Implementation of a Routine Screening Program for Latent Tuberculosis Infection among Patients with Acute Leukemia at a Canadian Cancer Center

Round 1

Reviewer 1 Report (Previous Reviewer 2)

All recommendations was accepted 

Author Response

Thank you for your review.

Sincerely, Coleman

Reviewer 2 Report (Previous Reviewer 3)

The authors based their study on the premise that screening for latent tuberculosis infection (LTBI) in patients with hematologic malignancies is advisable because of the increased incidence of tuberculosis (TB). They employed the tuberculin skin test (TST) in patients with acute leukemia (AL) and analyzed subsequent LTBI treatment outcomes. The study included AL patients with a TST/+ve result. Based on their results, the authors conclude that, in general, TST screening shows a low predictive value in AL patients but may be suggestive in individuals from TB-endemic countries.

Compared to the previous version, the paper shows a noticeable improvement. However, the simplistic approach prevails, using a screening test with a wide range of uncertainty. Nevertheless, the significance of the study partly justifies its publication as a minimum required contribution.

 

Therefore, the manuscript is endorsed for publishing in “Current Oncology” once the writing flaws have been corrected.

Author Response

The English language has been upgraded. 

Sincerely, Coleman

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

This study adds to the existing literature on patients with hematological malignancies screened for LTBI using TST. However, the cut-off used is not one that is recommended by the TB guidelines. For persons considered to be immunocompromised, it is standard to use a lower cut-off of 5mm to account for the likely under-detection caused by the immune alterations. That first step, the choice for that case definition of LTBI, should be better explained in the paper. Under-detection of LTBI is a concern, given the lower prevalence of LTBI found here compared to other studies, and also suggested by the findings of apical fibrosis, a radiographic hallmark of old TB among 10 patients who were TST negative, and other findings such as granulomas, pleural scarring, which are also typical of old TB, albeit admittedly not diagnostic.

The use of 2013-2014 data would be interesting with the ability to provide longer follow up of outcomes, and more details on these numbers would be welcome, starting in Figure 1, through the methods, results, and more detailed discussion. It is mentioned that patients were followed for up to 8 years, but it's only in Figure 2 that one can discern that only 2 patients with LTBI who received treatment were still in follow up by 8 years? In addition, how was the absence of active TB determined during that period of time? Were the patients matched against a national TB registry? Why follow only those who received LTBI? One would expect LTBI to work and those persons not to develop active TB. Why not follow those who didn't receive LTBI treatment both TST+ (with LTBI diagnosis) and TST- but who had radiographic suggestion of LTBI? The numbers may have been too low for meaningful interpretation, but their outcomes are the ones of more interest.

Using the same data, the study could be enhanced by looking at those who had 5-9 mm TSTs. Assuming they weren't offered LTBI treatment, contrast their radiographic findings, and present their follow up over 8 years. 

The conclusion as presented with the current data may not be valid given the LTBI case definition used, and the absence of outcomes data for those who were TST negative.

Other minor comments:

Line 193: 90% of LTBI patients have no findings on CXR... it'd be incorrect to say that the 11/17 who had CXRs with no findings were not compatible with LTBI.

The paper could use a refresh on the references cited for treatment of LTBI in the discussion. The mainstay of LTBI therapy has really changed in the past 5-6 years to short-coursed, rifampin-based therapies of 3 to 4 months with similar efficacy as INH, although these regimens were not likely the norm in 2013-2014.

Reviewer 2 Report

Thank you very much for your kind invitation to review the article.

In the article colleagues have introduced relevant and useful data for improving LTTB  with acute leukemia.

However, the structure and content of the article should be improved.

The following items should be corrected:

-          The epidemiology data from the WHO Report 2021 should be included in the introduction.

-            Moreover, pay attention to the authors that it is necessary to include the WHO guideline from 2018. (Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/handle/10665/260233, accessed 23 February 2022).

-          It means that your data should be added to the WHO guideline. (Public Health Agency of Canada. Tuberculosis in Canada 2008-2018 Data. Minister of Health).  Because, it not quite clear why colleagues have used only TST and have not used IGRA tests (ELISPOT or QFT -plus).

-          Also, it’s unclear how can colleagues compare the concordance of TST screening with computerized tomography (CT) imaging of the chest consistent with a diagnosis of granulomatous disease. It would be better to compare the results of immunologic tests than principal different methods.

-          It”s not clear why colleagues have examined only  ≥16 years of age patients. You should include data related to BCG vaccination. What age of the patients was limited? (What exclusion criteria  was?).

-          In the materials and methods the design of the study should be presented with inclusion and exclusion criteria. It should be presented data: immunosuppression therapy; TB contact; information about active TB in anamnesis.

 

-          Conclusion is not clear. Colleagues did not provide their analysis data, and explain received conclusion.

Reviewer 3 Report

The authors based their study on the premise that screening for latent tuberculosis infection (LTBI) in patients with hematologic malignancies is advisable because of the increased incidence of tuberculosis (TB). They assessed the usefulness of tuberculin skin testing (TST) in patients with acute leukemia (AL) and analyzed the subsequent outcomes of LTBI treatment. Retrospectively (2013-2014), they evaluated TST in AL patients before initiating antineoplastic chemotherapy treatment and compared both clinical-demographic information and LTBI treatment outcomes between AL patients who tested TST/+ve or TST/-ve. The study included 389 patients, of whom 37 were TST/+ve and only 31 received LTBI treatment. The overall survival of the latter was 54% at two years after induction chemotherapy, and none developed active tuberculosis. Based on their findings, the authors conclude that, universally, TST screening shows a low predictive value in AL patients but may be suggestive in individuals from TB-endemic countries.

The paper has a sufficient scientific basis. However, although it identifies the problem, it has been approached simplistically, using a screening test with a wide range of uncertainty (i.e., TST for LTBI). Furthermore, LBTI screening and early detection are important in any population, so applying it to LA patients is unclear (as perceived in the manuscript). Therefore, it is recommended to reframe the manuscript from the scientific basis to the application. Also, as a piece of advice for writers, please rely on researchers with experience in scientific writing.

 

Given the above, the current version is not endorsed for publication in "Current Oncology".