pre-operative assessment takes account of the residual lung function with which the patient will be left post-operatively. Appropriate timing of surgery, before too much of the remaining lung is affected by disease, and selection of the procedure to maximize removal of non-functioning tissue whilst minimizing removal of non-diseased lung are key determinants of a successful surgical outcome.

Current treatment guidelines issued by the World Health Organization (WHO) and US Centres for Disease Control and Prevention suggest that surgical interventions may be appropriate as an adjunct to chemotherapy when skilled thoracic surgeons and good postoperative care are available [6, 7]. Intensive chemotherapy prior to surgery and postoperative chemotherapy for 12–24 months is also recommended [6, 7]. Iseman et al. established criteria for surgical intervention in MDR-TB [8], including (i) drug resistance so extensive that there is a high probability of failure or relapse, (ii) disease sufficiently localised that the majority of the disease can be resected, with the expectation of adequate cardiopulmonary capacity post surgery and (iii) sufficient drug activity to diminish the mycobacterial burden enough to facilitate probable healing of the bronchial stump. There is a specific window of opportunity for surgery, as it is rarely an immediate choice upon MDR diagnosis, but is also not suited as a last resort rescue therapy. Other guidelines refer to surgery being used for localized disease, when drug resistance is extensive, and as an adjunct to chemotherapy after at least two months of surgery with the completion of 12–24 months chemotherapy post operatively [6]. Guidelines emphasis the importance of only offering surgery in areas where there is sufficient local surgical expertise and adequate infection control available.

Systematic reviews on the application of surgery for MDR-TB were last published in 2012 [9]; and 2013 [10]. To inform the 2015/16 revision of the WHO MDR-TB treatment guidelines an updated systematic review was required which included a widened, global search of multiple international databases.

We conducted a systematic review and aggregated-data meta-analysis to assess existing evidence for the effectiveness of surgery on the outcomes of patients with MDR-TB.

Though the methods are summarized briefly below, the full review protocol and PRISMA checklist are available in the Additional file 1 and a summary of the study protocol is registered on the prospective register of systematic reviews (PROSPERO reference: CRD42015029501) [11]. Minor amendments were made to the original protocol where clarity was required to ensure consistent interpretation. These included searching Google Scholar rather than Google and the exclusion of articles with fewer than 10 patients recruited in the surgery arm rather than overall.

This meta-analysis of 14 observational studies indicates a substantially increased likelihood of a successful treatment outcome (cure or treatment completion) in MDR-TB patients undergoing adjunctive surgery (OR 2.62, 95 % CI 1.94–3.54). Restricting the outcome of interest to cure reveals a similar effect size, albeit with wider confidence intervals reflecting the smaller number of contributing studies (5 studies, OR 3.03, 95 % CI 1.59–5.78).

The direction of this positive effect of surgery on treatment success is consistent with previous reviews by Marrone et al. [10] (OR 2.24, 95 % CI 1.68–2.97) and Falzon et al. [20] (OR 1.5, 95%CI 0.9–2.6), albeit with a marginally greater magnitude. A strength of our review is the large number of globally-representative databases searched, therefore the meta-analysis reported here included a number of additional pre-2012 papers and also included several more recently published papers [20, 30].

Adjunctive surgery was also associated with a reduction in loss to follow-up and treatment failure. For both these analyses the estimated effects reported by individual studies all reported a reduction due to surgery. The confidence intervals of the summary estimate for effect of surgery on death (assessed as TB mortality or all cause mortality) crossed the null (OR 0.82, 95 % CI 0.41–1.64), therefore there it was not possible to demonstrate that surgery has an effect upon mortality.

Analyses were planned for several sub-populations, including children, patients with diabetes, pregnant women and patients with HIV, but either no relevant data were identified or reporting was insufficient to stratify for these subgroups. For patients with HIV, only one meta-analysis [37] that included 12 studies with data on HIV patients was identified; however, none of the studies analysed the effect of surgery stratified by HIV status. Only three of the 14 original research articles clearly stated the type of surgery undertaken, the remainder classified surgical intervention in more general terms as resective surgery of localized lesions. As the studies provided very limited, if any, information on the type of surgery, sub-analyses comparing types of surgery were not possible. Given the considerable difference between a pneumonectomy and a segmentectomy this remains an important knowledge gap and unsatisfactorily forces analyses into the binary surgery/non-surgery approach which clearly conceals major heterogeneity in procedures utilised.

