- Research Process
Literature Review in Research Writing
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Table of Contents
Research on research? If you find this idea rather peculiar, know that nowadays, with the huge amount of information produced daily all around the world, it is becoming more and more difficult to keep up to date with all of it. In addition to the sheer amount of research, there is also its origin. We are witnessing the economic and intellectual emergence of countries like China, Brazil, Turkey, and United Arab Emirates, for example, that are producing scholarly literature in their own languages. So, apart from the effort of gathering information, there must also be translators prepared to unify all of it in a single language to be the object of the literature survey. At Elsevier, our team of translators is ready to support researchers by delivering high-quality scientific translations , in several languages, to serve their research – no matter the topic.
What is a literature review?
A literature review is a study – or, more accurately, a survey – involving scholarly material, with the aim to discuss published information about a specific topic or research question. Therefore, to write a literature review, it is compulsory that you are a real expert in the object of study. The results and findings will be published and made available to the public, namely scientists working in the same area of research.
How to Write a Literature Review
First of all, don’t forget that writing a literature review is a great responsibility. It’s a document that is expected to be highly reliable, especially concerning its sources and findings. You have to feel intellectually comfortable in the area of study and highly proficient in the target language; misconceptions and errors do not have a place in a document as important as a literature review. In fact, you might want to consider text editing services, like those offered at Elsevier, to make sure your literature is following the highest standards of text quality. You want to make sure your literature review is memorable by its novelty and quality rather than language errors.
Writing a literature review requires expertise but also organization. We cannot teach you about your topic of research, but we can provide a few steps to guide you through conducting a literature review:
- Choose your topic or research question: It should not be too comprehensive or too limited. You have to complete your task within a feasible time frame.
- Set the scope: Define boundaries concerning the number of sources, time frame to be covered, geographical area, etc.
- Decide which databases you will use for your searches: In order to search the best viable sources for your literature review, use highly regarded, comprehensive databases to get a big picture of the literature related to your topic.
- Search, search, and search: Now you’ll start to investigate the research on your topic. It’s critical that you keep track of all the sources. Start by looking at research abstracts in detail to see if their respective studies relate to or are useful for your own work. Next, search for bibliographies and references that can help you broaden your list of resources. Choose the most relevant literature and remember to keep notes of their bibliographic references to be used later on.
- Review all the literature, appraising carefully it’s content: After reading the study’s abstract, pay attention to the rest of the content of the articles you deem the “most relevant.” Identify methodologies, the most important questions they address, if they are well-designed and executed, and if they are cited enough, etc.
If it’s the first time you’ve published a literature review, note that it is important to follow a special structure. Just like in a thesis, for example, it is expected that you have an introduction – giving the general idea of the central topic and organizational pattern – a body – which contains the actual discussion of the sources – and finally the conclusion or recommendations – where you bring forward whatever you have drawn from the reviewed literature. The conclusion may even suggest there are no agreeable findings and that the discussion should be continued.
Why are literature reviews important?
Literature reviews constantly feed new research, that constantly feeds literature reviews…and we could go on and on. The fact is, one acts like a force over the other and this is what makes science, as a global discipline, constantly develop and evolve. As a scientist, writing a literature review can be very beneficial to your career, and set you apart from the expert elite in your field of interest. But it also can be an overwhelming task, so don’t hesitate in contacting Elsevier for text editing services, either for profound edition or just a last revision. We guarantee the very highest standards. You can also save time by letting us suggest and make the necessary amendments to your manuscript, so that it fits the structural pattern of a literature review. Who knows how many worldwide researchers you will impact with your next perfectly written literature review.
Know more: How to Find a Gap in Research .
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How to write review of related literature (RRL) in research
A review of related literature (a.k.a RRL in research) is a comprehensive review of the existing literature pertaining to a specific topic or research question. An effective review provides the reader with an organized analysis and synthesis of the existing knowledge about a subject. With the increasing amount of new information being disseminated every day, conducting a review of related literature is becoming more difficult and the purpose of review of related literature is clearer than ever.
All new knowledge is necessarily based on previously known information, and every new scientific study must be conducted and reported in the context of previous studies. This makes a review of related literature essential for research, and although it may be tedious work at times , most researchers will complete many such reviews of varying depths during their career. So, why exactly is a review of related literature important?
Table of Contents
Why a review of related literature in research is important
Before thinking how to do reviews of related literature , it is necessary to understand its importance. Although the purpose of a review of related literature varies depending on the discipline and how it will be used, its importance is never in question. Here are some ways in which a review can be crucial.
- Identify gaps in the knowledge – This is the primary purpose of a review of related literature (often called RRL in research ). To create new knowledge, you must first determine what knowledge may be missing. This also helps to identify the scope of your study.
- Avoid duplication of research efforts – Not only will a review of related literature indicate gaps in the existing research, but it will also lead you away from duplicating research that has already been done and thus save precious resources.
- Provide an overview of disparate and interdisciplinary research areas – Researchers cannot possibly know everything related to their disciplines. Therefore, it is very helpful to have access to a review of related literature already written and published.
- Highlight researcher’s familiarity with their topic 1 – A strong review of related literature in a study strengthens readers’ confidence in that study and that researcher.
Tips on how to write a review of related literature in research
Given that you will probably need to produce a number of these at some point, here are a few general tips on how to write an effective review of related literature 2 .
- Define your topic, audience, and purpose: You will be spending a lot of time with this review, so choose a topic that is interesting to you. While deciding what to write in a review of related literature , think about who you expect to read the review – researchers in your discipline, other scientists, the general public – and tailor the language to the audience. Also, think about the purpose of your review of related literature .
- Conduct a comprehensive literature search: While writing your review of related literature , emphasize more recent works but don’t forget to include some older publications as well. Cast a wide net, as you may find some interesting and relevant literature in unexpected databases or library corners. Don’t forget to search for recent conference papers.
- Review the identified articles and take notes: It is a good idea to take notes in a way such that individual items in your notes can be moved around when you organize them. For example, index cards are great tools for this. Write each individual idea on a separate card along with the source. The cards can then be easily grouped and organized.
- Determine how to organize your review: A review of related literature should not be merely a listing of descriptions. It should be organized by some criterion, such as chronologically or thematically.
- Be critical and objective: Don’t just report the findings of other studies in your review of related literature . Challenge the methodology, find errors in the analysis, question the conclusions. Use what you find to improve your research. However, do not insert your opinions into the review of related literature. Remain objective and open-minded.
- Structure your review logically: Guide the reader through the information. The structure will depend on the function of the review of related literature. Creating an outline prior to writing the RRL in research is a good way to ensure the presented information flows well.
As you read more extensively in your discipline, you will notice that the review of related literature appears in various forms in different places. For example, when you read an article about an experimental study, you will typically see a literature review or a RRL in research , in the introduction that includes brief descriptions of similar studies. In longer research studies and dissertations, especially in the social sciences, the review of related literature will typically be a separate chapter and include more information on methodologies and theory building. In addition, stand-alone review articles will be published that are extremely useful to researchers.
The review of relevant literature or often abbreviated as, RRL in research , is an important communication tool that can be used in many forms for many purposes. It is a tool that all researchers should befriend.
- University of North Carolina at Chapel Hill Writing Center. Literature Reviews. https://writingcenter.unc.edu/tips-and-tools/literature-reviews/ [Accessed September 8, 2022]
- Pautasso M. Ten simple rules for writing a literature review. PLoS Comput Biol. 2013, 9. doi: 10.1371/journal.pcbi.1003149.
Q: Is research complete without a review of related literature?
A research project is usually considered incomplete without a proper review of related literature. The review of related literature is a crucial component of any research project as it provides context for the research question, identifies gaps in existing literature, and ensures novelty by avoiding duplication. It also helps inform research design and supports arguments, highlights the significance of a study, and demonstrates your knowledge an expertise.
Q: What is difference between RRL and RRS?
The key difference between an RRL and an RRS lies in their focus and scope. An RRL or review of related literature examines a broad range of literature, including theoretical frameworks, concepts, and empirical studies, to establish the context and significance of the research topic. On the other hand, an RRS or review of research studies specifically focuses on analyzing and summarizing previous research studies within a specific research domain to gain insights into methodologies, findings, and gaps in the existing body of knowledge. While there may be some overlap between the two, they serve distinct purposes and cover different aspects of the research process.
Q: Does review of related literature improve accuracy and validity of research?
Yes, a comprehensive review of related literature (RRL) plays a vital role in improving the accuracy and validity of research. It helps authors gain a deeper understanding and offers different perspectives on the research topic. RRL can help you identify research gaps, dictate the selection of appropriate research methodologies, enhance theoretical frameworks, avoid biases and errors, and even provide support for research design and interpretation. By building upon and critically engaging with existing related literature, researchers can ensure their work is rigorous, reliable, and contributes meaningfully to their field of study.
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Q: What is the importance of a review of related literature in the study – and how do you organize it?
Asked by Kenn Ables on 07 Oct, 2020
Hello Kenn – Welcome to the forum!
A review of related – and preferably recent – literature is meant to set your research in the context of what is currently known about the topic and to establish that what you have to offer is novel , something different from what has been already attempted. The review also reassures the referees that you are familiar with current developments in your field: if all of the papers that you cite in the review are, for example, at least 3–5 years old, the referees are bound to notice!
Coming to the second part of your query, a good review is not a chronological inventory. Do not simply list all the papers in the order in which they were published; a thematic organization is more effective. For example, in one paragraph, you may cite papers related to what is currently known about the topic; in another, you can mention papers that specifically relate to the method you have chosen. Another possibility is to group the papers by region: global studies forming one group, for example, and regional studies and national-level studies forming two more groups. Yet another possibility is by results: all the papers with similar results forming one group and those proposing a different hypothesis forming a different group, and so on.
Hope that helps. For more information on writing a review of related literature (RRL), you may refer to these previous queries by other researchers:
- How do I do a review of related literature (RRL)?
- What would be the review of related literature (RRL) for my topic?
All the best for your review!
[With inputs from Yateendra Joshi ]
Answered by Editage Insights on 08 Oct, 2020
- Upvote this Answer
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Learn how to write a review of literature
What is a review of literature.
The format of a review of literature may vary from discipline to discipline and from assignment to assignment.
A review may be a self-contained unit — an end in itself — or a preface to and rationale for engaging in primary research. A review is a required part of grant and research proposals and often a chapter in theses and dissertations.
Generally, the purpose of a review is to analyze critically a segment of a published body of knowledge through summary, classification, and comparison of prior research studies, reviews of literature, and theoretical articles.
Writing the introduction
In the introduction, you should:
Define or identify the general topic, issue, or area of concern, thus providing an appropriate context for reviewing the literature.
