Keywords
miliary TB; tuberculosis; children
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Buonsenso D, Mariani F, Morello R and Song R. State-of-the-art of miliary tuberculosis in children: protocol for a scoping review of the literature [version 1; peer review: 1 approved]. F1000Research 2023, 12:309 (https://doi.org/10.12688/f1000research.132068.1)
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Study Protocol
State-of-the-art of miliary tuberculosis in children: protocol for a scoping review of the literature
[version 1; peer review: 1 approved]
PUBLISHED 21 Mar 2023
OPEN PEER REVIEW
REVIEWER STATUS
This article is included in the Pathogens gateway.
Abstract
Corresponding author:
Danilo Buonsenso
Competing interests:
No competing interests were disclosed.
Grant information:
The author(s) declared that no grants were involved in supporting this work.
Copyright:
© 2023 Buonsenso D et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Buonsenso D, Mariani F, Morello R and Song R. State-of-the-art of miliary tuberculosis in children: protocol for a scoping review of the literature [version 1; peer review: 1 approved]. F1000Research 2023, 12:309 (https://doi.org/10.12688/f1000research.132068.1)
First published: 21 Mar 2023, 12:309 (https://doi.org/10.12688/f1000research.132068.1)
Latest published: 21 Mar 2023, 12:309 (https://doi.org/10.12688/f1000research.132068.1)
Introduction
Miliary tuberculosis (TB) is a rare and often fatal (if untreated) form of TB characterized by massive lymphohematogenous dissemination from a Mycobacterium tuberculosis-laden focus.1 Historically, the term was coined by John Jacob Manget when he described the anatomical-pathological findings in certain TB patients who had numerous small lesions which resembled millet seeds in size and appearance.2
Although miliary TB has been formally described three centuries ago, several uncertainties remain around this topic. First, several publications confound miliary and disseminated TB or use these terms interchangeably.1,3 However, although the pathogenesis of these two manifestations is similar due to hematogenous spread of the bacilli, the anatomical-pathological findings are different, with the ‘miliary pattern’ being documented only in some of the patients with multiorgan TB involvement. Therefore, current agreement for the diagnosis of miliary TB is presence of a diffuse miliary infiltrate on chest radiograph or high-resolution computed tomography (CT) scan, or evidence of miliary tubercles in multiple organs at laparoscopy, open surgery, or autopsy.1 However, such definition has intrinsic limitations for the recognition of miliary TB in children, as invasive procedures for anatomical-pathological diagnosis are less frequently performed in children, and CT scan (and sometimes even X-ray) is rarely available in low-to-middle income countries where TB incidence is highest. For these reasons, the current understanding of miliary TB in children is still limited.
Two recent reviews, published in 2006 and 2016,1,3 analyzed together adults and children and highlighted current knowledge gaps in clinical recognition, diagnosis, optimal treatment and outcomes. Therefore, a systematic approach in collecting comprehensive information from pediatric miliary TB literature has never been performed. Importantly, since the publication of these reviews, the TB diagnostic field has evolved significantly, with the advent of interferon-gamma release assays (IGRAs),4 and the wide-spread availability of molecular (PCR-based) TB tests.5 To date the published literature on the diagnostic performance of current commercially available PCR-based TB assays in children with miliary TB remains limited to a single study that showed lower sensitivity in children with miliary TB, but the assessment of miliary TB was not a primary aim of the study.4
In addition, there is lack of data on treatments, complications and outcomes on children with miliary TB. Older reports from low-resource settings suggested that miliary TB is associated with a mortality of 30-50%,1,3 however most of these reports were published before 2000 or only reported data from resource-limited settings, where high-level intensive care support is less available. Importantly, even in high income countries intensive care support has significantly improved and may have positively affected outcomes of children with miliary TB.
Given the mentioned gaps, we will perform a scoping review aiming to summarize the current literature on the main characteristics of pediatric miliary TB covering epidemiology and clinical characteristics, diagnostic and therapeutical options and outcomes. We decided to propose a scoping review because of the need of examining a wide area of knowledge to identify knowledge and research gaps and to provide indicators of topics for a subsequent systematic review. To ascertain that no such reviews were available, a search was performed on MEDLINE, the Cochrane Database of Systematic Reviews, JBI Evidence Synthesis and PROSPERO on December 15th, 2022.
Review questions
What are the main clinical characteristics and outcomes of pediatric miliary TB reported in the literature?
This review will investigate these sub-questions:
1. What is known about the epidemiology of pediatric miliary TB?
2. What is known about the diagnostic accuracy of microbiological tests in children with miliary tuberculosis?
3. What is known about the diagnostic accuracy of immunological tests in children with miliary tuberculosis?
4. Which are the main therapeutical options (e.g. number and length of treatment with anti-mycobacterial agents and use of steroids or other adjunctive therapeutics) in the treatment of pediatric miliary TB?
5. What outcomes are reported in the literature on pediatric miliary TB?
Inclusion criteria
Participants
In this review will be included studies performed on pediatric patients younger than 19 years with a diagnosis of miliary TB according to the currently agreed definitions1,3
Context
No limitation of care setting will be included. Articles will be considered for inclusion in this review independently to the care setting of children so we will consider both inpatients and outpatients.
Type of sources
This review will include both randomized controlled trials and non-randomized controlled trials. All the type of observational studies, prospective and retrospective (including case-control, cohort and cross-sectional studies, small case series or single case reports) will be included.