As discussed recently by Roberts and Ker, the inclusion of very small studies in systematic reviews can lead to an exaggerated estimate of treatment effect due to publication bias and the tendency towards lower quality and oversight [41]. Small case series often have less rigorous inclusion criteria and are thus more prone to recruitment bias. Therefore, in this review studies reporting fewer than 10 surgical cases were excluded. A sensitivity analysis including such articles demonstrated that this had little effect on the effect estimates and did not affect the conclusions. Two papers by Kim et al. [31, 32] had potentially overlapping patients as two of the ten years reported in the 2007 paper may have also been included in the 2008 paper. A sensitivity analysis to exclude the 2007 paper gave a similar effect estimate, demonstrating that this potential overlap would not bias conclusions drawn.

Overall, the quality of evidence across each outcome measure with available data was assessed as “very low” using GRADE methodology. Most of the outcomes had clear directionality and sufficiently narrow CIs to suggest that surgery had a positive effect on patient outcomes, with the exception of death for which the summary CIs crossed the null. However, the event rate for death was low and a post-hoc optimum information size calculation indicated that there was insufficient power. This combined with the heterogeneity in the outcome definition suggest that the null result could conceivably be a product of these methodological issues. Therefore the reviewers are cautious to over-interpret the null result.

The most notable methodological issue is the absence of experimental studies in the current body of evidence, which thus consists entirely of observational studies (mainly retrospective cohort studies). Reliance on such study designs mean inherent biases such as lack of blinding or randomisation cannot be managed, and residual confounding is not managed through study design. The most important limitation in the meta-analysis was the inability to appropriately adjust for known confounding: eight of the 12 retrospective cohort studies did not sufficiently address confounding [24‐26, 28‐31, 34], which could have a major influence upon the reported treatment effects.

No studies explicitly evaluated the timing of surgery or considered it as a confounding variable in a multivariate regression, though two reported a wide range over which surgery was performed [28, 34]. A window of opportunity exists for indication of surgery, as those with less severe disease tend to be allocated to medical treatment alone, whereas in more severe disease there may be reticence to operate owing to the risk of death or complications during the procedure and the anticipated inadequacy of post-surgery respiratory reserve. Although the timing of surgery is highly likely to influence outcome, the available data on this important confounding variable are scarce.

The experience of the surgeon and quality of surgical facilities and post-surgical care likely affect estimation of surgical risk in different settings. This, combined with the lack of an evidence-based well-established guideline, results in variation in the criteria used to determine whether surgery is indicated. Since groups receiving surgery are heterogeneous and their characteristics not well reported, the authors propose the development of a standardised minimum dataset for use by surgeons to record their rationale for the surgery/no surgery decision (e.g. clinical characteristics of lung involvement, safety considerations), and for clearly recording the intervention and patient outcomes. Incorporated in to an international registry (potentially online) this observational data could quickly grow into an informative dataset to help understanding of international practice, the drivers of heterogeneity and practices more commonly associated with a more favourable outcome.

Studies were identified from Asia, Africa and Europe, so provide some global representativeness, but were mostly from relatively high income settings. Therefore, although surgery was largely associated with positive outcomes in the results reported here, caution is advised in generalising this finding to more resource-constrained settings. Surgical expertise is a clear determinant of outcome and most studies included in this meta-analysis were from well-resourced tertiary referral centres. Clearly such low-frequency surgery should be undertaken only in centres of expertise; whether in low income settings the rates of post-operative complications such as infection, pneumothorax or other morbidities arising from less intensive post-operative supervision would be different is not known.

The paucity of reported adverse event data for both medical and surgical arms also limit our conclusions. Previously reported morbidity from surgery for MDR-TB ranges between 9.4 to 46 % [42] while the frequent side effects occurring during 2 years of anti-tuberculosis treatment for MDR-TB are well documented [43]. Consideration of surgical complication risk is an important part of the decision-making process for surgeon and patient, though as surgery is an adjuvant not a replacement therapy, patients who undergo surgical resection are not spared any of the risk of drug therapy adverse effects to which their non-surgical counterparts are also exposed.

This work indicates that the existing evidence, determined through the GRADE assessment as being of very low quality, may support the use of adjuvant surgery in the management of MDR-TB. However, due to potentially important residual confounding, caution is advised in the interpretation of these results. It is also self evident that surgery is not a sensible proposition for all MDR-TB patients. The nature of patient and surgeon decision-making about whether to proceed to surgery is not at all well captured by this type of analysis nor by the constituent articles, and remains a key obstacle to the generation of unbiased evidence with minimal confounding.

AHRQ, Agency for Healthcare Research and Quality; CI, confidence interval; GRADE, Grading of recommendations, assessment, development and evaluations; MDR TB, multidrug-resistant tuberculosis; OR, odds ratio; XDR TB, extensively drug resistant tuberculosis.