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http://orcid.org/0009-0004-7514-9667 Thiala Santos Duarte de Oliveira 1 ,
Mônica Leila Portela de Santana 1 ,
Valterlinda Alves de Oliveira Queiroz 1 ,
Karine Brito Beck da Silva 2 ,
Poliana Cardoso Martins 3 ,
Emile Miranda Pereira 4 ,
http://orcid.org/0000-0003-3809-9037 Priscila Ribas de Farias Costa 1
1 School of Nutrition , Federal University of Bahia , Salvador , Brazil
2 University of the State of Bahia , Salvador , Brazil
3 Multidisciplinary Health Institute , Federal University of Bahia , Salvador , Brazil
4 Elpis Addictions Treatment Service Clinic , Salvador , Brazil
Correspondence to Mrs Thiala Santos Duarte de Oliveira; thialasd{at}ufba.br

Introduction Eating disorders can be irreversible and, in many cases, fatal. However, the symptoms full recovery is possible, and early diagnosis is one, of many, important factors for the success of treatment. In this sense, the screening of risk behaviours arises as a relevant alternative to improve the prognosis of patients. This review will analyse the diagnostic accuracy of self-administered screening tests for eating disorders in adolescent and adult users of primary healthcare.

Methods and analysis A systematic review will be performed by independent reviewers. The databases used will be Medline, Embase, the Latin American and Caribbean Health Sciences Literature, the Cumulative Index to Nursing and Allied Health Literature, Web of Science, PsycINFO, ProQuest Dissertations and Theses Database and Google Scholar without restrictions on the year of publication and language. Studies that compared the results of self-administered screening tests for eating disorders in adolescents and adults in primary care with the results of clinical interviews will be included. Data extraction will consist of the identification of the publication, study and participant characteristics, general information about the tools and data on the diagnostic accuracy properties. The risk of bias in the studies will be assessed via the Quality Assessment of Diagnostic Accuracy Studies. Qualitative data will be presented in narrative form. The meta-analysis will be conducted via the random effects model with the metadata command of Stata. The summary statistics for sensitivity and specificity, as well as their 95% CI, will be generated.

Ethics and dissemination This systematic review is based on published literature; therefore, submission to an ethics committee is not necessary. The dissemination of the study will be carried out through technical reports, scientific articles, posters, meeting presentations, specific forums, national congresses and international media.

PROSPERO registration number CRD42023476156.

Eating disorders

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2024-086361

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STRENGTHS AND LIMITATIONS OF THIS STUDY

Our protocol follows the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols.

The search will be carried out in eight electronic databases, including grey literature, in addition to article reference lists and consultation with experts, which increases retention of non-indexed articles.

We will include eligible studies conducted in any country, without geographical limits, without restrictions based on the year of publication and language, which allows greater generalisation of the analysis.

We will include studies conducted among different populations and using different evaluation tools, which may limit the performance of meta-analysis depending on the number of articles retained.

Subgroup analysis will be considered whenever possible.

Eating disorders (EDs) are psychiatric diseases that have a significant impact on the eating behaviour and overall health of people who experience them. 1 They are characterised by obsessive and persistent thoughts about food and calories and patterns of severe restriction or excessive consumption, in addition to constant concern and dissatisfaction with weight, shape and body image. 2 The clinical complications of EDs are severe and can lead to fatal consequences, either by worsening the disease or by increasing the risk of suicide. 3

In recent years, EDs have become a growing public health concern. Between 2000–2006 and 2013–2018, the global prevalence increased by approximately 123%. 4 Higher rates of binge eating disorder (BED), bulimia nervosa (BN) and anorexia nervosa (AN) are reported in adolescent and young adult women. 4 5 However, these disorders affect a wide variety of groups at the global level, surpassing the barriers of age, gender, culture, socioeconomic status, body size and weight. 6

The complications of EDs vary significantly between adolescents and adults, although they share some common features. In adolescents, vulnerability to physical complications such as malnutrition and weight loss, if untreated, increases the risk of permanent osteopenia and osteoporosis. 6 7 In contrast, adults with ED often face more serious complications, such as fractures associated with osteoporosis, in addition to having more prevalent purging behaviours, which increases the risk of electrolyte and metabolic disorders. In addition, ED in this adult age group is strongly associated with metabolic comorbidities, including diabetes, hypertension and high cholesterol and triglyceride levels. 7

The psychosocial repercussions of ED also vary according to age. In adolescents, EDs impact psychosocial development, intensifying social isolation and hindering adjustment in a crucial transition phase. 6 7 For adults, ED significantly compromises psychosocial functioning and quality of life, with a more notable impact on interpersonal relationships. In adolescents, a potentially lower neurobiological and social impact is observed, possibly due to the higher levels of psychiatric comorbidities than in adults. 7 In the context of brain changes, adolescents may exhibit a slight reduction in grey matter that persists even after weight regain, while in adults, these changes are more often reversed with prolonged weight maintenance. 7 These distinctions reinforce the need for screening methods adapted to each age group, improving diagnostic accuracy and facilitating more effective interventions.

The detection of the risk of ED, performed with screening tests, can decrease the duration of the disease and reduce negative outcomes such as disability and high mortality rates, especially due to malnutrition and suicide. 3 Primary healthcare (PHC) is a favourable environment for early diagnosis. People with ED do not seek psychiatric care as a first alternative but tend to seek primary care settings frequently for other reasons. 8

Thus, PHC professionals are in a favourable position for the early detection of the risk of EDs given the regularity with which the patient presents themselves in this environment and the trust relationship between the professional and the patient. 9 In this scenario, effective screening for ED is essential, but it is important to ensure that the tests are appropriate for detecting the risk of a full range of ED. Therefore, verification of the diagnostic accuracy of these tests is essential.

The scientific literature presents studies that address the diagnostic accuracy of screening tests for ED on different fronts. A systematic review published on the subject synthesised data from the USA, limiting the evaluation of screening tests translated into other languages and cultures. 10 A previous meta-analysis evaluated the diagnostic efficacy of the Sick Control One Stone Fat Food Questionnaire (SCOFF) for the detection of ED in eight different countries and in seven different languages. This generalisation was positive, as it allowed the comparison and synthesis of results in different countries and languages. However, the limitations of this study include its use of a single screening tool, SCOFF. 11

Given the need for early diagnosis of ED to reduce disease prolongation and negative outcomes, verification of the diagnostic accuracy of screening tests will guide future choices about which test will best be applied in PHC. This review aims to verify the diagnostic accuracy of self-administered screening tests for EDs used in adolescents and adults in the PHC in comparison with the reference standard of clinical interviews.

Methods and analysis

Study design.

This is a protocol for a systematic review of diagnostic accuracy with meta-analysis developed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocol (PRISMA-P) 12 and checklist ( online supplemental appendix 1 ). The protocol was registered in PROSPERO under number CRD42023476156 on 8 November 2023.

Supplemental material

The review will follow the acronym PIRO. Population: adolescent (10 to 18 years old) and adult (18 to 65 years old) users of PHC or generalisable primary care settings, regardless of gender, race, ethnicity and geographical location, who underwent screening tests for ED; Index test: validated or no validated tests self-administered screening tests to screen the risk of ED on the basis of symptoms; Reference standard: structured or semistructured clinical interview on the basis of the diagnostic criteria of the DSM-5 or ICD or other mental illness classification system; Outcome: accuracy of self-administered screening tests for AN, BN and BED.

Eligibility criteria

Cohort, cross-sectional and case-control studies that have compared the results of self-administered screening tools for ED with the results of clinical interviews are considered the gold standard. This comparison should allow the preparation of a 2×2 contingency table, detailing the test results classified as true positive (TP), false positive (FP), true negative (TN) and false negative (FN).

Studies with participants who do not fit the age group of interest will be excluded; studies with data reported by parents; studies in clinical populations undergoing treatment for ED; and studies with pregnant or lactating adolescents, children and elderly individuals. Studies that analysed the reference standard only in the subgroup that screened positive for ED in the index test will not be considered yet. Studies conducted in settings outside the scope of PHC, for example, bariatric surgery centres or hospitals, outpatient clinics, communities or schools not linked to PHC will be excluded.

Information sources and search strategy

The search was performed by reviewer (TSDO) in the following databases: Medline (PubMed), Embase (Elsevier), Latin American and Caribbean Health Sciences Literature, Cumulative Index to Nursing and Allied Health Literature, Web of Science and PsycINFO. Additionally, grey literature will be searched in the ProQuest Dissertations and Theses Database and Google Scholar. A manual search of the reference lists of studies included in the review or relevant reviews identified during the selection phases and consultations with experts in the field will be performed in order to retrieve studies that have not been retained by the search in the databases. Limits of date, language or country/region will not be imposed on the search, nor will any search filter. The search strategy was initially designed via Medline (PubMed) and then adjusted to the other databases. Online supplemental appendix 2 presents the complete search strategy for all eight databases. The search in the database began on 19 October 2023, and the entire review process is expected to be completed on 30 December 2024.

Study selection

To assist in conducting the systematic review, we will use Covidence review software, developed by Veritas Health Innovation, Melbourne, Australia (available at www.covidence.org ). All the articles captured in the search will be exported to Covidence, where duplicates will be removed. Two independent reviewers (TSDO and EMP) will select the articles in two stages. First, the titles and abstracts will be read. Articles that meet the eligibility criteria will be read in full in the second stage. Those with confirmed eligibility criteria will be included in the review, and the others will be excluded. Inconsistencies in the classification of decisions will be discussed with a third reviewer (PRFC) and documented. The PRISMA flowchart will be automatically generated by Covidence, which will present the total number of articles found in the search, those excluded after screening with their respective reasons for exclusion and those included in the study.

Data extraction and data items

The extraction of data from the included studies after triage will be performed in Covidence review software by two reviewers (TSDO and KBBS) independently, and discrepancies will be resolved by a third reviewer (VAOQ). The studies will be read in full again, and then data collection will begin, which will include identification of the publication, characteristics of the study and participants, and general information about the tools and data on the diagnostic accuracy properties, as shown in table 1 .