Point out overall trends in what has been published about the topic; or conflicts in theory, methodology, evidence, and conclusions; or gaps in research and scholarship; or a single problem or new perspective of immediate interest.
Establish the writer’s reason (point of view) for reviewing the literature; explain the criteria to be used in analyzing and comparing literature and the organization of the review (sequence); and, when necessary, state why certain literature is or is not included (scope).
Writing the body
In the body, you should:
Group research studies and other types of literature (reviews, theoretical articles, case studies, etc.) according to common denominators such as qualitative versus quantitative approaches, conclusions of authors, specific purpose or objective, chronology, etc.
Summarize individual studies or articles with as much or as little detail as each merits according to its comparative importance in the literature, remembering that space (length) denotes significance.
Provide the reader with strong “umbrella” sentences at beginnings of paragraphs, “signposts” throughout, and brief “so what” summary sentences at intermediate points in the review to aid in understanding comparisons and analyses.
Writing the conclusion
In the conclusion, you should:
Summarize major contributions of significant studies and articles to the body of knowledge under review, maintaining the focus established in the introduction.
Evaluate the current “state of the art” for the body of knowledge reviewed, pointing out major methodological flaws or gaps in research, inconsistencies in theory and findings, and areas or issues pertinent to future study.
Conclude by providing some insight into the relationship between the central topic of the literature review and a larger area of study such as a discipline, a scientific endeavor, or a profession.
For further information see our handouts on Writing a Critical Review of a Nonfiction Book or Article or Reading a Book to Review It .
To learn more about literature reviews, take a look at our workshop on Writing Literature Reviews of Published Research.
Sample Literature Reviews
An important strategy for learning how to compose literature reviews in your field or within a specific genre is to locate and analyze representative examples. The following collection of annotated sample literature reviews written and co-written by colleagues associated with UW-Madison showcases how these reviews can do different kind of work for different purposes. Use these successful examples as a starting point for understanding how other writers have approached the challenging and important task of situating their idea in the context of established research.
- Sample 1 (PDF) A brief literature review within a political scientists’ National Science Foundation Graduate Research Fellowship grant
- Sample 2 (PDF) A several-page literature review at the beginning of a published, academic article about philosophy
- Sample 3 (PDF) A brief literature review at the beginning of a published, academic article about photochemistry
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Frequently asked questions
What is the purpose of a literature review.
There are several reasons to conduct a literature review at the beginning of a research project:
- To familiarize yourself with the current state of knowledge on your topic
- To ensure that you’re not just repeating what others have already done
- To identify gaps in knowledge and unresolved problems that your research can address
- To develop your theoretical framework and methodology
- To provide an overview of the key findings and debates on the topic
Writing the literature review shows your reader how your work relates to existing research and what new insights it will contribute.
Frequently asked questions: Academic writing
You may have seen both “appendices” or “appendixes” as pluralizations of “ appendix .” Either spelling can be used, but “appendices” is more common (including in APA Style ). Consistency is key here: make sure you use the same spelling throughout your paper.
The purpose of a lab report is to demonstrate your understanding of the scientific method with a hands-on lab experiment. Course instructors will often provide you with an experimental design and procedure. Your task is to write up how you actually performed the experiment and evaluate the outcome.
In contrast, a research paper requires you to independently develop an original argument. It involves more in-depth research and interpretation of sources and data.
A lab report is usually shorter than a research paper.
The sections of a lab report can vary between scientific fields and course requirements, but it usually contains the following:
- Title: expresses the topic of your study
- Abstract: summarizes your research aims, methods, results, and conclusions
- Introduction: establishes the context needed to understand the topic
- Method: describes the materials and procedures used in the experiment
- Results: reports all descriptive and inferential statistical analyses
- Discussion: interprets and evaluates results and identifies limitations
- Conclusion: sums up the main findings of your experiment
- References: list of all sources cited using a specific style (e.g. APA)
- Appendices: contains lengthy materials, procedures, tables or figures
A lab report conveys the aim, methods, results, and conclusions of a scientific experiment . Lab reports are commonly assigned in science, technology, engineering, and mathematics (STEM) fields.
The abstract is the very last thing you write. You should only write it after your research is complete, so that you can accurately summarize the entirety of your thesis , dissertation or research paper .
If you’ve gone over the word limit set for your assignment, shorten your sentences and cut repetition and redundancy during the editing process. If you use a lot of long quotes , consider shortening them to just the essentials.
If you need to remove a lot of words, you may have to cut certain passages. Remember that everything in the text should be there to support your argument; look for any information that’s not essential to your point and remove it.
Revising, proofreading, and editing are different stages of the writing process .
- Revising is making structural and logical changes to your text—reformulating arguments and reordering information.
- Editing refers to making more local changes to things like sentence structure and phrasing to make sure your meaning is conveyed clearly and concisely.
- Proofreading involves looking at the text closely, line by line, to spot any typos and issues with consistency and correct them.
The literature review usually comes near the beginning of your thesis or dissertation . After the introduction , it grounds your research in a scholarly field and leads directly to your theoretical framework or methodology .
A literature review is a survey of scholarly sources (such as books, journal articles, and theses) related to a specific topic or research question .
It is often written as part of a thesis, dissertation , or research paper , in order to situate your work in relation to existing knowledge.
Avoid citing sources in your abstract . There are two reasons for this:
- The abstract should focus on your original research, not on the work of others.
- The abstract should be self-contained and fully understandable without reference to other sources.
There are some circumstances where you might need to mention other sources in an abstract: for example, if your research responds directly to another study or focuses on the work of a single theorist. In general, though, don’t include citations unless absolutely necessary.
An abstract is a concise summary of an academic text (such as a journal article or dissertation ). It serves two main purposes:
- To help potential readers determine the relevance of your paper for their own research.
- To communicate your key findings to those who don’t have time to read the whole paper.
Abstracts are often indexed along with keywords on academic databases, so they make your work more easily findable. Since the abstract is the first thing any reader sees, it’s important that it clearly and accurately summarizes the contents of your paper.
In a scientific paper, the methodology always comes after the introduction and before the results , discussion and conclusion . The same basic structure also applies to a thesis, dissertation , or research proposal .
Depending on the length and type of document, you might also include a literature review or theoretical framework before the methodology.
Whether you’re publishing a blog, submitting a research paper , or even just writing an important email, there are a few techniques you can use to make sure it’s error-free:
- Take a break : Set your work aside for at least a few hours so that you can look at it with fresh eyes.
- Proofread a printout : Staring at a screen for too long can cause fatigue – sit down with a pen and paper to check the final version.
- Use digital shortcuts : Take note of any recurring mistakes (for example, misspelling a particular word, switching between US and UK English , or inconsistently capitalizing a term), and use Find and Replace to fix it throughout the document.
If you want to be confident that an important text is error-free, it might be worth choosing a professional proofreading service instead.
Editing and proofreading are different steps in the process of revising a text.
Editing comes first, and can involve major changes to content, structure and language. The first stages of editing are often done by authors themselves, while a professional editor makes the final improvements to grammar and style (for example, by improving sentence structure and word choice ).
Proofreading is the final stage of checking a text before it is published or shared. It focuses on correcting minor errors and inconsistencies (for example, in punctuation and capitalization ). Proofreaders often also check for formatting issues, especially in print publishing.
The cost of proofreading depends on the type and length of text, the turnaround time, and the level of services required. Most proofreading companies charge per word or page, while freelancers sometimes charge an hourly rate.
For proofreading alone, which involves only basic corrections of typos and formatting mistakes, you might pay as little as $0.01 per word, but in many cases, your text will also require some level of editing , which costs slightly more.
It’s often possible to purchase combined proofreading and editing services and calculate the price in advance based on your requirements.
There are many different routes to becoming a professional proofreader or editor. The necessary qualifications depend on the field – to be an academic or scientific proofreader, for example, you will need at least a university degree in a relevant subject.
For most proofreading jobs, experience and demonstrated skills are more important than specific qualifications. Often your skills will be tested as part of the application process.
To learn practical proofreading skills, you can choose to take a course with a professional organization such as the Society for Editors and Proofreaders . Alternatively, you can apply to companies that offer specialized on-the-job training programmes, such as the Scribbr Academy .
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What this handout is about.
This handout will explain what literature reviews are and offer insights into the form and construction of literature reviews in the humanities, social sciences, and sciences.
OK. You’ve got to write a literature review. You dust off a novel and a book of poetry, settle down in your chair, and get ready to issue a “thumbs up” or “thumbs down” as you leaf through the pages. “Literature review” done. Right?
Wrong! The “literature” of a literature review refers to any collection of materials on a topic, not necessarily the great literary texts of the world. “Literature” could be anything from a set of government pamphlets on British colonial methods in Africa to scholarly articles on the treatment of a torn ACL. And a review does not necessarily mean that your reader wants you to give your personal opinion on whether or not you liked these sources.
What is a literature review, then?
A literature review discusses published information in a particular subject area, and sometimes information in a particular subject area within a certain time period.
A literature review can be just a simple summary of the sources, but it usually has an organizational pattern and combines both summary and synthesis. A summary is a recap of the important information of the source, but a synthesis is a re-organization, or a reshuffling, of that information. It might give a new interpretation of old material or combine new with old interpretations. Or it might trace the intellectual progression of the field, including major debates. And depending on the situation, the literature review may evaluate the sources and advise the reader on the most pertinent or relevant.
But how is a literature review different from an academic research paper?
The main focus of an academic research paper is to develop a new argument, and a research paper is likely to contain a literature review as one of its parts. In a research paper, you use the literature as a foundation and as support for a new insight that you contribute. The focus of a literature review, however, is to summarize and synthesize the arguments and ideas of others without adding new contributions.
Why do we write literature reviews?
Literature reviews provide you with a handy guide to a particular topic. If you have limited time to conduct research, literature reviews can give you an overview or act as a stepping stone. For professionals, they are useful reports that keep them up to date with what is current in the field. For scholars, the depth and breadth of the literature review emphasizes the credibility of the writer in his or her field. Literature reviews also provide a solid background for a research paper’s investigation. Comprehensive knowledge of the literature of the field is essential to most research papers.
Who writes these things, anyway?
Literature reviews are written occasionally in the humanities, but mostly in the sciences and social sciences; in experiment and lab reports, they constitute a section of the paper. Sometimes a literature review is written as a paper in itself.
Let’s get to it! What should I do before writing the literature review?
If your assignment is not very specific, seek clarification from your instructor:
- Roughly how many sources should you include?
- What types of sources (books, journal articles, websites)?
- Should you summarize, synthesize, or critique your sources by discussing a common theme or issue?
- Should you evaluate your sources?
- Should you provide subheadings and other background information, such as definitions and/or a history?