Methods
Search strategy
We will systematically search the following bibliographic databases up to the 31st of January 2022: the Cochrane Library (Cochrane database of Systematic Reviews, Cochrane Central Register of Controlled Trials Central), MEDLINE, Web of Science and SCOPUS.
There will be no date restrictions, except inclusion of papers written in English. The search strategy will include the following word: “pediatric” and “miliary tuberculosis” (patients younger than 18 years of age will be considered as children or pediatrics). The search strategy for MEDLINE is available as Extended data6; the terms used for this search will be adapted for use with other bibliographic databases.
We will also conduct a web search, via Google, to find gray literature and unpublished material.
If the final analysis were to be performed 6 months after the bibliographic search, the search string will be launched again to evaluate the presence of new studies to be included in the work.
Study selection
We will export studies in Rayyan. A first screen to exclude duplicates will be performed by one author.
Titles and/or abstracts of retrieved studies will be screened independently by two reviewers to identify those that could be included in the review. Full texts of potentially eligible studies will subsequently be retrieved and independently assessed for eligibility by two blinded reviewers. Disagreement about studies’ elegibility will be resolved through discussion and, in case of further disagreement, by discussion with a third reviewer.
All studies that will not meet the inclusion criteria will be excluded and a figure with the reason why those studies were excluded will be inserted in the final manuscript.
The results of the search will be reported in the PRISMA flow diagram.
Data extraction
Two blinded reviewers will extract data independently on a different excel file. Any disagreement will be identified and resolved as previously mentioned.
An Excel file will be used to storage data; extracted information will include:
1. Study general features: title, author, year of publication, type of study, number of patients included in the study, geographical area where the study has been performed
2. Participant features: sample size of each group, nationality, age, socio-economic status
3. Main presenting signs and symptoms: fever (including days), cough (including days), weight loss, vomiting, diarrhea, rashes, neurological symptoms, eye symptoms and fundus oculi, others
4. Main imaging findings: type of lung involvement at chest X-Ray and/or CT scan, type of CNS involvement on CT scan or Magnetic Resonance Imaging (MRI), type of bone or other organ involvement evaluated by ultrasound or CT scan MRI of other organs)
5. TB localizations (e.g., lung, central nervous system, other organs), highlighting in which of these organs a miliary involvement was documented
6. Anatomical-pathological data, where available
7. Sensitivity (and specificity, if available) of microbiological tests (direct microscopy, culture or molecular diagnostics) on different specimens (e.g., gastric lavage, sputum, stools, cerebrospinal fluid, other)
8. Sensitivity (and specificity, if available) of immunological tests (tuberculin skin test, interferon gamma releasing assays of different generations (e.g., T-SPOT, QFT-Gold, QFT-Plus)
9. Antimicrobial treatments provided and length of therapy
10. Other treatments provided (e.g., steroids or other immunomodulatory medications)
11. Outcomes (death, survival; survival with or without sequelae; type of sequelae)
Data analysis and presentation
To report our findings, we will follow Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist.
We will produce a narrative synthesis of the findings from the studies included in the review describing the results we have obtained and provide our opinion on their interpretation. More specifically, we will summarize the evidence using a descriptive summary that includes the characteristics of included studies (number of studies, study design, year of publication, characteristics of the study populations, and countries where studies were conducted).
We will also use tables and charts to summarize the most important clinical, diagnostics, treatment and outcome data. We will provide five different summary tables or figures summarizing main data about clinical presentation, imaging characteristics, diagnostics (microbiology and immunology) information, treatments provided and outcomes. We will provide both descriptive findings and, were possible, sensitivity and specificity for diagnostics according to the study designs.
By doing so, we will be able to provide the most up-to-date and comprehensive platform of information about what is currently known of pediatric miliary TB and, therefore, guide future research projects to fill current gaps.
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CITE
how to cite this article
Buonsenso D, Mariani F, Morello R and Song R. State-of-the-art of miliary tuberculosis in children: protocol for a scoping review of the literature [version 1; peer review: 1 approved] F1000Research 2023, 12:309 (https://doi.org/10.12688/f1000research.132068.1)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 21 Mar 2023
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How to cite this report:
Soriano Arandes A. Reviewer Report For: State-of-the-art of miliary tuberculosis in children: protocol for a scoping review of the literature [version 1; peer review: 1 approved]. F1000Research 2023, 12:309 (https://doi.org/10.5256/f1000research.144966.r167136)
The direct URL for this report is:
https://f1000research.com/articles/12-309/v1#referee-response-167136
https://f1000research.com/articles/12-309/v1#referee-response-167136
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 12 Apr 2023
Approved
VIEWS 5
Dear authors,
Thank you very much for submitting this scoping review. The methods you use for the review are appropriate and the review of this issue is necessary due to the lack of scientific evidence as you ... Continue reading
Thank you very much for submitting this scoping review. The methods you use for the review are appropriate and the review of this issue is necessary due to the lack of scientific evidence as you ... Continue reading
CITE
HOW TO CITE THIS REPORT
Soriano Arandes A. Reviewer Report For: State-of-the-art of miliary tuberculosis in children: protocol for a scoping review of the literature [version 1; peer review: 1 approved]. F1000Research 2023, 12:309 (https://doi.org/10.5256/f1000research.144966.r167136)
The direct URL for this report is:
https://f1000research.com/articles/12-309/v1#referee-response-167136
https://f1000research.com/articles/12-309/v1#referee-response-167136
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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