View inline

Information collection

If the necessary information is not clear in the studies, the team will contact the authors (maximum of three attempts by email) to request the missing data. The entire process will be documented and filed. Multiple articles from the same study will be identified by the name of the authors, city and location of the study, specific details of the study methodology, date and duration of the study and excluded. If doubts remain, the authors of the articles will be contacted.

Outcome assessment

The outcome of interest is the accuracy of the self-administered screening tests for AN, BN and BED presented through performance measures: sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), positive and negative likelihood ratios and ORs of diagnosis.

Risk of bias assessment strategy

The evaluation of methodological quality will be performed only for studies included in the systematic review. Therefore, a revised version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS- 2) 13 will be used because it is appropriate for assessing quality and is divided into ‘risk of bias’ and ‘concerns regarding applicability’. This evaluation will be conducted independently by two reviewers and disagreements will be discussed and resolved in a consensus meeting with a third reviewer.

The results will be presented through narrative descriptions, tables demonstrating each aspect of the methodological quality for each individual study, a global evaluation of the set of studies and ‘traffic light’ graphs generated with Review Manager software. 14

Analysis, data synthesis, publication bias and reporting

Qualitative data will be presented in narrative form to summarise and explain the results stratified for AN, BN and BED. For combinable studies, 15 16 quantitative data syntheses will be performed via meta-analysis. The extent of meta-analysis heterogeneity will be tested via the Cochran Q test and quantified via the inconsistency test (I 2 statistic). A p value is often cited as an indication of the extent of variability between studies. Thus, the χ 2 test will be used to assess the significance of heterogeneity. For this purpose, a significance level of p<0.10 will be used to detect the true heterogeneity between the results of the studies. 15 16

The magnitude of heterogeneity will be identified by calculating the I 2 , which ranges from 0% to 100%. Thus, an I 2 close to zero suggests that all dispersion can be attributed to the random error of the study; that is, there is no heterogeneity. If an I 2 value close to 25% is calculated, it indicates low heterogeneity between studies; if it is greater than 50%, it indicates moderate heterogeneity; and if it is greater than 75%, it indicates high heterogeneity. 15 16

In the presence of high heterogeneity, a meta-analysis will be performed via the random effects model conducted with the metadata command of Stata . Data from diagnostic test studies usually result from a 2×2 cross-tabulation of the results of an index test versus the reference standard. The data in the four cells represent the TP, FP, TN and FN. The sum of TP and FN is the total with the outcome, and the sum of TN and FP is the total without the outcome. The metadata command requires five variables to run, which include TP, FP, TN, FN and the study identifier. Thus, the summary statistics sensitivity and specificity will be generated, as well as their respective 95% CI will be generated and presented in Forest plot figures.

Potential variables that may influence the high heterogeneity between studies will be investigated through subgroup analysis (for dichotomous variables: age group, ethnicity and socioeconomic status) and meta-regression (for continuous variables: mean age, sample size and mean BMI). If 10 or more studies are included in the meta-analysis, the Egger test and the funnel plot will be used to assess publication bias.

Patient and public involvement

Patients and/or the public were not involved.

Ethics and dissemination

Approval from the ethics committee was not requested because the data collected and analysed will be obtained from primary studies, with no link to specific people.

The transfer of study results will be performed through technical reports with project data, with the goal of disseminating the results to managers and health professionals to the academic community through scientific articles, presentations at meetings, specific forums, local events and/or national and/or international events. In addition, infographics will be prepared with simple and direct language of the main results to be disseminated on social networks (the Instagram profile of the School of Nutrition of UFBa and the Eating Behaviour and Health research group), and a press release will be issued if deemed necessary. The research report will be published in printed and/or electronic versions and presented at a meeting with the Department of Science and Technology of the Department of Science, Technology, Innovation and Strategic Inputs in Health of the Ministry of Health (Decit/SCTIE/MS).

Ethics statements

Patient consent for publication.

Not applicable.

Acknowledgments

We thank all the researchers involved in this project for their availability and generosity in sharing their scientific knowledge.

APA- American Psychiatric Association
NIMH-National Institute of Mental Health
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Contributors MLPS conceived the original idea for this systematic review. TSDO and MLPS drafted the manuscript. TSDO designed the search strategy. MLPS and PRFC revised the search strategy. MLPS and PRFC provided content expertise on eating disorders in adolescents and adults and diagnostic test accuracy. All authors ( TSDO, MLPS, VAOQ, KBBS, PCM, EMP, PRFC) read, critically reviewed, provided feedback and approved the final manuscript. MLPS is the guarantor of the review. All authors agreed to publish this protocol and to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding National Council for Scientific and Technological Development - CNPq - n° 408315/2022-9.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Chien-Hung Lin 1 , 2 , 3 ,
Wen-Sheng Liu 2 , 3 , 4 , 5 , 6 ,
Chuan Wan 7 , 8 ,
http://orcid.org/0009-0008-2885-1305 Hsin-Hui Wang 1 , 2 , 9
1 Division of Pediatric Immunology and Nephrology, Department of Pediatrics, Taipei Veterans General Hospital , Taipei , Taiwan
2 School of Medicine, National Yang Ming Chiao Tung University , Taipei , Taiwan
3 College of Science and Engineering , Fu Jen Catholic University , Taipei , Taiwan
4 Division of Nephrology, Department of Medicine, Taipei City Hospital Zhongxing Branch , Taipei , Taiwan
5 Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University , Hsinchu , Taiwan
6 Department of Special Education, University of Taipei , Taipei , Taiwan
7 Department of Pediatrics , Taipei City Hospital Zhongxing Branch , Taipei , Taiwan
8 Institute of Clinical Medicine, National Yang Ming Chiao Tung University , Taipei , Taiwan
9 Institute of Emergency and Critical Care Medicine, National Yang Ming Chiao Tung University , Taipei , Taiwan
Correspondence to Dr Hsin-Hui Wang; hhwang{at}vghtpe.gov.tw ; Dr Chuan Wan; dac78{at}tpech.gov.tw

Objectives This study aimed to evaluate the real-world effectiveness of tofacitinib for treating moderate-to-severe ulcerative colitis (UC).

Design Systematic review and meta-analysis.

Data sources PubMed, EMBASE and Cochrane CENTRAL databases were searched from inception up to 18 July 2023. Reference lists of included studies were manually searched to identify potentially relevant studies not found in the databases.

Eligibility criteria Eligible studies included real-world observational studies, reported in English, on patients with moderate-to-severe UC treated with tofacitinib, defined by the Partial Mayo Score. Excluded were clinical trials, reviews, letters, conference abstracts, case reports and studies involving patients with mixed Crohn’s disease.

Data extraction and synthesis Two independent reviewers extracted data and recorded it in Excel. Quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was performed using random-effects models due to high heterogeneity across studies.

Results 19 studies containing a total of 2612 patients were included. Meta-analysis revealed that clinical response rates were 58% at week 8, 61% at weeks 12–16, 51% at weeks 24–26 and 51% at week 52. Clinical remission rates were 39% at week 8, 43% at weeks 12–16, 40% at weeks 24–26 and 43% at week 52. Corticosteroid-free clinical remission rates were 33% at week 8, 37% at weeks 12–16, 32% at weeks 24–26 and 40% at week 52.

Conclusion This meta-analysis of real-world studies indicates that treatment of UC with tofacitinib is associated with favourable clinical response and remission rates in the induction and maintenance phases.

CLINICAL TRIALS
COLORECTAL DISEASES
DRUG METABOLISM
ULCERATIVE COLITIS
META-ANALYSIS

Data availability statement

The data used in this systematic review and meta-analysis are derived from publicly available sources, such as published articles and reports. All data supporting the findings of this review are included within the manuscript.

https://doi.org/10.1136/bmjgast-2024-001347

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Clinical trials have established the efficacy of tofacitinib in treating ulcerative colitis (UC). However, the relevance of these findings to real-world scenarios remains uncertain.

WHAT THIS STUDY ADDS

The systematic review and meta-analysis offers insights into the efficacy of tofacitinib in treating UC based on the latest real-world data. Notably, it extends the analysis of tofacitinib’s effects to 52 weeks post-treatment initiation.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

These findings provide clinicians and policy-makers with real-world evidence to guide treatment decisions and shape guidelines for UC.

Introduction

Ulcerative colitis (UC) is a recurring, chronic inflammatory bowel disease (IBD) characterised by mucosal inflammation that begins in the distal regions of the colon and can extend upward, ultimately affecting the entire colon. 1 In 2023, it was estimated that UC affected approximately 5 million individuals globally, with a rising global incidence. 2 While UC can manifest at any age, it most commonly occurs between the ages of 20 and 40, with roughly equal frequency in men and women. 3 Traditional treatments for UC include mesalamine, glucocorticoids, immunomodulators and biologics offer relief to some patients. 4 However, despite progress in treatment methods, clinical remission is only achieved in a relatively small number of patients. 5

Tofacitinib has been approved by the US Food and Drug Administration for the treatment of UC. Controlled clinical trials have shown that oral tofacitinib is effective for treating UC in adults and is associated with high clinical response and clinical remission rates. 6–10 Tofacitinib is a reversible, competitive inhibitor of Janus kinase (JAK), specifically targeting JAK1 and JAK3. Inhibition prevents the phosphorylation of JAK proteins, thereby blocking the activation of the STAT pathway and downstream signalling of cytokines such as interleukin (IL)-2, IL-4, IL-7, IL-15 and IL-21, as well as the production of proinflammatory proteins associated with mucosal inflammation. 11

Although clinical trials have shown that tofacitinib is effective for treating UC and has an acceptable safety profile, findings from controlled trials are not always the same as when the drug is used in an uncontrolled clinical practice. Real-world studies can assess tofacitinib’s performance in diverse patient populations, taking into consideration factors such as demographics, comorbidities, concurrent medications and treatment adherence. 12 Previous meta-analyses and systematic reviews, which have included data from real-world studies, have suggested that tofacitinib is a safe and effective treatment for UC. However, it is worth noting that the most recent studies included in these reviews only extended up to 2021. Additionally, few studies have examined the effectiveness of tofacitinib at 1 year after beginning treatment. 13 14

Thus, our purpose was to perform a systematic review and meta-analysis of the effectiveness of tofacitinib for treating UC using only data from real-world studies. In addition, the analysis includes studies that provide outcome data at 1 year or more after beginning treatment. 15

Search strategy

The current systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 15 ( online supplemental file, PRISMA checklist ). We conducted a comprehensive literature search of public databases including PubMed and EMBASE, for studies published from inception up to 18 July 2023. The specific keywords “tofacitinib”, “ulcerative colitis” and “real-world” were combined with Boolean operators and Medical Subject-Headings (MeSH) terms where appropriate were used in the searches to identify eligible studies. The exact search string used for PubMed and EMBASE was

Supplemental material

( tofacitinib OR XELJANZ) AND (“ulcerative colitis”) AND (real-world OR observational ).