Look for other literature reviews in your area of interest or in the discipline and read them to get a sense of the types of themes you might want to look for in your own research or ways to organize your final review. You can simply put the word “review” in your search engine along with your other topic terms to find articles of this type on the Internet or in an electronic database. The bibliography or reference section of sources you’ve already read are also excellent entry points into your own research.
Narrow your topic
There are hundreds or even thousands of articles and books on most areas of study. The narrower your topic, the easier it will be to limit the number of sources you need to read in order to get a good survey of the material. Your instructor will probably not expect you to read everything that’s out there on the topic, but you’ll make your job easier if you first limit your scope.
Keep in mind that UNC Libraries have research guides and to databases relevant to many fields of study. You can reach out to the subject librarian for a consultation: https://library.unc.edu/support/consultations/ .
And don’t forget to tap into your professor’s (or other professors’) knowledge in the field. Ask your professor questions such as: “If you had to read only one book from the 90’s on topic X, what would it be?” Questions such as this help you to find and determine quickly the most seminal pieces in the field.
Consider whether your sources are current
Some disciplines require that you use information that is as current as possible. In the sciences, for instance, treatments for medical problems are constantly changing according to the latest studies. Information even two years old could be obsolete. However, if you are writing a review in the humanities, history, or social sciences, a survey of the history of the literature may be what is needed, because what is important is how perspectives have changed through the years or within a certain time period. Try sorting through some other current bibliographies or literature reviews in the field to get a sense of what your discipline expects. You can also use this method to consider what is currently of interest to scholars in this field and what is not.
Strategies for writing the literature review
Find a focus.
A literature review, like a term paper, is usually organized around ideas, not the sources themselves as an annotated bibliography would be organized. This means that you will not just simply list your sources and go into detail about each one of them, one at a time. No. As you read widely but selectively in your topic area, consider instead what themes or issues connect your sources together. Do they present one or different solutions? Is there an aspect of the field that is missing? How well do they present the material and do they portray it according to an appropriate theory? Do they reveal a trend in the field? A raging debate? Pick one of these themes to focus the organization of your review.
Convey it to your reader
A literature review may not have a traditional thesis statement (one that makes an argument), but you do need to tell readers what to expect. Try writing a simple statement that lets the reader know what is your main organizing principle. Here are a couple of examples:
The current trend in treatment for congestive heart failure combines surgery and medicine. More and more cultural studies scholars are accepting popular media as a subject worthy of academic consideration.
You’ve got a focus, and you’ve stated it clearly and directly. Now what is the most effective way of presenting the information? What are the most important topics, subtopics, etc., that your review needs to include? And in what order should you present them? Develop an organization for your review at both a global and local level:
First, cover the basic categories
Just like most academic papers, literature reviews also must contain at least three basic elements: an introduction or background information section; the body of the review containing the discussion of sources; and, finally, a conclusion and/or recommendations section to end the paper. The following provides a brief description of the content of each:
- Introduction: Gives a quick idea of the topic of the literature review, such as the central theme or organizational pattern.
- Body: Contains your discussion of sources and is organized either chronologically, thematically, or methodologically (see below for more information on each).
- Conclusions/Recommendations: Discuss what you have drawn from reviewing literature so far. Where might the discussion proceed?
Organizing the body
Once you have the basic categories in place, then you must consider how you will present the sources themselves within the body of your paper. Create an organizational method to focus this section even further.
To help you come up with an overall organizational framework for your review, consider the following scenario:
You’ve decided to focus your literature review on materials dealing with sperm whales. This is because you’ve just finished reading Moby Dick, and you wonder if that whale’s portrayal is really real. You start with some articles about the physiology of sperm whales in biology journals written in the 1980’s. But these articles refer to some British biological studies performed on whales in the early 18th century. So you check those out. Then you look up a book written in 1968 with information on how sperm whales have been portrayed in other forms of art, such as in Alaskan poetry, in French painting, or on whale bone, as the whale hunters in the late 19th century used to do. This makes you wonder about American whaling methods during the time portrayed in Moby Dick, so you find some academic articles published in the last five years on how accurately Herman Melville portrayed the whaling scene in his novel.
Now consider some typical ways of organizing the sources into a review:
- Chronological: If your review follows the chronological method, you could write about the materials above according to when they were published. For instance, first you would talk about the British biological studies of the 18th century, then about Moby Dick, published in 1851, then the book on sperm whales in other art (1968), and finally the biology articles (1980s) and the recent articles on American whaling of the 19th century. But there is relatively no continuity among subjects here. And notice that even though the sources on sperm whales in other art and on American whaling are written recently, they are about other subjects/objects that were created much earlier. Thus, the review loses its chronological focus.
- By publication: Order your sources by publication chronology, then, only if the order demonstrates a more important trend. For instance, you could order a review of literature on biological studies of sperm whales if the progression revealed a change in dissection practices of the researchers who wrote and/or conducted the studies.
- By trend: A better way to organize the above sources chronologically is to examine the sources under another trend, such as the history of whaling. Then your review would have subsections according to eras within this period. For instance, the review might examine whaling from pre-1600-1699, 1700-1799, and 1800-1899. Under this method, you would combine the recent studies on American whaling in the 19th century with Moby Dick itself in the 1800-1899 category, even though the authors wrote a century apart.
- Thematic: Thematic reviews of literature are organized around a topic or issue, rather than the progression of time. However, progression of time may still be an important factor in a thematic review. For instance, the sperm whale review could focus on the development of the harpoon for whale hunting. While the study focuses on one topic, harpoon technology, it will still be organized chronologically. The only difference here between a “chronological” and a “thematic” approach is what is emphasized the most: the development of the harpoon or the harpoon technology.But more authentic thematic reviews tend to break away from chronological order. For instance, a thematic review of material on sperm whales might examine how they are portrayed as “evil” in cultural documents. The subsections might include how they are personified, how their proportions are exaggerated, and their behaviors misunderstood. A review organized in this manner would shift between time periods within each section according to the point made.
- Methodological: A methodological approach differs from the two above in that the focusing factor usually does not have to do with the content of the material. Instead, it focuses on the “methods” of the researcher or writer. For the sperm whale project, one methodological approach would be to look at cultural differences between the portrayal of whales in American, British, and French art work. Or the review might focus on the economic impact of whaling on a community. A methodological scope will influence either the types of documents in the review or the way in which these documents are discussed. Once you’ve decided on the organizational method for the body of the review, the sections you need to include in the paper should be easy to figure out. They should arise out of your organizational strategy. In other words, a chronological review would have subsections for each vital time period. A thematic review would have subtopics based upon factors that relate to the theme or issue.
Sometimes, though, you might need to add additional sections that are necessary for your study, but do not fit in the organizational strategy of the body. What other sections you include in the body is up to you. Put in only what is necessary. Here are a few other sections you might want to consider:
- Current Situation: Information necessary to understand the topic or focus of the literature review.
- History: The chronological progression of the field, the literature, or an idea that is necessary to understand the literature review, if the body of the literature review is not already a chronology.
- Methods and/or Standards: The criteria you used to select the sources in your literature review or the way in which you present your information. For instance, you might explain that your review includes only peer-reviewed articles and journals.
Questions for Further Research: What questions about the field has the review sparked? How will you further your research as a result of the review?
Once you’ve settled on a general pattern of organization, you’re ready to write each section. There are a few guidelines you should follow during the writing stage as well. Here is a sample paragraph from a literature review about sexism and language to illuminate the following discussion:
However, other studies have shown that even gender-neutral antecedents are more likely to produce masculine images than feminine ones (Gastil, 1990). Hamilton (1988) asked students to complete sentences that required them to fill in pronouns that agreed with gender-neutral antecedents such as “writer,” “pedestrian,” and “persons.” The students were asked to describe any image they had when writing the sentence. Hamilton found that people imagined 3.3 men to each woman in the masculine “generic” condition and 1.5 men per woman in the unbiased condition. Thus, while ambient sexism accounted for some of the masculine bias, sexist language amplified the effect. (Source: Erika Falk and Jordan Mills, “Why Sexist Language Affects Persuasion: The Role of Homophily, Intended Audience, and Offense,” Women and Language19:2).
In the example above, the writers refer to several other sources when making their point. A literature review in this sense is just like any other academic research paper. Your interpretation of the available sources must be backed up with evidence to show that what you are saying is valid.
Select only the most important points in each source to highlight in the review. The type of information you choose to mention should relate directly to the review’s focus, whether it is thematic, methodological, or chronological.
Use quotes sparingly
Falk and Mills do not use any direct quotes. That is because the survey nature of the literature review does not allow for in-depth discussion or detailed quotes from the text. Some short quotes here and there are okay, though, if you want to emphasize a point, or if what the author said just cannot be rewritten in your own words. Notice that Falk and Mills do quote certain terms that were coined by the author, not common knowledge, or taken directly from the study. But if you find yourself wanting to put in more quotes, check with your instructor.
Summarize and synthesize
Remember to summarize and synthesize your sources within each paragraph as well as throughout the review. The authors here recapitulate important features of Hamilton’s study, but then synthesize it by rephrasing the study’s significance and relating it to their own work.
Keep your own voice
While the literature review presents others’ ideas, your voice (the writer’s) should remain front and center. Notice that Falk and Mills weave references to other sources into their own text, but they still maintain their own voice by starting and ending the paragraph with their own ideas and their own words. The sources support what Falk and Mills are saying.
Use caution when paraphrasing
When paraphrasing a source that is not your own, be sure to represent the author’s information or opinions accurately and in your own words. In the preceding example, Falk and Mills either directly refer in the text to the author of their source, such as Hamilton, or they provide ample notation in the text when the ideas they are mentioning are not their own, for example, Gastil’s. For more information, please see our handout on plagiarism .
Revise, revise, revise
Draft in hand? Now you’re ready to revise. Spending a lot of time revising is a wise idea, because your main objective is to present the material, not the argument. So check over your review again to make sure it follows the assignment and/or your outline. Then, just as you would for most other academic forms of writing, rewrite or rework the language of your review so that you’ve presented your information in the most concise manner possible. Be sure to use terminology familiar to your audience; get rid of unnecessary jargon or slang. Finally, double check that you’ve documented your sources and formatted the review appropriately for your discipline. For tips on the revising and editing process, see our handout on revising drafts .
We consulted these works while writing this handout. This is not a comprehensive list of resources on the handout’s topic, and we encourage you to do your own research to find additional publications. Please do not use this list as a model for the format of your own reference list, as it may not match the citation style you are using. For guidance on formatting citations, please see the UNC Libraries citation tutorial . We revise these tips periodically and welcome feedback.
Anson, Chris M., and Robert A. Schwegler. 2010. The Longman Handbook for Writers and Readers , 6th ed. New York: Longman.
Jones, Robert, Patrick Bizzaro, and Cynthia Selfe. 1997. The Harcourt Brace Guide to Writing in the Disciplines . New York: Harcourt Brace.
Lamb, Sandra E. 1998. How to Write It: A Complete Guide to Everything You’ll Ever Write . Berkeley: Ten Speed Press.
Rosen, Leonard J., and Laurence Behrens. 2003. The Allyn & Bacon Handbook , 5th ed. New York: Longman.
Troyka, Lynn Quittman, and Doug Hesse. 2016. Simon and Schuster Handbook for Writers , 11th ed. London: Pearson.
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More information: Andrew Bazemore et al, The Impact of Interpersonal Continuity of Primary Care on Health Care Costs and Use: A Critical Review, The Annals of Family Medicine (2023). DOI: 10.1370/afm.2961 Journal information: Annals of Family Medicine
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- Open Access
- Published: 19 May 2023
Fatigue in patients with syndromic heritable thoracic aortic disease: a systematic review of the literature and a qualitative study of patients’ experiences and perceptions
- Gry Velvin ORCID: orcid.org/0000-0002-5521-778X 1 ,
- Heidi Johansen 1 ,
- Amy Østertun-Geirdal 2 &
- Trine Bathen MSc 1
Orphanet Journal of Rare Diseases volume 18 , Article number: 119 ( 2023 ) Cite this article
The purpose of this study was to explore the literature on fatigue in patients with syndromic heritable thoracic aortic disease (sHTAD), including Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), vascular Ehlers Danlos syndrome (vEDS) and other sHTADs, critically appraise and synthesize the relevant literature. We also aimed to investigate how adults with sHTAD experience and perceive fatigue, and to discuss clinical implications and direction for further research.
First, a systematic review was performed by searching the published literature in all relevant databases and other sources until 20th October 2022. Second, a qualitative focus group interview study was conducted of 36 adults with sHTADs (LDS n = 11, MFS n = 14, vEDS n = 11).
In the systematic review, 33 articles satisfied the eligibility criteria (3 reviews and 30 primary studies). Of the primary studies: 25 dealt with adults (MFS n = 17, MFS/EDS n = 1, EDS n = 2, LDS/vEDS n = 3, different sHTADs n = 2), 5 with children (MFS n = 4, different sHTADs n = 1). Twenty-two were cross-sectional quantitative studies, 4 prospective and 4 qualitative studies. The quality of the included studies was mostly good, but many had small sample sizes, low response rates and/or participants without verified diagnosis. Despite these limitations, studies indicated high prevalence of fatigue (ranging from 37 to 89%), and fatigue was associated with both health and psychosocial aspects. Few studies found that fatigue was associated with disease-related symptoms. In the qualitative focus groups most of the participants reported that they had experienced fatigue which influenced several aspects of life. Four themes related to fatigue were elucidated: (1) different diagnoses–different fatigue?, (2) the nature of fatigue, (3) searches for causes of fatigue, (4) dealing with fatigue in daily life. The four themes seemed mutually interrelated in terms of barriers, strategies and facilitators for dealing with fatigue. The participants experienced fatigue as a consistent dilemma between self-assertion and inadequacy. Fatigue seems to influence several aspects of daily life and may be one of the most debilitating symptoms of having a sHTAD.
Fatigue seems to negatively impact the lives of people with sHTADs and should be recognized as an important aspect in the lifelong follow-up of these patients. The life-threatening complications of sHTADs may result in emotional stress, including fatigue and the risk of developing a sedentary lifestyle. Research and clinical initiatives should consider rehabilitation interventions aiming at postponing the onset or reducing symptoms of fatigue.
- Heritable thoracic aortic disease
Heritable thoracic aortic disease (HTAD) is a term that defines a large group of disorder characterized by the occurrence of aortic events, mainly represented by aneurysm or dissection [ 1 ]. HTAD can be classified as non-syndromic if the disorder is limited to the aorta, and syndromic when associated to extra aortic features [ 1 , 2 , 3 ]. Genetic testing is essential since it allows confirmation of the etiological diagnoses for HTAD. An extensive list of human genes and other clinical features associated with HTADs is mentioned in several papers [ 4 , 5 , 6 ]. Renard et al. [ 6 ] found that approximately 53 candidate genes were associated with HTADs, but only 11 genes ( COL3A1, FBN1, SMAD3, TGFB2, TGFBR1, TGFBR2, ACTA2, MYH11 , MYLK, LOX and PRKG1 ) were identified as “HTAD” genes as they were assessed as having a “definitive” and “strong” gene-disease association during the curation process [ 6 ]. Mutations in the five last genes described above are known as non-syndromic HTAD (nsHTAD), as they are associated with vascular manifestation alone [ 2 , 6 , 7 ]. Mutations in the six first genes are known to cause syndromic HTAD (sHTAD), with systemic manifestations and genetic phenotype, including cardiovascular, musculoskeletal, craniofacial and ocular systems, and cutaneous features [ 4 , 5 ]. The most common diseases of sHTAD are Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS) and vascular Ehlers-Danlos syndrome (vEDS) [ 2 , 4 , 7 ]. The focus of the present study is sHTAD.
The most serious complications in sHTADs are related to the risk of aneurysm and dissection of aorta and other large arteries [ 2 ]. Life-threatening complications can require emergency intervention, with increased risk of morbidity and mortality [ 2 , 8 ]. Because of the risk of aortic dissection, many patients are advised to refrain from contact sport, to limit their physical exertion and to control their blood pressure strictly [ 9 , 10 ]. Unfortunately, they often follow by a sedentary lifestyle [ 10 , 11 , 12 , 13 ]. Many have skeletal signs with hypermobile joints, chest deformities and scoliosis [ 4 , 5 , 6 ]. Physical impairment, chronic pain and fatigue associated with sHTADs may be exacerbated by the fact that most sHTADs have no effective treatment or cure [ 2 , 4 , 14 ]. Living with a sHTAD may be vastly more complex than just its medical features [ 15 , 16 , 17 , 18 ]. Many aspects of an individual`s life may be affected such as family life, education, work-life and leisure activities [ 13 , 19 , 20 ].
Rationale for the study in the context of what is already known
In recent years, fatigue has increasingly been studied in genetic conditions, and recognized as an important clinical factor affecting several aspects of patients’ lives [ 21 ]. Through our work in a resource center for rare diseases, we frequently encounter patients who report fatigue as a serious problem. Many patients also experience lack of understanding and support from professionals regarding their fatigue. There is a risk that health professionals do not pay attention to fatigue because it is overshadowed by other more potential life-threatening aspects of the disease. Often, medical causes of fatigue may be ignored [ 21 ].
A challenge is that fatigue is a complex phenomenon lacking a clear definition. Many studies fail to explain their definition of fatigue [ 21 , 22 ]. Authors often do not explicitly define fatigue, but rather imply its meaning by the concept associated with the instrument used for measuring fatigue. Other terms used in the literature for fatigue included “tiredness”, “exhaustion” or “lack of vitality” [ 23 ]. A common definition of fatigue is “an overwhelming sense of tiredness, lack of energy and feeling of exhaustion, mental, physical or both” [ 24 ]. Other attempts to classify fatigue according to the affected domains are (motor versus cognitive) or the presumptive origin (central versus peripheral) [ 25 ]. Penner et al. [ 25 ] have proposed a unifying taxonomy that discriminates between fatigue (in sense of self-perception) and performance (fatigability). Self-perceived fatigue can be quantified by scales that cover physical, psychosocial and/or cognitive aspects, whereas fatigability can be quantified by measuring the decline in performance of given tasks (such as motor fatigability and decline reaction time, often measured in laboratories) [ 22 , 25 ]. In this study, the focus is on self-perceived fatigue.
There is a wealth of distinct and often discrepant scales that have been designed to measure both generic and disease-specific fatigue [ 21 , 23 ]. To the best of our knowledge, no disease specific scales have been developed to measure self-perceived fatigue in persons with sHTADs. Brown et al. [ 26 ], Penner et al. [ 25 ] and McCabe et al. [ 27 ] have described vitality as the opposite of fatigue, with a low degree of vitality indicating severe fatigue. The RAND version of SF-36 Health Survey [ 28 ] is a health related quality of life measure where the subscale of vitality is defined as a scale for measuring general energy, lack of vitality, i.e. similar to fatigue [ 26 , 27 , 29 ] 36-Item Short Form Survey (SF-36) Scoring Instructions | RAND. Vitality is found to strongly correlate with different validated measures of fatigue [ 26 , 27 ]. Vitality can also be used to assess a general level of fatigue in the preceding 4 weeks [ 29 ]. Overman et al. [ 29 ] indicate that the scores of 35 and lower of the SF-36 vitality score (0–100) indicate severe fatigue. We therefore included studies with outcomes on SF-36 vitality (SF-36vt) in the review part of this study.
In chronic diseases, fatigue may have multiple contributing factors e.g. sleep disorders, pain, reduced physical activity, depression and pharmacotherapy [ 25 , 30 ]. As complex disorders, there are numerous factors in sHTADs that could interfere with physical, psychological and social function [ 31 ]. It is hypothesized that a number of factors may cause fatigue in patients with sHTADs such as physical (cardiovascular and respirators factors, working capacity, use of beta-blockers, reduced visual acuity and joint hypermobility), and mental/psychological comorbidity (cognitive dysfunction and psychological distress) [ 13 , 16 , 17 , 19 , 20 , 31 , 32 ]. The research on prevalence, associations, patient experiences and impact of fatigue in sHTADs appears to be fragmented and not well known. We therefore decided to undertake an overview of the literature and combine it with a qualitative study of the patients’ perceptions and coping strategies regarding self-perceived fatigue. We did this in the hope of developing a more evidence-based clinical practice.
The aims of the study
To identify, critically appraise and synthesize available research about self-perceived fatigue in sHTADs.
To investigate the experiences and perceptions of fatigue in adults with different sHTADs.
To investigate key concepts of fatigue, identify knowledge gaps, and discuss clinical implications and direction for further research on fatigue in sHTADs.
Methods and materials
- Systematic review
Owing to the limited number of studies on fatigue in sHTADs, all studies stating that at least one aim was to study fatigue in sHTADs were included in the review. The review was conducted according to the recommendation for systematic reviews [ 33 , 34 ], and PRISMA checklist for systematic reviews [ 35 ] (Additional file 1 ). Each study was examined independently [ 33 , 34 , 36 ]. Standardized specific criteria were used to critically appraise the different types of studies [ 37 , 38 , 39 ]. In the evaluation of knowledge on fatigue, only the fatigue part of the studies was addressed. The review protocol is included in Additional file 2 .