In addition, we conducted a handsearch of the reference lists in the included studies to identify any potentially relevant studies not identified in the database searches. Two reviewers independently screened the citations for eligibility to ensure accuracy and reliability in the selection process.

Selection criteria

This review was conducted following the PICOS criteria, which is based on participants (P), interventions (I), comparisons (C), outcomes (O) and study design (S). Eligible studies were those including patients with moderate-to-severe, active UC (P) who were treated with tofacitinib (I). The severity of UC is characterised by the Partial Mayo Score (PMS), which includes stool frequency, rectal bleeding and physician’s global assessment. Moderate-to-severe UC is typically defined by a PMS of 5–9. The comparator group could comprise patients on other JAK inhibitors, tumour necrosis factor inhibitors (TNFi) or none (C). The outcome of interest (O) was clinical remission rates, clinical response rates and corticosteroid (CS)-free clinical remission at the assessed time points. Only real-world observational studies with one or two arms were eligible for inclusion (S).

We excluded clinical trials, review articles, letters, commentaries, editorials, proceeding research, meeting abstracts, case reports and personal communications. Non-English studies, those involving tofacitinib combined with other biologics as treatment, and studies of patients with mixed Crohn’s disease were also excluded. Eligibility was confirmed by two independent reviewers, and any conflicts or uncertainties were resolved through discussion to reach a consensus.

Main outcome measures and data extraction

Primary outcomes were clinical remission rate and clinical response rate at various time points. Secondary outcomes were the CS-free clinical remission rate at given time points and adverse effects. Clinical remission was defined as a PMS of less than 3, with a combined stool frequency and rectal bleeding subscale score of 1 or less. Clinical response was defined as a reduction in the PMS by 3 points or more and at least 30% from baseline, along with a decrease of at least 1 point in the rectal bleeding subscale. CS-free clinical remission refers to a state in which a patient achieves and maintains clinical remission without the need for CS therapy.

Two independent reviewers read the full text of eligible articles, manually extracted the data and recorded it in Excel. Any inconsistencies were resolved through discussion. The following information was extracted from eligible studies, name of the first author, publication year, study design, country of the study, the number of patients with moderate-to-severe, active UC, mean patient age, the percentage of males, the mean follow-up duration and data regarding the outcomes of interest.

Quality assessment

The quality of the included studies was assessed using the Newcastle-Ottawa scale (NOS), following the recommendations of the Cochrane Non-Randomised Studies Methods Working Group. 16 The NOS assigns a maximum of 9 points to each study, 4 points for the appropriate selection of patients, 2 points for comparability of participants in terms of design and analysis and 3 points for adequate outcome ascertainment. Two independent reviewers conducted the quality assessment, and any uncertainties were resolved through discussion.

Statistical analysis

The inverse-variance method, which is based on a weighted average of effect sizes from individual studies, was used to create forest plots displaying proportions with 95% CIs for individual studies and overall studies. Both fixed-effects and random-effects models were applied to calculate the pooled estimates presented in the forest plots. Heterogeneity among the studies was assessed using the I 2 statistic, with the following criteria, 0%–24% indicated no heterogeneity, 25%–49% indicated moderate heterogeneity, 50%–74% indicated large heterogeneity and 75%–100% indicated extreme heterogeneity. Funnel plots were generated, and Egger’s test was applied to detect potential publication bias in the meta-analysis. The meta-analysis was performed using R-studio, and we used the R packages ‘meta,’ ‘dmetar,’ ‘metafor,’ ‘esc’ and ‘tidyverse.’ All analyses were two sided, and a value of p<0.05 was considered to indicate statistical significance.

Search results

A flow diagram of the database search results and study inclusion is shown in figure 1 . After the removal of duplicate entries, 168 potentially eligible studies were identified, and a preliminary screening of them was done based on their titles and abstracts. Subsequently, 34 full-text articles were assessed for eligibility, and 15 studies were excluded. Finally, 19 studies 17–35 were included in the systematic review and meta-analysis.

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A flow diagram of the database search results.

Characteristics of included studies

The 19 studies contained a total of 2612 patients with moderate-to-severe, active UC. The mean age of the patients ranged from 26.0 to 46.4 years, and the proportion of males ranged from 38.5% to 68.9%. All of the studies provided information regarding the proportions of patients with extensive disease or pancolitis, 15 studies reported data on patients previously exposed to anti-TNF treatments, 16 studies had information on patients with prior vedolizumab (VDZ) exposure, 13 studies included patients with prior ustekinumab (UST) exposure and 9 studies reported the proportion of patients who had received 2 or more prior biological treatments. The details of the included studies are summarised in table 1 . The dose of tofacitinib is documented in online supplemental table S1 .

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Characteristics of the included studies and patients

Meta-analysis

Clinical response.

A total of 11 studies 19–22 24 26 27 30 32 33 35 assessed the clinical response rate at various time points. Due to the heterogeneity (I 2 ranging from 64% to 91%) across the studies, estimates by random-effects models were used as the pooled effect. The pooled estimates for clinical response rate were, 0.58 (95% CI 0.49 to 0.67) at week 8, 0.61 (95% CI 0.58 to 0.67) at weeks 12–16, 0.51 (95% CI 0.40 to 0.68) at weeks 24–26 and 0.51 (95% CI 0.26 to 0.77) at week 52 ( figure 2 ).

Forest plots for clinical response rate at weeks 8, 12–16, 24–26, and 52.

Clinical remission

A total of 13 studies 19–24 26 27 29 31–33 35 assessed the clinical remission rate at various time points. Due to the heterogeneity (I 2 ranging from 71% to 78%) across the studies, estimates by random-effects models were used for the pooled effect. The pooled estimates for clinical remission rates were 0.39 (95% CI 0.31 to 0.44) at week 8, 0.43 (95% CI 0.37 to 0.49) at weeks 12–16, 0.40 (95% CI 0.32 to 0.48) at weeks 24–26 and 0.43 (95% CI 0.35 to 0.50) at week 52 ( figure 3 ).

Forest plots for clinical remission rate at weeks 8, 12–16, 24–26 and 52.

CS-free clinical remission

A total of 12 studies 18 20–22 24 25 27–30 33 34 provided data on the CS-free clinical remission rate. Due to the heterogeneity (I 2 ranging from 74% to 88%) across the studies, estimates by random-effects models were used for the pooled effect. The pooled estimates for CS-free clinical remission rates were 0.33 (95% CI 0.24 to 0.41) at week 8, 0.37 (95% CI 0.29 to 0.45) at weeks 12–16, 0.32 (95% CI 0.23 to 0.41) at weeks 24–26 and 0.40 (95% CI 0.31 to 0.50) at week 52 ( figure 4 ).

Forest plots for CS-free clinical remission rate at weeks 8, 12–16, 24–26 and 52.

Due to the limited availability of data from only a few studies on serious adverse events (AEs) and infections, a quantitative synthesis could not be conducted. Specifically, Ma et al 23 reported an AE rate of 9.6 serious AEs per 100 person-years, and Deepak et al 17 reported a rate of 10.0 serious AEs per 100 person-years. Straatmijer et al 18 reported a rate of 9.2 serious AEs per 100 person-years, and Shin et al 29 reported a rate of 9.68 per 100 person-years. With respect to infections, Chaparro et al 35 reported an infection rate of 1.67 per 100 person-years, and Ma et al 23 reported a slightly higher rate of 2.1 infections per 100 person-years. Treatment discontinuation rates ranged from 12% to 56.1% among the 15 studies that reported this outcome ( online supplemental table S2 ).

Publication bias

Funnel plots were created to assess the potential presence of publication bias. Three funnel plots were generated for the outcomes investigated, incorporating data from all study periods. Egger’s regression results suggested no evidence of publication bias, with p values of 0.12 for clinical response rate ( online supplemental figure 1a ), 0.17 for clinical remission rate ( online supplemental figure 1b ) and 0.46 for CS-free clinical remission rate ( online supplemental figure 1c ).

The NOS quality assessment of the studies is shown in table 1 . The total score ranged from 5 to 8, suggesting that the quality of the included studies is moderate to high ( table 1 ).

In this updated systematic review and meta-analysis focusing on the real-world use of tofacitinib for treating UC, tofacitinib demonstrated a strong clinical response rate of 61% and a remission rate of 43% during the initial phase of treatment. At 52 weeks, the clinical response rate was 51% and the remission rate was 43%. In addition, the pooled CS-free clinical remission rate in the induction phase was 37%, which increased to 40% at the 1-year follow-up. These results suggest that tofacitinib is an effective option for treating UC, with sustained improvements in UC symptom relief over time. However, the relatively high rates of treatment discontinuation in some studies underscore the need for individualised treatment approaches and ongoing research to optimise the use of tofacitinib for treating UC.