Systematic searches were conducted on relevant literature until October 2022, in PubMed, CINAHL, Embase, Ovid, MEDLINE, the Cochrane and Google Scholar. First, we conducted a search of terms related to HTAD, resulting in 15,872 hits. Then, we conducted a search of terms related to fatigue, resulting in 9547 hits. Third, we combined the two searches, resulting in 845 hits after duplications were omitted. We also examined the citations in the papers that were obtained, and conducted searches in Open grey literature (OpenGrey, PsycEXTRA and Home—ClinicalTrials.gov), resulting in 22 papers. Experts with clinical experiences and scientific publications on pain, fatigue or other relevant aspects of sHTADs were asked, but no additional papers were found. The search terms and search strategy is described in Table 1 .
Eligibility criteria: Articles were considered for inclusion if they investigated fatigue in sHTADs. The eligibility criteria were developed based on preliminary review of a random subset of relevant fatigue studies, a scoping review of fatigue in rare diseases [ 21 ], as well as theoretical literature about the concept of fatigue. The three basic inclusion criteria were as follows: (i) all individuals affected by a specific sHTAD as defined in the search criteria. Studies with mixed population including sHTADs that did not report subgroup analysis were excluded; (ii) all types of studies, peer-reviewed articles presenting own results, published in English, French, German, Norwegian, Danish or Swedish language; and (iii) where the aim and outcome of the studies “included examining self-perceived fatigue or vitality, and/or predicting variables or factors associated with fatigue/vitality in sHTADs” as a primary or secondary outcome.
No exclusions were made on the basis of age, gender or ethnicity. Unpublished data or case-report, conference abstract, posters, letter to editors, expert opinions, guideline, unpublished data and study protocols and studies with less than six participants were excluded.
Selection of publications
Two researchers (GV/HJ) independently reviewed the abstracts and/or articles from each publications that was identified through the search strategy described above. When considered potentially eligible, the full text of these studies was obtained and reviewed by the same two researchers against the eligibility criteria to determine their eligibility. A third (TB) and fourth researcher (AMG) verified the articles inclusion or exclusion in accordance with the final eligibility criteria.
Handling data, critical appraisal and data extraction
All included articles were screened and categorized independently by three researchers (GV, HJ, TB) on the basis of the content of the article [ 36 , 39 , 40 ]. Discrepancy and disagreement were discussed and resolved by involving a fourth researcher (AØG). The studies were first categorized according to which sHTADs the study dealt with. Specific validated criteria were used for critical appraisal of quantitative [ 39 ], qualitative [ 41 ] and review [ 42 ] articles. Seven criteria were used to evaluate the quantitative studies: (i) sample size (ii) sample representativeness (iii) control group (iv) the validity of the measurement (v) drop-out/missing data (vi) blindness and (vii) credibility assessment [ 39 ]. No controlled trials or randomized controlled trials (RCT) were found; therefore, the criterion about blindness was omitted. Six validated criteria were used for assessing the qualitative studies [ 41 ] and seven criteria for assessing reviews [ 42 ]. In addition to the validated criteria (questions) for critical appraisement of the different types of studies, we added two criteria (questions): To which degree the papers discussed the limitations of the study and the extent of contribution on new results about fatigue/vitality in sHTADs. Because of the complicated process leading to the diagnosis of sHTADs, we also collected information from the included articles about their use of diagnostic criteria and/or genetic testing to identify their study population. The quality assessment criteria for quantitative, qualitative and review studies and the justifications for the assessment of each article are reported in Additional file 3 .
The studies were too heterogeneous to perform statistical pooling and meta-analyses. Therefore we performed a narrative synthesis of the findings, taking into account methodological quality and analytic rigor in the examination of the reported findings [ 42 , 43 ].
A mixed method thematic analysis was conducted to structure and depict all variables involved in the reviewed studies [ 44 ]. All included articles were screened and categorized independently by two researchers (GV/HJ) on the basis of the of the content in the articles. Discrepancy and disagreement were discussed by involving a third (TB) or a fourth (AØG) researcher. Information was extracted on study population, diagnoses, recruitment sources, study designs, methodology, fatigue measurements and other validated instruments, key predictor variables, main results and authors’ conclusions. Each study was categorized according to whether fatigue/vitality was the primary (major) or secondary outcome. Using a matrix [ 44 , 45 ] the key features were summarized and synthesized. The relationship between variables and between different levels and groups of variables (main-/sub-variables) were indicated. A mixed-methods approach [ 44 ] was used to integrate the conclusions from the qualitative and quantitative strands (comparing, contrasting building on or embedding with the other) in order of to provide a fuller understanding of fatigue in sHTADs. Finally, the results of the articles were synthesized and summarized in three different main themes (i) the prevalence of fatigue in sHTADs (ii) the associations/predictors of fatigue and (iii) fatigue in children and adolescents with sHTADs.
Qualitative focus group interviews
The qualitative focus group study has been approved by the Regional Committee for Medical Research Ethics (Health Region South-East) (2017/745). The study was conducted according to the COREQ-checklist for qualitative research [ 46 ]. We have previously published an article with comprehensive description of methodology of the focus group interviews [ 12 ], therefore only a brief summary about the methodology is presented in this paper.
Study design and informants
Patients with a confirmed diagnosis MFS, LDS and vEDS, registered at TRS National Resource Center for Rare Diseases in Norway were eligible and were invited to participate between October 2017 and April 2018. A combination of convenience and purposive selection method was used. The intention was to include approximately 36 patients, as this was considered appropriate to capture unique variation and saturation of the data.
Strategies for ensuring trustworthiness and credibility
Three researchers (GV, HJ, TB) ensured trustworthiness and credibility throughout the data collection and analysis process [ 46 , 47 ]. The study reporting adheres to the consolidating criteria for reporting qualitative research [ 46 ], and the Standards for Reporting Qualitative Research [ 47 ].
Procedures and analyses
A semi-structured interview-guide was developed as a framework for the focus group interviews. The interviews lasted for an average of 110 min (range 90–120 min) and were audiotaped and transcribed verbatim by two researchers (GV/HJ). An Inductive Systematic Text Analysis (ISTA) was conducted [ 48 , 49 ]. To ensure the robustness of the study we followed the principles of Malterud [ 48 , 49 ] of six step-by-step analysis (Additional file 4 ), based on the four criteria of credibility, dependability, confirmability and transferability [ 47 , 49 , 50 ]. Two researchers (GV/HJ) independently conducted the preliminary analysis and compared preliminary results. To assess the interpretative rigour of the analysis, we assessed inter-coder agreement to control the coding accuracy and monitor inter-coder reliability. Differences were discussed in an iterative process until consensus was reached among the research team (GV, HJ, TB, AØG).
Systematic review results
The search strategy is presented in the flow chart in Fig. 1 . A total of 867 articles were identified, 251 were read full text, of these 33 articles satisfied the eligibility criteria and were included in this review. There were 30 primary and three secondary (review) studies.
Flowchart of search, screening and inclusion process of the systematic review
Included secondary studies: review articles
Three review articles fulfilled our inclusion criteria [ 19 , 20 , 51 ], but in no reviews the primary outcome was fatigue. Two review articles dealt with psychosocial aspects of MFS. One [ 20 ] included 11 articles dealing with fatigue, and the other [ 19 ] four articles. The last review article [ 51 ], addressing quality of life (QoL) in people with HTADs, included five articles of fatigue. All three review articles indicated that fatigue appears to be prevalent in patients with sHTADs, but none reported the estimated prevalence of fatigue of included studies. Nevertheless, all reported that fatigue in patients with MFS seems to have a huge impact on their QoL and daily life.
Included primary studies: fatigue in sHTADs
Of the 30 primary studies dealing with fatigue in different sHTADs, 25 dealt with adults while five with children/adolescents. Twenty-one articles on patients with MFS (17 on adults and 4 on children), one article on MFS and EDS, two on EDS, three on vEDS/LDS, and three on different sHTADs (two on adults/one on children). One third (n = 10) of the studies [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ] did not describe if they included patients with verified diagnoses. The diagnoses were either self-reported or the confirmation of diagnoses was not reported in the study. The rest of the studies either included patients diagnosed according to the Ghent Nosology for MFS, or genetic verified diagnoses for LDS, vEDS and the other sHTADs. Eighty-three percent of the articles were published from 2010 to October 2022, with 70% published from 2015 onward. Twenty-three articles (77%) were from Europe, six (20%) from USA, and one (3%) from Korea (Table 2 ).
Methodological appraisal of primary studies
Study design and level of focus on fatigue: Of the 30 primary articles 22 studies were cross-sectional quantitative questionnaire studies [ 11 , 13 , 16 , 17 , 31 , 32 , 52 , 53 , 54 , 56 , 57 , 58 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. Four were prospective: one pilot rehabilitation intervention study [ 71 ], two experimental studies [ 55 , 72 ] and one longitudinal study [ 73 ]. Four studies were qualitative and used different methods: individual interviews [ 74 ], focus groups [ 12 ], document analyses [ 59 ] and combining individual interviews with focus groups [ 60 ]. Three of the qualitative studies dealt with children/adolescents [ 59 , 60 , 74 ]. No randomized controlled studies were identified.
In only eight [ 16 , 17 , 31 , 32 , 55 , 57 , 61 , 68 ] of the 30 articles the primary outcome was to investigate fatigue. All these were cross-sectional quantitative studies. Four were on MFS, two on EDS, one on vEDS/LDS, and one on children with different sHTADs (MFS, vEDS) (Table 3 ).
Recruitment and sample sizes: In most papers [ 11 , 12 , 13 , 16 , 17 , 31 , 32 , 52 , 55 , 58 , 60 , 61 , 62 , 63 , 65 , 66 , 67 , 68 , 69 , 70 , 72 , 73 , 74 ] the participants were recruited from the clinic where the researchers worked, and in some [ 54 , 56 , 57 , 59 , 64 ] from the patient organization, or from both [ 53 , 71 ]. Approximately, a total of 2,479 adults were included in the articles, with a variation of 16 [ 31 ] to 318 [ 54 ] respondents (mean 94/median 64), and in most studies the response rate was low. Four studies had more than 200 participants [ 54 , 57 , 63 , 64 ], but the sample size of these studies probably represents a small percentage of the estimated national patient populations. In the largest study [ 54 ], the diagnosis was self-reported and the link to the survey was sent to 13,280 persons, of whom 318 completed the survey, indicating a response rate of 2% of the study population.
Instruments for assessing fatigue and vitality
Ten studies [ 11 , 16 , 17 , 31 , 63 , 66 , 67 , 69 , 71 , 72 ] used Fatigue Severity Scale (FSS) two [ 55 , 68 ] used Multidimensional Fatigue Inventory (MFI-20), two [ 32 , 57 ] used Checklist Individual Strength (CIS), one [ 31 ] Fatigue Questionnaire and one [ 54 ] Quality of Life index. Eleven studies [ 13 , 56 , 57 , 58 , 62 , 63 , 64 , 65 , 68 , 71 , 73 ] used SF-36 and one [ 52 ] used SF-12. Two studies [ 53 , 64 ] used study specific questions to measure fatigue. Some studies [ 31 , 57 , 63 , 64 , 68 , 71 ] combined two measurements. In studies of children, one study [ 70 ] used Patient Reported Outcomes Measurement Information System (PROMIS) and the other [ 61 ] Fatigue 10a Paediatric v20 short form. Table 4 shows an overview of the instruments used in the studies measuring fatigue and vitality.