Tofacitinib is a small molecule inhibitor of Janus kinases (JAK), which include JAK-1, JAK-2, JAK-3 and TyK-2. 36 37 Tofacitinib primarily inhibits JAK-1 and JAK-3 and is used to treat moderate-to-severe rheumatoid arthritis, psoriatic arthritis and IBD, including UC. 36 37 The JAKs are important for immune activation and haematopoiesis, and the immunomodulatory effects of tofacitinib are a result of blocking these pathways. 36 37 Risk stratification is important for the use of JAK inhibitors, including tofacitinib, as they may increase the risk of thromboembolic events, and major cardiovascular events in persons 50 years of age and older with pre-existing cardiovascular risk factors. 37

Tofacitinib has become an important treatment for UC worldwide and is especially useful for patients in whom standard conventional or biological treatment have failed or who did not tolerate the treatment. 38 A long list of studies has examined the effectiveness and safety tofacitinib for treating UC and other rheumatic conditions. 38 This has resulted in multiple meta-analyses, mainly based on the results of clinical trials, examining its effectiveness and safety, and overall the studies have shown that tofacitinib is effective in treating UC with a good safety profile.

A few systematic reviews or meta-analyses using real-world data have been conducted previously, although with smaller sample sizes and shorter follow-up durations in comparison to the present study. Among, a prior real-world meta-analysis of the effectiveness of tofacitinib for treating UC was published by Taxonera et al . 13 A total of 1162 patients with UC were included, and remission was achieved in 35% of patients at week 8 and 38% at month 6. The response rate was 62% at week 8 and remained high at 51% at 12 months. The incidence of serious AEs and herpes zoster per 100 patient-years was 8.9 and 6.9, respectively. However, that study did not assess 1-year clinical remission rate as evaluated in the present meta-analysis. Moreover, the mentioned meta-analysis incorporated conference abstracts, commonly considered ‘grey literature’, which could hinder the reliability of the pooled results.

Another real-world meta-analysis conducted by Lucaciu et al 14 included 830 patients, of which 81% were previously treated with anti-TNF and 57% with VDZ. 14 At week 8, 51% of patients achieved a clinical response and 37% remission. At 24 weeks, the rates were 40% and 29%, respectively. Still, the 1-year remission or response rate documented in the current meta-analysis was not reported by them.

Two other recent meta-analyses have found results similar to the two aforementioned studies. Taneja et al 39 examined 26 studies in their meta-analysis and reported clinical response rates of 59% and 51% at week 8 and 1 years, respectively, and remission rates of 30% and 31%, respectively. The pooled incidence of AEs across all dosages was 4.4 per 100 patient-years, and a higher dose was associated with a higher frequency of AEs. CS-free remission rate was not assessed by them. That review also did not exclude meeting abstracts, and results from randomized controlled trials (RCTs) and real-world studies were combined together, possibly introducing bias into their findings. Lastly, Macaluso et al 40 performed a meta-analysis of real-world studies that included 759 patients in seven studies. In contrast to our 1-year observation period, that review covered a temporal range of up to 24 to 26 weeks. At induction the clinical response rate was 49%, the clinical remission rate was 40%, and the CS-free clinical remission rate was 34%. Notably, the pooled incidence of AEs was high at 53.0 per 100 person-years, however, this may have been related to the criteria used in the analysis.

The OCTAVE Open trial examined the safety and effectiveness of tofacitinib for treating UC, with up to 7 years of treatment. 41 In the analysis of outcomes by 12 months, 9 the efficacy appeared to be better than the outcomes observed in the present meta-analysis of real-world studies. Specifically, after de-escalating tofacitinib, 84.1% sustained a clinical response at 12 months. In the dose escalation group, 64.9% had a clinical response by 12 months, with remission rates of 35.1% and 49.1% at the same intervals, respectively. The difference in observed efficacy between the OCTAVE Open and the present meta-analysis of real-world studies may stem from several factors. First, RCTs are conducted under controlled conditions with strict protocols, often resulting in higher efficacy. Second, RCTs generally involve more homogeneous patient populations, while real-world studies include a broader range of patients with varying stages of disease and comorbidities, which can impact outcomes. Third, patients in real-world settings may not adhere to treatment protocols as closely as those in RCTs, leading to lower observed efficacy.

In the final analysis of OCTAVE Open, 41 81.5% of patients initially received tofacitinib 10 mg two times per day. By month 36, clinical response rates were 66.9% for patients on 5 mg and 40.3% for those on 10 mg, with endoscopic improvement seen in 64.6% and 37.1%, and remission maintained or achieved in 58.9% and 33.7%, respectively. With regard to AEs, the incidence rates (2440 patient-years) were death, 0.25, serious infections, 1.61, herpes zoster (all), 3.16 (2.47–3.97), opportunistic infections, 0.87 and major adverse cardiovascular events, 0.16. The incidences of other AEs studied were all ≤1. Discontinuation occurred in 48.0% of patients in the tofacitinib 5 mg bid group and in a much higher proportion, 86.5%, in the tofacitinib 10 mg bid group. Notably, 22.4% of patients in the 10 mg bid group discontinued by month 2 due to insufficient clinical response. The study conclusion was that tofacitinib demonstrated consistent safety up to 7 years. 41 Another recent study examined up to 7.8 years of safety data from the Global Clinical Programme for the treatment of UC with tofacitinib. 42 The incidence rates of AEs were similar to those reported in the aforementioned study, deaths, 0.23, serious infections, 1.69, herpes zoster (all), 3.30 and opportunistic infections, 1.03. Notably, the incidence of major cardiovascular events was 0.29, deep vein thrombosis was 0.03 and pulmonary embolism was 0.19.

According to our review, treatment discontinuation ranged from 12% to 56.1% across the studies that reported this outcome. The reasons for tofacitinib discontinuation poststudy enrolment varied. For example, several studies documented that non-response, or a lack of initial therapeutic effect, led to discontinuation as continued treatment was deemed ineffective. 18 19 21–23 31 In other cases, AEs such as serious infections, rash and anaemia necessitated discontinuation due to safety and tolerability concerns. 17–22 24–28 31 33–35 Additionally, loss of response, characterised by initial improvement followed by regression, prompted a strategic reassessment of treatment and subsequent discontinuation. 18 21 26

Another important issue is that, across different outcomes, moderate to large heterogeneity was detected among the studies. This variability likely stems from differences in demographics and treatment histories among the included studies. Such variations challenge the robustness of our interpretations. Additionally, there was significant variability in the patients’ treatment histories, particularly concerning prior exposures to anti-TNF agents, VDZ and UST. These factors might also contribute to the observed heterogeneity. Accordingly, future meta-analyses should consider conducting subgroup analyses to address this heterogeneity when more studies become available.

Strengths and limitations

The primary strength of this meta-analysis is its comprehensive inclusion and analysis of real-world data, offering insights into the effectiveness of treatment at various time points up to 1 year after beginning treatment. In addition, the meta-analysis included approximately 2600 patients, a more than threefold increase compared with the previous analysis by Lucaciu et al 14 and more than double the number of patients in the review by Taxonera et al . 13 However, notable heterogeneity among the included studies across the outcomes evaluated is a significant limitation of the present meta-analysis. Further, the exclusion of grey literature represents a trade-off. While it can be considered a strength by focusing on peer-reviewed studies only, it may also lead to publication bias, as it potentially omits studies reporting negative or less significant results. Retrospective studies can introduce selection bias, which is a limitation of this meta-analysis.

This updated meta-analysis supports tofacitinib as an effective treatment for UC in the real world, particularly high clinical response and remission rates during the induction phase and the maintenance period, indicating its potential for long-term symptom relief. Additional meta-analyses to quantitatively synthesise the long-term safety outcomes are highly recommended.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

This systematic review and meta-analysis did not use raw patient data or private information. As a result, there was no requirement for approval of the protocol by the hospital Institutional Review Board (IRB) or for patient informed consent.

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CW and H-HW contributed equally.

Contributors C-HL: conception and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript; statistical analysis; literature research; administrative, technical or material support; supervision. W-SL: acquisition of data; analysis and interpretation of data; critical revision of the manuscript; administrative, technical or material support; supervision; guarantor of integrity of the entire study. CW: conception and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript; administrative, technical or material support; supervision. H-HW: conception and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript; literature research; administrative, technical or material support.

Funding NSTC: 107-2314-B-075-036, 108-2314-B-075-043 -MY2, 110-2314-B-075-017, 111-2314-B-075-046-MY2; VGH: V111C-177, V112C-177, V113C-174.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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Yanying Shen 1 ,
Ling Zhao 1 ,
Anqi Li 2 ,
Qi Peng 1 ,
Qiang Liu 1 ,
http://orcid.org/0000-0002-4033-9856 Lisha Wang 3 ,
http://orcid.org/0000-0003-4682-1253 Zebing Liu 4
1 Department of Pathology , Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
2 Department of Pathology , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
3 Department of Pathology , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , Massachusetts , USA
4 Department of Pathology , Shanghai Jiao Tong University School of Medicine , Shanghai , China
Correspondence to Dr Zebing Liu, Department of Pathology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; zebing080{at}163.com

We report a case of a middle-aged woman with a rapidly growing abdominal mass that was diagnosed as myxoid pleomorphic liposarcoma, a recently recognised, rare and aggressive subtype of liposarcoma. The tumour exhibits a combination of histological features from both myxoid liposarcoma and pleomorphic liposarcoma. Genetic analysis revealed mutations in TP53 and RB1, along with widespread loss of heterozygosity. However, no DDIT3 gene translocation or MDM2/CDK4 gene amplification was detected. These genetic characteristics can be used to distinguish this type of liposarcoma from others. Two unusual gene fusion/rearrangements, CREB5::TERT fusion and ETV1::LFNG rearrangement, were identified. The patient underwent complete removal of the tumour without the use of radiotherapy or chemotherapy. No recurrence was observed during the follow-up period of 18 months.

Soft Tissue Neoplasms
Genes, Neoplasm

https://doi.org/10.1136/jcp-2023-209223

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Introduction

Myxoid pleomorphic liposarcoma (MPLPS) is a newly recognised subtype of liposarcoma that primarily affects the mediastinum of young patients and exhibits a combination of histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma. To date, only a limited number of studies have been reported on this rare and aggressive tumour, and as a result, MPLPS remains poorly understood. In this study, we report a case of MPLPS that arose in the right psoas major of a middle-aged woman. The purpose of this study is to improve our understanding of MPLPS by analysing the clinicopathological characteristics of this specific case, conducting a comprehensive immunohistochemical and genetic examination, and reviewing relevant literature.

Clinical presentation

We present the case of a woman, in the mid-50s, with an unremarkable medical history. She had no history of cancer in either of her parents. During a physical examination, an abdominal mass in the right psoas major was discovered, which had been present for 2 years. The mass was not painful but had significantly increased in size over the past year. B-ultrasound revealed that the maximum diameter of the mass was only 1.5 cm whereas enhanced MRI results one year later showed that the size of the mass had grown to 6×5×3 cm. The mass appeared well-defined, hypointense on T1-weighted images and hyperintense on T2-weighted images ( figure 1A, B ). Limited diffusion was observed on diffusion weighted imaging, and sustained enhancement was noted after contrast enhancement. The patient subsequently underwent excision of the mass. During the surgical procedure, it was discovered that the mass was located in front of the right psoas major muscle and was closely adhered to it.

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Clinical examination results of myxoid pleomorphic liposarcoma (MPLPS). MRI showed a well-defined tumour arising in the right psoas major muscle, with a low signal on T1 (A) and a high signal on T2 (B); (C–H) histopathological features of MPLPS. In total, 80% of the tumour areas exhibited morphological features similar to myxoid liposarcoma, including abundant myxoid matrix, chicken wire-like vasculature, relatively bland round to slightly spindled cells (C, H&E staining×200), scattered univacuolated signet ring-like lipoblasts (D, H&E staining×200) and multivacuolated lipoblasts (E, H&E staining×400). Abundant lymphocyte infiltration was observed in local areas, resembling well-differentiated liposarcoma, inflammatory subtype (F, H&E staining×200). A total of 20% of the tumour areas had morphological features similar to pleomorphic liposarcoma: a gradual increase in cellularity (G, H&E staining×100) and scattered enlarged, hyperchromatic cells and mitotic activity (H, H&E staining×400). The arrow indicates a pathological mitosis; the tumour showed diffuse CD34 (I) and p16 (J) expression; fluorescence in situ hybridisation analysis showed a loss of RB1 signals (K, green: RB1) (Product No.: GSP RB1, LBP, Guangzhou, China).

Grossly, the mass was surrounded by fibroadipose tissue, and the cut surface was greyish yellow, translucent and tender. Histological examination demonstrated that most areas of the mass had a prominent mucinous matrix. Scattered lipoblasts, including univacuolated signet ring-like lipoblasts and multivacuolated lipoblasts, relatively bland round to slightly spindled cells, and chicken wire-like vasculatures were observed ( figure 1C–E ). Local areas of the mass exhibited abundant lymphocyte infiltration ( figure 1F ). Adjacent to these areas, a transition to more cellular and pleomorphic areas with marked cytological atypia and increased mitotic activity was also seen ( figure 1G, H ). These latter features represented approximately 20% of the tumour.

Immunohistochemical results showed diffuse strong positivity for CD34 and p16 in the tumour cells ( figure 1I, J ), while MDM2 was negative. P53 revealed strong and diffuse nuclear positivity. The Ki67 proliferation index was estimated to be 15%–20%. Fluorescence in situ hybridisation (FISH) studies yielded negative results for the FUS (16p11) and CHOP (12q13) gene rearrangements, as well as MDM2 gene amplification. Additionally, FISH analysis revealed that 70% of the tumour cells exhibited deletions of the RB1 gene ( figure 1K ). A clinically validated next-generation sequencing (NGS) targeted DNA and RNA fusion assay was performed to identify potential therapeutic targets. A total of 723 genes known to be recurrently involved in cancer-associated variations were included in the panel design. Table 1 summarises the NGS analysis results, which revealed one nonsense mutation in the TP53 and RB1 genes. Furthermore, two uncommon gene fusion/rearrangements, namely, CREB5::TERT fusion and ETV1::LFNG rearrangement, were identified. The ETV1::LFNG rearrangement detected by DNA sequencing in this sample involves a gene rearrangement between exon 7–14 of the ETV1 gene and exon 3–9 of the LFNG gene. The breakpoints are located in intron 6 of the ETV1 gene and intron 2 of the LFNG gene, respectively. Another novel gene fusion, CREB5::TERT fusion, was identified through RNA sequencing. It involves the fusion of exons 1–4 of the CREB5 gene with exons 2–16 of the TERT gene. In addition to the identified gene fusions and mutations, the NGS analysis results revealed amplification of several oncogenes including TERT , DROSHA , FGF10 , RICTOR and SKP2 , with copy numbers ranging from 5.6 to 24.2. Copy number profiling of the tumour DNA exhibited a complex genomic profile characterised by extensive gains and losses. Regions of gain involved chromosomes 1, 2, 5, 7, 8, 9, 19, 20 and X, and regions of loss involved chromosomes 13 and 16. Allelic imbalance analysis conducted using Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS, an open-source software) indicated widespread loss of heterozygosity (LOH) in this case ( figure 2 ). The tumour was determined to be microsatellite stable and had a tumour mutation burden of 9.4 mutations per megabase. Based on these findings, the tumour was diagnosed as MPLPS.

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Summary of genetic variations with clear or potential clinical significance in myxoid pleomorphic liposarcoma (MPLPS)

Integrated visualisation of Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) analysis of whole-exome sequencing data of myxoid pleomorphic liposarcoma. The top panel displays the total copy number log-ratio (logR), and the second panel presents allele-specific log-OR data (logOR) with alternating chromosomes in blue and grey. The third panel plots the corresponding integer (total, minor) copy number calls. The red line in the third panel represents the minor copy number, and the black line indicates the total copy number. A complex genomic profile with numerous extensive losses and gains (gains involving chromosomes 1, 2, 5, 7, 8, 9, 19, 20 and X, and losses involving chromosomes 13 and 16) is depicted. Widespread loss of heterozygosity was also observed through allelic imbalance analysis with FACETS data.

MPLPS was first described in a study by Alaggio et al in 2009, which focused on liposarcomas in patients under the age of 22 years. 1 The study reported 12 cases of MPLPS in young patients, with a combination of histological features seen in both conventional myxoid liposarcoma and pleomorphic liposarcoma. MPLPS lacks the characteristic gene fusions and amplifications seen in myxoid liposarcoma, atypical lipomatous tumours and dedifferentiated liposarcoma. Alaggio et al observed that MPLPS had a higher incidence in women and a tendency to occur in axial sites, particularly the mediastinum. Additionally, these cases were associated with poor clinical outcomes. Some patients with MPLPS have TP53 gene germline mutation, which is associated with Li-Fraumeni syndrome. 2–4 These unique clinicopathological characteristics led to the recognition of MPLPS as a novel entity within the most recent WHO Classification of Tumors of Soft Tissue and Bone.

MPLPS is an extremely rare subtype of liposarcoma, with a total of only 13 related studies, including 47 cases reported to date. 1–13 Therefore, this tumour remains very poorly understood. We analysed the clinicopathological characteristics of 48 cases of MPLPS in total, including 47 cases of MPLPS reported previously and the case reported in current study ( online supplemental table 1 ). The age of patients with MPLPS ranged from 1 to 74 years, with a mean of 31 years. The sex ratio was roughly equal, with 23 men and 25 women. The most common site of MPLPS is the mediastinum (35.4%, 17/48), followed by the extremities (20.8%, 10/48). Other sites include the head and neck, shoulders, waist, back, abdominal cavity, sacrococcygeal region, and perineum, among others. In general, age and common location of MPLPS were consistent with the report by Alaggio et al , 1 but there was no female predisposition. In our study, we present a case involving a middle-aged woman with MPLPS occurring in the abdominal cavity, specifically originating from the right psoas major muscle. This atypical location and age of onset further expand the disease spectrum of MPLPS. To achieve a comprehensive understanding of this rare tumour, we conducted detailed investigations, including imaging, histological, immunohistochemical and genetic analyses.

Supplemental material

The differential diagnosis of MPLPS includes conventional myxoid liposarcoma, well/dedifferentiated liposarcoma and pleomorphic liposarcoma. MPLPS lacks DDIT3 rearrangement and MDM2 amplification; these two molecular genetic features allow MPLPS to be easily distinguishable from myxoid liposarcoma and well/dedifferentiated liposarcoma. However, the differential diagnosis between MPLPS and pleomorphic liposarcoma, particularly the myxofibrosarcoma-like variant, has always been difficult and subjective. The two subtypes of liposarcoma not only have overlapping histological images but also have similar immunophenotypes, with variable expression of S100, CD34 and p16. 5 6 Genetically, high frequencies of TP53 mutations, RB1 deletion and complex copy number profiles have been identified in both MPLPS and pleomorphic liposarcoma. 5 7–11 14 Unsupervised DNA methylation profiling analysis also shows MPLPS and conventional pleomorphic liposarcomas form a common methylation cluster, which is segregated from myxoid liposarcomas according to Creytens et al . 5 This has also led to a debate as to whether MPLPS is a separate liposarcoma subtype. It is worth mentioning that we observed widespread LOH in allelic imbalance analysis with FACETS data in our case. This phenomenon is also called uniparental isodisomy and has been reported in another reported case of MPLPS using an SNP array. 7 In a study by Dermawan et al , a total of 8 cases of MPLPS, 39 cases of myxoid liposarcoma and 23 cases of pleomorphic liposarcoma were included. Widespread LOH, averaging 80% of the genome, has been identified in MPLPS but not in myxoid liposarcoma or pleomorphic liposarcoma. 8 Therefore, widespread LOH can be used to distinguish MPLPS from pleomorphic liposarcoma. Due to the popularity of NGS detection in clinical applications, allelic imbalance analysis using FACETS data is clinically accessible. Therefore, this molecular genetic characteristic has practical value for distinguishing MPLPS from pleomorphic liposarcomas in clinical settings. These findings also support MPLPS as a separate subtype of liposarcoma.