Control groups: Four papers [ 32 , 57 , 58 , 61 ] compared the results of fatigue with normative data and subgroups, three [ 7 , 56 , 65 ] with healthy controls matched for age and gender, three [ 13 , 16 , 17 ] with normative data and other diseases, six [ 31 , 52 , 53 , 64 , 68 , 70 ] only with normative data. Two prospective studies [ 71 , 73 ] included pre-/post results and normative data. Seven studies [ 11 , 16 , 54 , 62 , 63 , 66 , 67 ] did not describe any comparison group. There were large variations in the use of control groups and comparison to the general population and to other patient groups. None of the qualitative studies compared the results with normative data or other groups.
Limitations and credibility: Most studies (83%) had thoroughly described factors (confounders) that may negatively impact the credibility of the study, while three studies [ 13 , 31 , 62 ] had very limited description and two studies [ 64 , 66 ] had no description of limitations. Omitting information about the study`s potential limitations may decrease the credibility of the study. The lack of credibility was also assessed related to other factors such as lack of verified diagnoses, small samples, limited transparency of the selection, methodology and analyzing process, the use of advanced statistical analyses in small sample sizes, no assessment of the validity and reliability of the measurements, low response rate and no drop-out or no non-response analyses. In addition, in qualitative studies, taking the role of the researcher into account and discussion on how researchers’ preconceptions may influence the results are important strategies for ensure trustworthiness and credibility of the study. (More detailed information about the assessments and justifications are available in Additional file 3 ).
Despite the included studies on fatigue in sHTADs being of limited in size, the overall quality of the methodology ranged from very good to fair, with most studies being rated as good. The credibility of a study combined with its results were used to decide how each study was assessed in contributing new knowledge about fatigue in sHTADs.
Synthesize and summary of results from included articles
Prevalence of fatigue and decreased vitality in adults with sHTADs: Several studies [ 13 , 16 , 17 , 32 , 53 , 55 , 57 , 58 , 62 , 64 , 72 , 73 ] presented increased fatigue (or decreased vitality) in adults with sHTADs compared to the general population, but the variation on prevalence of severe fatigue varied from 37% [ 32 ] to 88.5% [ 53 ] in MFS. Prevalence of severe fatigue in LDS was 58% [ 11 , 16 , 69 ] and 42% in vEDS [ 11 , 16 , 69 ], but these results were reported from the same study cohort. Comparing prevalence values was hampered by the fact that different instruments and cut of values were used for severe fatigue. Figure 2 shows the mean score of the different studies reported outcome on Fatigue Severity Scale (FSS). Four studies were not included in Fig. 2 because they reported results from the same study cohort as two studies illustrated in the figure. Higher fatigue scores signify more fatigue.
Mean Fatigue Severity Scale score in different sHTAADs
Prevalence of fatigue/reduced vitality was not reported in studies using SF-36. Figure 3 illustrate the mean score ( + 1SD) of the included studies reporting SF-36vt mean (SD). Very few studies indicated severe fatigue in adults with sHTADs according to SF-36vt scores of 35 and below [ 29 ], but results varied.
Mean SF-36 vitality score in the different sHTAADs
Some studies also compared their results to other diseases. Bathen et al. [ 17 ] found that adults with MFS had higher prevalence of fatigue than patients with rheumatoid arthritis, but lower than for other chronic conditions. Rand-Hendriksen et al. [ 13 ] found that the MFS study cohort scored lower of SF-36vt scores than all included comparison groups (hypertrophic cardiomyopathy, cystic fibrosis, Bechet’s syndrome). Rand-Hendriksen et al. [ 13 ] indicated that the low vitality score may reflect the common complaint of fatigue and reduced physical endurance among persons with MFS.
Associated factors to fatigue in adults with sHTADs: Many articles reported variables associated with fatigue and/or vitality. Fatigue was found to be positively associated with pain [ 16 , 17 , 32 , 57 ], disability [ 31 , 57 , 61 , 72 ], cardiovascular problems and multiorgan burden [ 16 ], sleeping problems or hyper somnolence [ 16 , 56 , 68 ], orthostatic intolerance [ 55 ], and psychological factors [ 16 , 31 , 32 ]. One study [ 53 ] indicated positive associations between fatigue and use of beta-blockers, while three other studies [ 17 , 31 , 55 ] found no such significant associations. One study [ 32 ] found that patients using losartan had less fatigue compared to those not using losartan. Factors associated with fatigue in sHTADs appear to be somewhat inconsistent, particularly about the association between medication and fatigue.
Fatigue was also found negatively associated to physical activity [ 11 ], work participation [ 17 , 64 , 66 , 67 , 69 ] and quality of life [ 54 , 63 , 65 , 67 , 69 , 71 ], and positively associated to being female [ 31 , 32 , 58 ]. Only one qualitative study [ 12 ] was identified reporting some results on fatigue in adults with sHTADs. This study mainly focused on physical activity, but described that adults experienced it difficult to cope with fatigue in daily life. Fatigue and less physical activity seem to have a mutually reinforcing negative effect [ 12 ].
Several studies also reported other aspects of fatigue. Rao et al. [ 64 ] noted that fatigue was ranked as the third highest disease concern, while cardiac and spine problems were ranked first and second. This study also emphasized that MFS patients experienced specific difficulties in executive functions such as mental fatigue, leading to diminishing QoL. Severe fatigue seems to significantly heighten the perception of their condition`s severity, and experienced psychological distress may also increase fatigue [ 31 , 32 , 53 , 54 ]. Interestingly, one pilot experimental intervention study [ 71 ] measured pre- and post-intervention fatigue and found that a three-week rehabilitation program significantly decreased the extent of fatigue in patients with MFS and LDS one year post-intervention. Several studies expressed the need for a specialized in-hospital rehabilitation program to deal with fatigue and other symptoms related to the disease.
Fatigue in children with sHTADs: The study samples of the five articles dealing with children and adolescents varied from 19 (74) to 147 (59) participants. Approximately, a total of 342 children and adolescents were included.
The results from the five studies [ 59 , 60 , 61 , 70 , 74 ] on children and adolescents with sHTADs are not consistent about the prevalence and extent of fatigue. One study [ 71 ] found that 44% of children with MFS reported fatigue sometimes or often. Another [ 61 ] found that children with MFS had less fatigue compared to the age matched norm data, and significantly lower prevalence of fatigue than children with hypermobile EDS. In the study [ 59 ] of adolescents with MFS on social media, fatigue was seldom not mentioned as a problem when discussing problems related to the diagnosis. Few studies had examined factors that are associated with fatigue in children with sHTADs, but one study [ 61 ] found that fatigue was significantly associated to disability and pain. Two qualitative studies [ 60 , 74 ] reported that children and adolescents with MFS experience fatigue that limits school participation in sport and other activities. Children also described difficulties keeping up with their peers, feeling being different and therefore avoid social activities. This indicates that fatigue seems to be prevalent in children with sHTADs. However, the results were not consistent and more research is warranted.
Results from the qualitative focus group interviews
A total of 36 individuals with sHTADs (14 with MFS, 11 with vEDS and 11 with LDS) participated in the focus group interviews. The participants represented a variety of diagnoses, gender, age, education and social backgrounds. The characteristics of the participants is shown in Table 5 .
Themes and categories
Four main themes emerged from the analyses: (1) Different diagnosis–different fatigue ? (2) Nature of fatigue (3) Searching for causes of fatigue (4) Dealing with fatigue in daily life . Overall fatigue was described as an overwhelming phenomenon, with an unpredictable character, and a feeling that fatigue dominated and controlled most life-situations. This is illustrated by the following quote:
“I really don’t know what to do, I never know and have no control, so for me fatigue is dominating my life” (an elderly woman with LDS).
Different diagnosis—different experiences of fatigue?
The focus groups were divided according to the diagnostic groups (2 groups with MFS, 2 groups with LDS and 2 groups with vEDS). No distinct differences emerged between the participants in the different disease groups on how they experienced and describes fatigue. They described that fatigue can be difficult to describe and explain, and many had rarely talked about it seriously before. Therefore, they emphasized that data collection with focus groups seemed to be constructive since it gave them opportunity to recall and confirm aspects with peers and share experiences. Most participants in all six focus groups reported that they experienced periodic or permanent fatigue, and there were no differences between the diseases. Despite the fact that having a sHTADs may be life threatening, many described fatigue as one of the most debilitating symptoms of the diagnosis. The following quote cover this on an overall level:
“I barely notice the severe symptoms of this diagnosis and sometimes I just forget it. But I get so tired of always being tired” (young man with vEDS).
Nature of fatigue—how do they experience fatigue?
Many of the participants experienced that fatigue was a combination of a bodily sensation and a foggy feeling. They described an overwhelming feeling of tiredness, and that parts of their body was heavy or paralyzed. Some described that their legs felt like lead, and they had trouble with moving. A misty feeling was described as having a glass bowl around their head, including brain fog. They felt it hard to concentrate, speak, listen or sort out impressions. Many described that it interfered with concentration at work and social interaction. The character of fatigue was also described as unpredictable, controlling their life, and being impossible to resist and combat.
“Yes, it’s weird, because I’m so incredibly tired. I can’t leave my bed, because my legs will not move, and my brain feels so foggy and I can’t think and talk right. This is not me… and I don’t know why” (woman with MFS).
Searching for causes of fatigue
Many expressed frustrations of neither knowing the cause of fatigue nor how to deal with an inexplicable exhaustion. Searching for biomedical and other reasonable reasons of fatigue was common. Some claimed that being hypermobile requires more body energy for stabilization of joint and muscles. Medication and use of blood pressure medicine was also mentioned as a possible explanation for fatigue. Others described how chronic pain and constant worrying about the life-threatening aspects of the condition for both them and family members made them exhausted. Many also described that being physically active and doing exercise was challenging, but despite that, exercise was emphasized as important in counteracting fatigue. Some mentioned also that physical activity was associated with anxiety and insecurity, due to the difficulties of finding the right balance between healthy and unhealthy activities. Avoiding physical activity was therefore a coping strategy for some, resulting in a negative spiral of inactivity, more fatigue and a sedentary life.
“I wish I had known the reason for my fatigue, it had been much easier to know what to do and combat it” (young man with LDS).
Another aspect many of the participants described as challenging was the suspicion and lack of understanding from other people about the phenomenon fatigue. When participants tried to convey the gravity of their experiences to others, they were not always understood. Participants described this as exhausting and it increased their uncertainty about the fatigue symptoms. This, in turn led to feeling of guilt, inadequacy and an inner struggle of their desires and what they could achieve.
“It is so invisible and common, everyone is exhausted sometimes… so people might understand in their own way… but they really don’t understand the reality of having “real fatigue” (middle aged woman with MFS).
Dealing with fatigue in daily life
Most of the participants described that fatigue impacted different aspects of daily life, such as family life, employment, and social life. Some emphasized that they had learned to cope with fatigue by energy economizing and prioritizing between different aspects of life. They realized that fatigue was not dangerous, but only frustrating and debilitating, and some tried to accept it as part of their illness. Others described that avoiding important life events because of exhaustion, was part of their daily choices. Difficulty of dealing with fatigue in the work situation was emphasized as a common challenge. With an overwhelming feeling of tiredness, it was impossible to fulfill their obligations as employees. For some, early retirement was the only solution. Others described attempts to strive to maintain full employment and trying to keep up the pace in what they perceived as a “normal life”. They used all their energy at work, which affected both family life and leisure activities. For some the long-term effect of keeping up the pace was increased fatigue because they were not able to rest enough. Others had found strategies for dealing with fatigue in the work life, particularly those who had informed their employer about their condition. More flexible work conditions and agreements with their employers, made it possible to maintain work ability, despite fatigue.
“For me, work is of invaluable value, I appreciate it so much, it gives me energy but it can also drain me of energy, so it is important to be aware and pay attention. Fatigue is so difficult to handle” (middle-aged man with MFS).
Systematic review of relevant research of fatigue in patient with sHTADs
Aim one was to identify, critically appraise and synthesize the research of self-perceived fatigue in sHTADs. We identified 33 articles dealing with fatigue in sHTADs, 3 reviews and 30 primary articles, but in only 8 articles, the primary outcome was to investigate fatigue. The results indicate that the amount and extent of studies on fatigue in sHTADs is very limited. Most articles included patients with MFS, presumably because MFS is more common and better known than the other diagnoses. The prevalence of these diseases worldwide is highly uncertain. Prevalence of MFS is estimated to be 10 per 100,000 [ 75 , 76 ], and prevalence of vEDS is estimated to be 0.5–2 per 100,000 [ 77 ], while prevalence of LDS is unknown but probably much lower than for MFS [ 78 ]. The prevalence of the other sHTADs is even lower [ 5 , 6 ]. Over the past two decades, there has been exponential increase in genetic research on pathogenic variants explaining sHTADs [ 1 , 5 , 6 ]. The increased focus on diagnostics, survival and treatment may have deflected clinical attention away from patient`s less dangerous symptoms, such as fatigue. LDS is a relatively new diagnosis, and first described in 2005 [ 4 , 79 ]. Most studies of LDS concern medical aspects related to the diagnoses. Because most of the symptoms of MFS are overlapping with symptoms of LDS, vEDS and other sHTADs [ 4 , 5 , 6 ], it seems likely that fatigue impacts these patient groups similarly, although the pathophysiological mechanisms of fatigue may be different.
Critical appraisal of included articles
Most studies used quantitative cross-sectional questionnaire design, besides four prospective and four qualitative studies. The identified articles and results consistently were based on small sample sizes and/or low response rates. The respondents were mainly recruited from the clinic where the researchers worked or from patient organizations. These recruitment strategies yield a risk of bias for recruiting motivated persons with particular medical problems. Thus, the findings may be different from the non-respondents and therefore represent a bias related to the total population. Nearly all the patient populations lived in Western developed countries; Europe and USA or Korea. As cross-cultural differences of fatigue have been found in several studies [ 80 ], more research from other countries and cultures is warranted.
Nearly all quantitative questionnaire studies (cross-sectional and prospective) used standardized instruments with generic scale design, besides two papers using study specific questions about “fatigue being present or absent”. The use of standardized instruments can provide quantitative indication of fatigue level, but incompletely reported results, use of different instrument and use of different cut of values for severe fatigue made meta-analyses or statistical pooling difficult. Such meta-analyses could have been useful for clinical practice. The huge variations in prevalence of fatigue and vitality score within and between the different sHTADs may reflect differences in study design, recruitment routines, methodology, and national differences in cultures and perceptions. The representativeness and generalizability of the results may be questioned; however, a strength was that the methodology of included studies was commonly rated as good, and that most emphasized and discussed limitations of their study. This in turn, increased the credibility of the studies.
Synthesis of the literature
The prevalence of fatigue: The results from the reviewed papers are equivalent when indicating that adults with MFS have vastly higher prevalence of fatigue than the general population; and it is likely that individuals with sHTADs may experience a significant impact of fatigue on daily life. This is in accordance with reports of fatigue in other severe conditions such as systemic sclerosis [ 81 ], multiple sclerosis [ 82 ], and cancer [ 83 ].
Fatigue seems to be complex and can occur as primary or secondary symptom, as well as a comorbidity of an underlying disease [ 31 , 68 , 78 ]. Disentangling the origin and nature of fatigue in patients with sHTADs may be challenging. Several studies [ 13 , 16 , 31 , 53 , 55 , 56 ] hypothesized that the biomedical aspects of sHTADs such as cardiovascular and respiratory factors, reduced visual acuity and joint hypermobility may impact fatigue, but only a few studies found such associations.
Fatigue has also been described as a well-recognized side-effect of blood pressure medicine [ 84 ], but the results from the included articles were contradictory. Only one [ 53 ] study found that medication was associated with more fatigue, while three studies found no such associations in patients with sHTADs. Interestingly the study of van Andel et al. [ 32 ] found that the use of losartan was associated with decreased fatigue. The effect of losartan on fatigue may be an under-researched aspect in these patient groups, and the limited and conflicting literature reveals that more research is needed. Our results also indicate that clinicians should be aware that fatigue may be exacerbated by the use of medication, and should enquire about the effects of medication on fatigue when assessing and prescribing new medications.
Chronic pain was also found to be significantly associated to fatigue in the included articles, similar to reports [ 85 , 86 , 87 ] on others chronic diseases. Pain in patients with sHTADs [ 14 , 15 , 16 , 18 ] may contribute to lower energy level and lower sense of well-being [ 64 ]. One explanation is that chronic pain negatively influences sleep quality, and less sleep can decrease one`s pain threshold and pain tolerance as well as intensify the pain, thus exacerbating sleep problems, and thus increasing fatigue [ 87 , 88 ].
Another aspect that emerged from the included articles was the close connection between physical activity and fatigue. Patients with sHTADs are often recommended physical restrictions because hemodynamic changes and increase in blood pressure are associated with an enhanced risk of aortic growth and acute aortic dissection [ 10 , 88 ]. However, they are also recommended to be physical active. Total absence of physical exercise is deleterious and may lead to muscle wasting, joint stiffness, and problems with social and professional reintegration, depression and fatigue [ 10 , 11 , 12 , 88 ]. Lack of exercise and deconditioning can cause tiredness and exhaustion. Finding the right balance between safe and unhealthy exercise for these patient groups can be a major problem [ 12 ]. Patients may experience anxiety related to physical activity, which in turn may lead to a sedentary lifestyle and more fatigue [ 9 , 11 , 12 , 53 , 89 , 90 ], with these effects probably being negatively mutually reinforcing [ 91 ]. There are promising results that exercise-based cardiac rehabilitation in MFS and LDS can help these patients to decrease fatigue and chronic pain, with increased physical endurance and quality of life [ 71 ]. More clinical research, including more knowledge-based practice and rehabilitation guidelines for patients with sHTADs seems to be needed.
Fatigue in children and adolescents: Research on fatigue in children with sHTADs is very limited and the results varied. In three studies [ 60 , 70 , 74 ], fatigue was reported to create challenges in daily life, while in another [ 61 ] children with MFS reported less fatigue than healthy controls. One study [ 59 ] also indicated that fatigue was nearly not mentioned on social media when young people shared experiences about MFS. Nevertheless, more information about the prevalence, associations and experiences of fatigue in these pediatric groups is needed. Studies of children with other chronic diseases have revealed that fatigue negatively impact QoL [ 92 ], so quantifying fatigue in children with sHTADs may be critical. Understanding the impact of fatigue may be the first step for improving the quality of life for these groups.
Focus group interviews combined with results from the review part
Aim two was to investigate the experiences and perceptions of fatigue in adults with different sHTADs. In the focus group interview, we did not measure the extent of fatigue, but our impression was that nearly all of the participants reported that they experienced fatigue. Participants in the focus group interviews emphasized that fatigue is one of the most debilitating symptoms of having a sHTAD, similar to the results from several of the studies from the review part. Fatigue seems to cause significant levels of distress, and the unpredictability and invisibility of the symptoms were emphasized as particularly challenging. Not being taken seriously and constantly being misunderstood was also highlighted as challenging and negatively affecting their self-esteem and self-understanding. Another challenge was to combine fatigue with the ability to work. Fatigue was reported to be the most prevalent reason for early retirement in the some of the included articles in the review [ 16 , 17 , 19 , 66 , 67 ].
Both in the review part and the focus groups it emerged that the subjective perception of the disease may have substantial impact on how people cope with fatigue [ 53 , 64 ]. The physical severity of sHTADs has been discussed [ 13 , 31 ], and in most papers, severity appears to be mainly associated with the cardiovascular manifestations [ 13 , 53 , 67 ]. The cardiovascular manifestations may be underestimated in both adults and children as long as the individuals experience no subjective complaints. The subjective severity seems to be mainly determined by the disease manifestations that is perceived by the patients or caused physical disability. The differences between physical severity and subjective severity may indicate that the patients perceive the disorder differently from the professionals. This is important for health care professionals to recognize when dealing with fatigue in these patient groups.
Overall, the results from our study indicate that the perception of fatigue is probably not an isolated problem, but rather a combination of factors related directly to the disease and psychological stress factors and indirectly to the lack of psychosocial support and the complex response of having a rare chronic disease. Based on these results, it is difficult to determine how widespread severe fatigue is among adults and children with sHTADs. Studies combining qualitative approaches with quantitative measurements such as FSS, MFI-20, CIS or other validated measurements could provide valuable information on both prevalence, associations and experiences of fatigue in these patient groups.
Clinical implications and direction for further research
The third aim was to investigate key concepts of fatigue, identify knowledge gaps, and discuss clinical implications and direction for further research on fatigue in sHTADs.