Two unusual gene rearrangements/fusions ( CREB5::TERT fusion, ETV1::LFNG rearrangement) were identified in this study. To the best of our knowledge, these two gene rearrangements/fusions have not been reported in MPLPS. Another TERT fusion, TRIO exon33- TERT exon2 fusion, which preserves the same region, has been detected in a subset of non-translocation-related sarcomas including myxofibrosarcoma, dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, pleomorphic rhabdomyosarcoma and leiomyosarcoma. Studies have shown that TERT mRNA expression levels are 100 times higher in liposarcoma samples with TRIO-TERT fusion than in samples without TERT fusion. 15 The biological significance of CREB5::TERT fusion remains unclear, necessitating further research and confirmation. The TERT gene was also amplified in this case. TERT gene amplification, as well as TERT promoter mutation, results in increased TERT protein expression. Increased TERT expression in a variety of tumours indicates a poor prognosis. The TERT fusion and TERT amplification detected in this case may suggest a poor prognosis for this patient. The rearrangement breakpoint of ETV1::LFNG is also situated in the classical region where ETV1 gene fusion occurs. The ETV1 gene encodes a transcription factor member of the ETS family. Abnormal expression of the ETS gene can lead to transcription and activation of downstream oncogenes, enhancing malignant features such as tumour invasion. However, ETV1::LFNG gene rearrangement was identified in DNA sequencing, but no corresponding gene fusion was detected in RNA sequencing. This may indicate that the rearrangement was not transcribed to form a functional fusion protein. The clinical significance of ETV1/LFNG rearrangement requires further validation through additional studies.

MPLPS is a highly aggressive tumour. Out of 36 previously reported MPLPS cases with follow-up data, 25 (69%) experienced disease recurrence. 1–13 Interestingly, the tumour’s location appears to be associated with the patient’s prognosis. All patients with MPLPS in the mediastinum had recurrence or metastasis after surgery. However, for patients with non-mediastinal MPLPS, the incidence of postoperative recurrence or metastasis is 45% (9/20). In our case, the tumour was located in the abdominal cavity, not the mediastinum. Despite having adverse prognostic factors such as TERT fusion and amplification, the patient did not experience any recurrence after 18 months of follow-up, without the need for radiotherapy or chemotherapy. This can be attributed to the clear boundary of the tumour, allowing for complete removal through surgery. For patients in whom the tumour cannot be completely removed or whose tumour cells are close to the surgical margin, adjuvant radiotherapy or chemotherapy can be considered, although the effectiveness remains unclear.

MPLPS is exceedingly rare. It is defined as a new entity of liposarcoma in the most recent WHO Classification of Tumors of Soft Tissue and Bone. MPLPS exhibits mixed histological features, combining those of myxoid liposarcoma (abundant myxoid matrix, bland round to spindle cells, scattered small lipoblasts and an arborizing capillary-sized vasculature) and pleomorphic liposarcoma (gradually increased cellularity with scattered enlarged, hyperchromatic cells and large lipoblasts). The molecular genetic characteristics of MPLPS include a lack of DDIT3 rearrangement, a lack of MDM2 amplification, TP53 mutation and the presence of widespread LOH. These features help to distinguish MPLPS from other liposarcoma subtypes, including myxoid liposarcoma, well/dedifferentiated liposarcoma and pleomorphic liposarcoma. MPLPS is highly aggressive, especially when it occurs in the mediastinum. Surgical resection is the primary treatment option.

Targeted genomic profiling by NGS

DNA and RNA were extracted from FFPE tumour samples and peripheral blood using QIAamp DNA FFPE Tissue Kit (Qiagen) and RNeasy DSP FFPE Kit (Qiagen), respectively. A comprehensive genomic analysis of the sample was conducted using a DNA+RNA cancer-related gene panel (723 DNA and 163 RNA gene panel, OrigiMed, Shanghai, China). Library preparations were performed according to the manufacturers’ instructions. The captured libraries were sequenced on Illumina NextSeq 550 with 2×150 bp paired-end reads (Illumina, San Diego, CA, USA). Proprietary algorithms, including Ori-Fusion, Ori-LongIndel and Ori-Microdel/dup, were used to detect various genetic variants. Gene‐level copy‐number variations and allele-specific copy number analysis were identified using FACETS. Detailed data analysis was described previously. 8

Ethics statements

Patient consent for publication.

Consent obtained directly from patient(s).

Ethics approval

This study involves human participants but internal review and ethics boards of the Renji Hospital, School of Medicine, Shanghai Jiaotong University (2022-2023) exempted this study. Participants gave informed consent to participate in the study before taking part.

Acknowledgments

We acknowledge Dr Jiang (Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University) for providing technical and diagnostic advice about the current case.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Data supplement 1

LW and ZL are joint senior authors.

Handling editor David Creytens.

X @lishawang9

Contributors YS conducted literature search, data collection, and analysis and drafted the manuscript. LZ and AL provided with molecular service (including FISH and NGS detections) and contributed to drafting the manuscript. QP conducted bioinformatical analysis. QL assisted in pathology analysis and in drafting the manuscript. LW and ZL performed the pathological analysis and drafted the manuscript. All authors have read and approved the final manuscript.

Funding Supported by the National Nature Science Foundation of China (820702070, 82002543).

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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Anterior Spinal Artery Syndrome After Bronchial Embolization for Hemoptysis: A Case Report and Literature Review

Author affiliations

Raza Gulzar Ghouri 1

Muhammad Mohsin Ali 2

Maryam Saleem Raza 1

Waqas Arshad 1

Background Bronchial artery embolization (BAE) is the established first-line treatment for patients presenting with massive haemoptysis, a life-threatening condition that can occur because of numerous underlying diseases. BAE is a relatively safe procedure with control of haemorrhage achieved in 77%–90% of cases and rare occurrence of complications. Spinal cord infarction is one such rare complication, which can have severe implications in terms of morbidity.

Case presentations We present a case of a 70-year-old man who developed paraplegia with loss of pain and temperature sensation as well as sphincteric involvement following BAE for hemoptysis. MRI of the spine was suggestive of an ischaemic event involving anterolateral spinal cord segment T4–T6, so a diagnosis of anterior spinal artery syndrome post BAE was made. The patient was given corticosteroids, dual antiplatelet medications, pregabalin, supportive management and regular physiotherapy. Follow-up of the patient at 3 and 6 months failed to show any significant improvement in neurological function, although the patient did not report problem of significant hemoptysis afterward.

Conclusion Spinal cord infarct is a rare and disabling complication of BAE despite it being a safe procedure with good long-term outcomes. Detailed knowledge about the anatomy of bronchial arteries and spinal arteries with detailed preprocedure investigations may lower the risk of this disabling complication.

Introduction

Massive hemoptysis is a potentially life-threatening complication of several underlying lung disorders that require urgent medical attention. Bronchial artery embolization (BAE) is currently the standard treatment for massive hemoptysis, with a long-term survival rate of around 85%. 1 Anterior spinal artery syndrome (ASAS) is a rare complication following BAE, the reported incidence of which is as high as 5%. 2 ASAS can lead to paraparesis and can significantly impair the functional status of patients despite treatment. We encountered a case of a 70-year-old man who underwent BAE for hemoptysis and was referred to us for problems of paraplegia and sphincteric involvement. Imaging confirmed spinal cord infarct. The patient did not show any improvement despite medical management. Despite BAE being a safe procedure with good outcomes, it can lead to lifelong disability by causing spinal cord infarction. So, this rare complication should be kept in mind, and the patient should be well informed before the procedure. This case report is per CARE guidelines. 3 The ethical committee of Pakistan Kidney and Liver Institute and Research Center exempted the review board for this study but consent was taken from the patient.

Case report

A 70-year-old man presented to the Interventional Radiology Outpatient Clinic after being referred by a pulmonologist in private practice with the problem of two episodes of hemoptysis in the last one and a half months. The patient previously was a known hypertensive with end-stage renal disease, on maintenance haemodialysis twice per week for the previous 2 years. He was a known smoker and had no other comorbid diseases. The workup for pulmonary tuberculosis had been done before presentation and was negative. The patient had undergone a bronchoscopy in a private set-up for haemoptysis after he had been referred for BAE with a presumptive diagnosis of bronchiectasis in bilateral upper lobes following a lower respiratory tract infection and was being managed on oral antibiotics and tranexamic acid with no clinical improvement. Preoperative clinical examination was significant for right upper lobe coarse crepitations and bibasilar fine crepitations only.

The patient underwent CT aortogram and CT chest and abdomen in the arterial phase as part of the preoperative assessment for BAE. CT findings revealed a dense consolidation patch with perilesional ground glass infective nodular infiltrates, atelectatic bands in the right apex and fibrotic bands in the bilateral apical regions, right middle lobe and lingular segment of the left lung. The right bronchial artery had a separate origin from the thoracic aorta, with a diameter of 3.2 mm ( figure 1 ). There was no common intercostobrachial trunk on the right side. The right bronchial artery was directly arterialising the consolidated area in the right apex, and some of the small branches were also seen coming from the subclavian artery with evidence of right apical bronchopulmonary shunting. Left bronchial arteries were of normal calibre and had a separate origin from the left anterolateral aspect of the thoracic aorta, just inferior to the arch of the aorta, having a diameter of 1 mm. Specks of atherosclerotic calcification were seen in the arch of the aorta, abdominal aorta and bilateral common iliac arteries. Other notable CT findings included bilateral small renal arteries with right distal renal artery aneurysms, cholelithiasis and CBD(common bile duct) stones.

Preprocedural CT aortogram showing the origin of the right bronchial artery (green arrow) from the thoracic aorta (yellow arrow).

BAE was performed under fluoroscopic guidance after puncturing and cannulating the right common femoral artery. The catheter-guidewire combination was advanced up to the right bronchial artery, and an angiogram showed diffuse vascularity towards the apex; however, there was no evidence to suggest that any radicular artery or the anterior spinal artery was arising from the right bronchial artery. Embospheres and microcoils were used to embolise the branches of the right bronchial artery. Subsequently, the right second intercostal artery was engaged, which showed an arteriopulmonary fistula. Embosphere (100–300 μm) was also used to embolise the branch of the second intercostal artery. An angiogram through the right subclavian artery did not show any supply.

Postprocedure angiogram showed adequate stasis. The patient developed sudden onset bilateral lower limb jerky movements during the procedure, followed by right lower limb weakness. After 6 hours, the patient gradually developed left lower limb weakness as well.

Physical examination

Physical examination showed afebrile, vitally stable male GCS 15/15, with intact cranial nerves. Fundus examination only revealed grade 2 hypertensive retinopathy with no papilloedema. The cerebellar examination was normal. Neurological examination of the upper limbs showed power 5/5 in both limbs, with intact sensory system and reflexes +3 (Hoffman sign positive). A note was made of an AV(arteriovenous) fistula on the left arm. The lower limb motor examination was notable for the power of 0/5 on the right and 1/5 on the left sides. Bilateral lower limb reflexes were 2+ with upgoing plantars. Sensory examination showed decreased pain and temperature sensation bilaterally up to T5–T6 dermatomal level, while proprioception and vibration were intact bilaterally. There was loss of sphincter control with urinary retention and constipation. The localised spine exam showed no tenderness, and signs of meningeal irritation were negative.

Investigations

MRI of the brain without contrast and lower cervical and upper dorsal spine with intravenous contrast was performed, followed by haemodialysis. MRI brain showed no evidence of acute brain infarct, whereas, in MRI of the spine, T2-weighted images demonstrated high signal area in anterolateral spinal cord segment T4–T6, with subtle diffusion restriction on diffusion-weighted imaging and restricted diffusion on axial apparent diffusion coefficient, suggestive of an ischaemic event involving anterolateral spinal cord segment T4–T6 ( figures 2 and 3 ).

Sagittal T2-weighted Image showing hyperintense signal in T4–T6 region of the anterior spinal cord.

Diffusion-weighted imaging (DWI) at T4 level showing diffusion restriction (hyperintense signal).

Following imaging, a diagnosis of ASAS post BAE was made.

Differential diagnosis

A diagnosis of ASAS post BAE was made based on clinical presentation, examination and relevant investigations.

The patient was started on corticosteroids, which were given for 2 weeks, pregabalin 50 mg at night, and dual antiplatelets (aspirin 75 mg and clopidogrel 75 mg) one time a day. A bowel regimen with lactulose was started, the patient was catheterised and regular physiotherapy with nursing care was instituted. Despite these measures, the patient failed to report any improvement in motor power and sphincter control. He was eventually discharged home on a single antiplatelet (aspirin 75 mg one time a day) and regular physiotherapy. Corticosteroids were continued for 2 weeks and then tapered off.

Outcome and follow-up

Follow-up of the patient at 3 and 6 months failed to show any significant improvement in neurological function, and he also developed complications due to long-term disability in the form of bed sores and depression. However, the patient did not have any problems of major haemoptysis afterward.

Massive haemoptysis is often a consequence of chronic inflammatory lung conditions, which lead to lung tissue destruction and local hypoxia. This triggers the recruitment of angiogenic growth factors and hypertrophy and proliferation of blood vessels, which can rupture because of friable walls and vascular inflammation, leading to the expectoration of large amounts of blood. 1 BAE is currently the established first-line treatment for massive haemoptysis and is generally a safe procedure with high efficacy. 1 2

Spinal cord ischaemia or infarction as a complication of BAE has been sparsely reported, with a prevalence ranging from 1.4% to 6.5%. 4 Nevertheless, this is one of the most severe complications of BAE, which can lead to lifelong neurological morbidity, as reported in our case. While iatrogenic complications can occur with every procedure, the main risk factor compounding spinal cord infarction is the presence of a radiculomedullary artery at the thoracic level, which follows the trajectory of a corresponding spinal nerve till it reaches the anterior spinal artery. 5 This artery can rarely originate directly from the bronchial artery in 5% of the cases or more commonly originate from the intercostobrachial trunk or an intercostal artery; visualisation of this artery is important especially when it arises directly from the bronchial artery, as the high risk for embolisation would then be an absolute contraindication for BAE. 6

According to existing evidence, the anterior spinal artery and radicular arteries typically do not arise from the bronchial artery alone. Still, they are more commonly associated with the intercostal artery alone or the intercostobronchial trunk involving the intercostal artery. This is consistent with the results of Brown and Ray. 1 Therefore, it seems likely that the spinal cord infarction in this case was related to the embolisation of the right second intercostal artery rather than the right bronchial artery. It has been hypothesised that haemodynamic changes during BAE can eventually occlude the distal outflow vessels, with resultant redirection of flow to the undetected medullary artery/anterior spinal artery—this could have been a possible cause of ASA embolisation in our patient. 1 The size of embosphere is important in this regard as well, and generally, embolisation particles larger than 350 µm in size are recommended as they are too large to penetrate the smaller end vessels that supply the cord.

The use of microcoils during BAE has classically been linked with a lower risk for spinal cord infarction. This can be explained if we consider the two main hypotheses for spinal cord infarction during BAE: the first one theorises backward reflux of embolic agents to proximal vessels such as the aorta, while the second one takes into consideration unintended embolisation of spinal arteries arising from distal part of target vessels. With microcoils, the potential for reflux is much lower due to their controlled embolisation nature, and they also embolise at the intended target instead of travelling further distally, as can be the case with other embolic agents. Only 1 out of 1577 patients had a spinal cord infarction when using coils, with significant differences compared with other embolic materials. The prevalence of spinal cord infarction after BAE with coils, GS particles and NBCA was 0.06% (1 of 1577 patients), 0.18% (12 of 6561 patients) and 0.71% (3 of 425 patients), respectively (p =0.04). 7

Detection of spinal cord infarction can be tricky, as not all patients may present with weakness immediately after the procedure. The evolution of neurological symptoms can take time, and most reported cases had the onset of neurological symptoms on the first postoperative day. 6 8 Suspected spinal cord infarction needs to be investigated thoroughly to rule out other causes, such as cerebral stroke, and an MRI of the brain and spine needs to be carried out. In our patient, an unusual point was the rapidity with which symptoms developed—within 6 hours, the patient developed paraplegia, and while his MRI brain with contrast was normal, the MRI spine suggested ischaemia involving anterolateral spinal cord segments T4–T6. Given that the patient had a history of ESRD (End stage renal disease) on haemodialysis, the possibility of a thromboembolic phenomenon causing his spinal cord infarction independent of the BAE could not be ruled out. Table 1 shows indications of BAE, clinical features, MRI findings, treatment given and outcomes of different reported studies.

Currently, no evidence-based treatment guidelines for spinal cord infarction post BAE exist, and it is generally treated as stroke with the addition of corticosteroids. 5 Isolated cases treated with fibrinolysis have been reported, 9 but in our patient involvement of the neurology team, arranging scans were done on the first postoperative day, and thus, conservative management was preferred. It must be noted that promptness in treating the underlying cause is the most important prognostic factor for anterior spinal cord syndrome 10 —risk factors for poor prognosis present in our patient included old age, initial severity and lack of improvement in the first 24 hours. 5 While up to 46% of patients can recover functional status and walk independently, 11 our patient did not unfortunately improve and is still undergoing rehabilitation and supportive care.

Despite BAE being a relatively safe procedure with beneficial good long-term outcomes as compared with its previous predecessors, the risk of spinal cord ischaemia can be a rare and disabling complication following the procedure. To some extent, spinal infarction can be preventable through knowledge about the anatomy of bronchial arteries and spinal arterial supply, angiography and investigations before embolization. But serious complication can happen following embolization despite taking all the necessary precautions. All patients undergoing emboliation should be well informed and counselled regarding this complication before undergoing such procedures.

Contributors: RGG: conceptualisation, manuscript writing. MMA: methodology. HN: editing and proof reading. WA: supervision. MSR: literature search.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

Data are available upon reasonable request. Data available.

Ethics statements

Consent obtained directly from patient(s)

Not applicable.

Gupta S , Prakash S , Mittal A , et al. Monoparesis post bronchial artery embolization: clinicoradiological discordance in anterior spinal artery infarct—case report and review of literature. J Clin Interv Radiol ISVIR 2019 ; 03 : 130–3 . doi:10.1055/s-0039-1694302 • Google Scholar
Padgett M , Abi-Jaoudeh N , Benn BS , et al. Anterior cord syndrome after embolization for malignant hemoptysis. Semin Intervent Radiol 2019 ; 36 : 111–6 . doi:10.1055/s-0039-1688424 • Google Scholar
Walsh C , Clarke Kregor A , Marie G Bonaguro A , et al. Collateral damage: a case of spinal infarction following bronchial artery embolization for massive hemoptysis. CHEST 2023 ; 164 . doi:10.1016/j.chest.2023.07.3522 • Google Scholar
Publication history
Accepted : 6 May 2024
First Published : 22 May 2024
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Croup (laryngotracheitis) is frequently encountered in the emergency department in a young child presenting with stridor. We describe a rare case of croup secondary to SARS-CoV-2 in an 18-month-old child who presented with stridor and respiratory distress and required urgent intubation. Subsequently, the child developed multisystem inflammatory syndrome in children (MIS-C). The child was monitored in paediatric intensive care unit. We would like to highlight that COVID-19 croup in children may be an indicator for MIS-C, and close monitoring is warranted as MIS-C is a life-threatening condition. Our limited experience suggests that COVID-19 croup especially if associated with MIS-C has an underlying more severe pathology and may require prolonged treatment in comparison with the typical croup or even COVID-19 croup. It is important to recognise this clinical entity during a time when most countries are in a third wave of COVID-19 pandemic.

paediatrics
respiratory medicine

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https://doi.org/10.1136/bcr-2021-244769

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The novel 2019 coronavirus SARS-CoV-2 responsible for COVID-19 was first identified in Wuhan, China, and has ever since swept across the globe. On 11 March 2020, the WHO declared COVID-19 a pandemic. Novel clinical presentations are being discovered daily. Croup (laryngotracheitis) traditionally has been linked to viral infection, notably, parainfluenza virus, respiratory syncytial virus, rhinovirus, enterovirus and others. To our knowledge, this is the first described case in the literature of croup in a child which turned out to be COVID-19 MIS-C. We would like to highlight that croup in a COVID-19 child may be an indicator for MIS-C.

Case presentation

A previously healthy and immunised 18-month-child presented to the emergency department with a 1-day history of noisy breathing. According to the mother, the child was febrile at home for the past 2 days with reduced oral intake. There was no history of cough, choking or foreign body inhalation or recent contact with patients who are COVID-19-positive. Parents, however, claim that the child was recently brought to a crowded mall 2 days prior to symptoms.

On arrival, the child was tachypnoeic at 72 breaths per minute with deep subcostal and intercostal recessions and audible biphasic stridor ( figure 1 ). His oxygen saturation was 76% under room air, the heart rate was 210 beats per minute and the recorded temperature was 39.7°C. Lung auscultation revealed reduced air entry bilaterally with no crepitation. Nebulised budesonide and intravenous dexamethasone administered showed no improvement. Subsequently, he was given nebulised epinephrine. Unfortunately, he developed generalised tonic-clonic seizure midway through the nebulisation, possibly due to hypoxia which aborted with intravenous diazepam.

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Laboured breathing with recessions.

Investigations

Blood gas on high-flow oxygen of 15 L showed pH of 7.21, partial pressure of carbon dioxide of 65.9 mm Hg, partial pressure of oxygen of 71 mm Hg, bicarbonate of 21 mmol/L and base excess of −2 mmol/L. In view of type II respiratory failure, intubation was proceeded by the anaesthetist team with a 4.5 mm endotracheal tube assisted by video laryngoscope. His larynx appeared inflamed, and the supraglottic structures were not oedematous or obstructing the airway ( figure 2 ). There was pooling of secretions below the vocal cords, and the subglottis looked oedematous.

Laryngoscopy showing inflamed supraglottis.

Nasopharyngeal swab for SARS-CoV-2 PCR test was positive with cycle threshold value of 34.42, and the respiratory pathogen nucleic acid amplication panel was positive for respiratory syncytial virus as well. During the second day in paediatric intensive care unit (PICU), he developed seven episodes of loose watery stools which were negative for rotavirus and other organisms ( Shigella , Salmonella , enteropathogenic Escherichia coli ). Blood investigation showed haemoglobin was 10.2 g/dL, and white cell count was 14.7×10 9 /L with lymphocytopenia of 2.97×10 9 /L. Inflammatory markers were raised with C reactive protein (CRP) of 13.8 mg/L, erythrocyte sedimentation rate of 45 mm/hour and fibrinogen of 5 g/L. There was also sign of coagulopathy evidenced by raised prothrombin time of 15 s and a positive D-dimer test of 1600–3200 ng/mL. He had elevated lactate dehydrogenase (LDH) of 385 U/L and low albumin of 26 g/L. Otherwise, his liver enzyme, kidney function and cardiac enzyme were normal ( table 1 ). Bronchoalveolar lavage was positive for respiratory syncytial virus but negative for SARS-CoV-2. Regrettably, no culture or viral immunofluorescence test was sent from vocal cord secretion. Blood cultures were normal. Chest X-ray showed relatively normal findings. SARS-CoV-2 antibody ELISA for qualitative detection of total antibodies in serum performed on day 8 of illness was found to be positive.

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Blood investigation trend

Differential diagnosis

Epiglotitis presents with inspiratory stridor and fever. However, pathognomic findings of thumb sign are found in lateral soft tissue neck radiograph. In bacterial tracheitis, the child presents with expiratory stridor with no classical radiographic findings. However, tracheoscopy will reveal inflamed and oedematous mucosa overlying the tracheal wall with positive bacterial culture. The child with foreign body inhalation may present with expiratory stridor but without a history of fever or upper respiratory tract infection. In addition, bouts of cough and choking along with witnessed foreign body inhaled have been reported.

Due to the possibility of multisystem inflammatory syndrome in children (MIS-C), the child was started on low-dose intravenous methylprednisolone (1.25 mg/kg/day) for 5 days in addition to intravenous ceftriaxone.

Outcome and follow-up

The child responded to treatment and was extubated after being ventilated for a total of 7 days. He was discharged well without complications. The child subsequently defaulted follow-up. Telephone conversation with his parent revealed that the child was active and thriving well without alarming symptoms.

Although a common presentation, croup in children during the COVID-19 period requires thorough assessment. To date, only two articles (a case series and a case report) have been reported on croup with COVID-19 in paediatric patients. 1 2 All the four patients described required ward admission for nebulisation and dexamethasone in addition to close observation for stridor. 1 2 Only one patient required non-invasive ventilation along with heliox in the PICU. Our patient demonstrated the stormiest clinical course among the other children with croup as he developed MIS-C. In retrospect, case 2 in the case series by Venn et al 1 had a history of maculopapular rash, while in the case report by Pitstick et al , 2 there was fever with high CRP, which if evaluated further could have fitted into the definition of MIS-C. It is imperative to be aware that croup in paediatric patients could be secondary to COVID-19 and croup in COVID-19 era may be an indicator for MIS-C.

Earlier, COVID-19 among children was associated with milder symptoms and presentations compared with adults. 3 Surveillance from various countries reported that children typically account for up to 13% of confirmed COVID-19 cases. 4 Despite the increasing number of COVID-19 hospitalisation, only a minority of children require admission. In the USA, the rate of hospitalisation was between 2.5% and 4.1%. 5 Among them, approximately 33% required intensive care and 6% needed invasive ventilation. 6 Clinical findings of COVID-19 in children are diverse, and the most common reported symptoms are fever or chills and cough. 5 Our child presented with febrile stridor and rapid breathing due to laryngotracheitis. It is possible that COVID-19 croup has an underlying more critical pathophysiology compared with the usual croup. 1

The incidence of MIS-C is still uncertain, and different case definitions have been described in varying studies. As growing evidence is emerging daily, it is coming to light that there is a wide spectrum of disease severity in MIS-C. 7 In our child, he presented with severe respiratory distress with type II respiratory failure, gastrointestinal symptom of diarrhoea on days 4 and 5 of illness requiring fluid correction, and neurocognitive complication of seizure. Our patient had mild anaemia, lymphocytopenia, raised inflammatory markers, coagulopathy and raised LDH with low albumin. His chest X-ray was normal, and surprisingly, both parents were tested negative for SARS-CoV-2. This suggests that the immune dysregulation is from an abnormal immune response to the virus. 7 As serial monitoring of his cardiac enzymes was normal, he was given echocardiogram appointment on discharge. Fortunately, he responded well to low-dose intravenous methylprednisolone without immunoglobulin or antiviral therapy.

WHO has established a preliminary set of case definition for MIS in children and adolescents. The listed criteria include fever for 3 or more days; two of the following: rash or bilateral non-purulent conjunctivitis or mucocutaneous inflammatory signs; hypotension or shock; heart abnormalities from echocardiogram or elevated troponin/N-terminal pro-hormone brain natriuretic peptide; evidence of coagulopathy; acute gastrointestinal pathology; elevated inflammatory markers (CRP, ESR or procalcitonin); and no other obvious microbial cause of inflammation and evidence of COVID-19 (PCR antigen or serology positive). In our patient suspected with MIS-C, we monitored his progress while under intubation by charting his inflammatory markers, D-dimer, ferritin, coagulation profile and cardiac enzyme to determine the need for immunoglobulin and further cardiac evaluation.

A multicentre study on paediatric patients hospitalised with severe acute COVID-19 and MIS-C also distinguished the differing patterns of presentation between the two. 8 Most patients with MIS-C had multiple organ involvement, more commonly cardiovascular, mucocutaneous and gastrointestinal involvement, whereas severe acute COVID-19 had more severe pulmonary disease without cardiovascular involvement. In addition, MIS-C commonly has markedly raised CRP (>100 mg/L), lymphopenia and thrombocytopenia. While it is premature to claim that croup may be an indicator of MIS-C based on limited case reports, further studies are needed to establish this link.

Patient’s perspective

As the child is a minor, his parents were filled with guilt when he was diagnosed with SARS-CoV-2. Later, they were perplexed as to why their child had such life-threatening events while they both tested negative for SARS-CoV-2.

Learning points

COVID-19 in children may present as croup, also known as acute laryngotracheobronchitis.

COVID-19 and croup in children can be an indicator of MIS-C (multisystem inflammatory syndrome in children).

SARS-CoV-2 and respiratory syncytial virus can exist together and lead to more severe and acute presentation refractory to initial treatments.

Corticosteroid remains a more accessible and viable armamentarium in the treatment of suspected MIS-C.

More studies are needed to establish the natural history and optimal treatment of presumed COVID-19 croup with MIS-C.

Ethics statements

Patient consent for publication.

Schmidt JM ,
Pitstick CE ,
Rodriguez KM ,
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Pilotto C ,
McGoogan JM
Stokes EK ,
Zambrano LD ,
Anderson KN , et al
Whitaker M ,
O'Halloran A , et al
Götzinger F ,
Santiago-García B ,
Noguera-Julián A , et al
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Turtle L , et al

Twitter @Otology

Contributors CCL was involved in drafting, writing, literature review and final approval; JS was involved in editing, literature review and final approval; JK was involved in editing, literature review and final approval.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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Anterior Spinal Artery Syndrome After Bronchial Embolization for Hemoptysis: A Case Report and Literature Review

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