The research on fatigue in the different sHTADs is limited, particularly in other sHTADs than MFS. Our results indicate that the concept of fatigue can be described in relation to its physical, cognitive, emotional and social impact. Further research in sHTADs can attempt to examine the concept of fatigue and unifying the taxonomy of discrimination between fatigue in sense of self-perception and performance (fatigability). This may help to clarify the complexity of the phenomenon. The negative consequences of fatigue seems to be consistent across sHTADs, as is the uncertainty concerning its underlying pathophysiological mechanisms. Therefore, more research about pathophysiologic mechanisms in sHTADs and other causes of fatigue are warranted.
Our results also indicate that it is important for health professionals to acknowledge and address the impact of fatigue on patients with sHTADs. The unpredictability of sHTAD related fatigue is dominant and pervasive, and is experienced as a vicious circle. Helping people to be able to understand and accept fatigue may be important to enable patients to manage and live with fatigue. Support from health professionals to manage fatigue and develop strategies to increase physical activity and maintain work is important for these patient groups.
Our review has shown that the use of many different fatigue measures and cut-off values, make comparisons across studies difficult. To overcome these challenges, our proposal is that multiple stakeholders like researchers, health professionals and patient organizations can cooperate to create standardized sets of outcomes relevant for the sHTADs. This will enable agreement on what aspects that are important to measure, how it should be measured and how results should be interpreted. International collaboration project for sHTADs may also be appropriate, including outcome measures for fatigue.
Limitations and strengths
Only literature written in English, German, French and the Nordic languages were included in the systematic review, this might be a limitation. However, no studies written in other languages with English abstract were found. Our choice of search words and our cultural conceptual understanding may have limited our identification of papers and our interpretation of the content from the identified studies. We excluded case reports and studies with less than six participants. A strength may be the use of predefined criteria for critically appraising the literature, blinded by two reviewers and independently selected and categorized the studies, with the supervision of one other.
There are several limitations related to the focus group interviews. The retrospective perspective may imply possibility for recall bias. Our findings may also be limited to the patients with sHTADs who were willing to talk about their experiences and challenges. Another limitation may be how the term fatigue and exhaustion were interpreted by the participants. They may have different understanding of these concepts, but one of our intentions was also to examine the differences in perceptions and experiences about the concept of fatigue. Both the moderators and the co-moderators were experienced clinicians and/or researchers, and they underlined the interest in all types of narratives. In the analysis we carefully tried to identify and exclude repetitive patterns concerning our expectation and pre-understandings, as recommended in the literature [ 48 , 50 ]. To ensure the transparency of the study, anonymized data are available on request to the authors (TRS, National resource Center).
This is the first systematic review and qualitative study of fatigue in sHTADs. Our study indicate that fatigue is an under-recognized and under-researched feature in patients with sHTADs. A total of 33 articles were found, including several types of study designs. The majority dealt with MFS, and very few studies addressed other sHTADs. The studies were limited by small study sizes, low response rates, inadequate description of inclusion criteria and the patients’ diagnoses, and incomplete descriptions of the analyses. Despite these limitations, all studies indicated that the prevalence of severe fatigue in sHTADs is much higher than for the general population. The nature and impact of fatigue seems not to be experienced differently between the patients in the various sHTADs. Both the results from the included articles and the focus groups indicated that fatigue seems to have remarkable negative impact on daily life and quality of life. Fatigue may also be a major reason for early retirement. This suggests that fatigue should be considered as a core symptom and outcome measure in clinical trials and clinical practice for all patients with sHTADs. As most patients with sHTADs will not be cured in their lifetime, identifying causes of fatigue and developing appropriate treatment programs is warranted. Therefore, more research on fatigue in the different sHTADs are crucial.
Availability of data and materials
The dataset supporting the systematic review part of the article is included within the article (and its Additional files). The dataset (transcribed interviews) from the qualitative focus group study is available on reasonable request to the corresponding author.
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We are grateful for the support and inspiration from TRS National Resource Centre for Rare Disorders, the Norwegian Patient Associations (Norwegian Marfan syndrome Association and Norwegian Ehlers-Danlos Association), and special thanks to the study reference group (Kari Anne, Roald and Elin) and all the participants in the focus groups.
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Velvin, G., Johansen, H., Østertun-Geirdal, A. et al. Fatigue in patients with syndromic heritable thoracic aortic disease: a systematic review of the literature and a qualitative study of patients’ experiences and perceptions. Orphanet J Rare Dis 18 , 119 (2023). https://doi.org/10.1186/s13023-023-02709-2
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DOI : https://doi.org/10.1186/s13023-023-02709-2
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Review article, single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with the scn5a and apoa5 gene mutation: a case report and review of the literature.
- 1 Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- 2 Department of Medical Technology, Jinan Vocational College of Nursing, Jinan, Shandong, China
- 3 Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China
We present a 55-year-old man with chest tightness and dyspnoea after activity lasting for 2 months who was diagnosed with single coronary artery (SCA) and presented with dilated cardiomyopathy (DCM) with the c.1858C > T mutation in the SCN5A gene. The computed tomography coronary angiogram (CTCA) showed congenital absence of the right coronary artery (RCA), and the right heart was nourished by the left coronary artery branch with no apparent stenosis. Transthoracic echocardiography (TTE) revealed enlargement of the left heart and cardiomyopathy. Cardiac magnetic resonance imaging (CMR) revealed DCM. Genetic testing showed that the c.1858C > T variant of the SCN5A gene could lead to Brugada syndrome and DCM. SCA is a rare congenital anomaly of the coronary anatomy, and this case reported as SCA accompanied by DCM is even rarer. We present a rare case of a 55-year-old man with DCM with the c.1858C > T (p. Arg620Cys)/c.1008G > A (p.(Pro336=) variant of the SCN5A gene, congenital absence of RCA, and c.990_993delAACA (p. Asp332Valfs*5) variant of the APOA5 gene. To our knowledge, this is the first report of DCM combined with the SCN5A gene mutation in SCA after searching the PubMed, CNKI and Wanfang databases.
Coronary artery abnormalities include abnormal number and origin, while single coronary artery (SCA) is relatively rare, accounting for 0.031% in coronary angiography ( 1 , 2 ) and 0.024%–0.066% in the general population ( 3 , 4 ). It is unclear whether SCA is an isolated congenital heart disease or is associated with other congenital abnormalities. Dilated cardiomyopathy (DCM) is currently defined by the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions (hypertension, valve disease) or coronary artery disease sufficient to cause global systolic impairment ( 5 , 6 ). The causes of DCM are heterogeneous ( 7 ), and we believe this is the result of genetic predisposition interacting with extrinsic or environmental factors ( 8 , 9 ). The SCN5A gene mutation is associated with a range of clinical diseases. Here, we present a rare case of SCA with DCM accompanied by the SCN5A gene mutation.
2. Case presentation
A 55-year-old male was admitted to our hospital because of dyspnoea. That day, he felt dyspnoea after 200 metres of flat walking. Emergency medical services were called, and he was transported to the emergency department at our hospital. On evaluation, the systolic blood pressure was 116/91 mmHg, the pulse was 115 beats per minute, the respiratory rate was 17 breaths per minute, and the oxygen saturation was 100%. An electrocardiogram (ECG) showed sinus bradycardia with T-wave inversions and premature ventricular contractions ( Supplementary Figure S1 ). On arrival, the patient reported paroxysmal dyspnoea. He had multiple similar episodes during the previous 20 days, without fever, cough, vomiting or diarrhoea. The symptoms were usually provoked by physical exertion, mental stress or intense emotion. Evaluations at other hospitals showed chronic bronchitis and emphysema, an enlarged left ventricle and decreased cardiac function, and further treatment was recommended. The patient had no other illnesses. His family history was unremarkable. He was a farmer. He drank alcohol occasionally, and had smoked in the past 30 years, and did not use illicit drugs or herbal preparations. There were no recent exposures to ill persons. Physical examination showed oedema of both lower limbs, while the other limbs were normal. Levels of sodium, chloride, carbon dioxide, D-dimer, magnesium and tests of liver function and renal function were normal. Troponin I and serum NT-proBNP were rising. A 24-h Holter monitor revealed occasional atrial premature beats, frequent multiple ventricular premature beats and ST-T changes. Transthoracic echocardiography (TTE) showed decreased systolic function (LVEF = 29%), an enlarged left ventricle (LVEDD = 60 mm), cardiomyopathy, moderate mitral regurgitation and moderate pulmonary hypertension ( Figure 1 ). There was no family history of cardiovascular disease. Drugs improving microcirculation and cardiac function were administered, and he was then admitted to our ward. Laboratory tests were conducted, and the results are shown in Table 1 .
Figure 1 . Transthoracic echocardiography was routinely examined from left parasternal long-axis view ( A ) and apical four-chamber view ( B ).
Table 1 . Laboratory data.
Based on the above clinical examination, computed tomography coronary angiogram (CTCA) was performed for the patient to rule out atherosclerotic coronary artery disease. To our surprise, the patient had a very rare SCA, a congenital abnormality of the coronary artery system that may provide low perfusion to the entire heart muscle, which causes chest pain, angina or dyspnoea. CTCA showed that a coronary artery from Valsalva's left sinus was divided into the left anterior descending branch (LAD) and the left circumflex branch (LCX). The distal end of the LCX continued its course beyond the crux into the atrioventricular groove, supplying the right atrium and right ventricle with a superdominant LCX without stenosis and a calcium score of zero Agatston units ( Figure 2 ). Because no intervention would be appropriate in the absence of significant coronary artery stenosis in CTCA, we decided not to perform invasive coronary angiography. To identify the cause of heart failure, we performed cardiovascular magnetic resonance (CMR) on the patient. CMR showed reduced left ventricular systolic function (LVEF = 17.2%), left ventricular enlargement (LVEDV = 296.2 ml), thinning of the myocardium and abnormal delayed reinforcement in the basal segment of the ventricular septum, which was consistent with the diagnosis of DCM ( Figure 3 ). Although improved cardiac imaging techniques have made endomyocardial biopsy (EMB) less necessary, it has traditionally been used to confirm the aetiology in some forms of DCM. However, EMB is no longer frequently performed and was not conducted in this case.
Figure 2 . Computed tomography coronary angiogram. ( A ) Course of the LCx on the posterior atrioventricular groove and continuation of its course in the RCA territory along with take-off of the posterior descending artery. ( B ) Absence of take-off of the RCA from the right coronary sinus of Valsalva (yellow arrow) and normal origin of the LMS which bifurcates into the LAD and LCX. LAD, left anterior descending artery; LCX, left circumflex artery; LMS, left main stem artery; RCA, right coronary artery.
Figure 3 . Cardiac magnetic resonance imaging showed DCM. CMR detected dilation of the left ventricle (LVEDV = 296.2 ml), reduction of cardiac systolic function (CO = 3.47l/min, LVEF = 17.2%) and increase of left ventricular mass (LVM = 170.5 g), no signs of storage disease or inflammation. CMR, Cardiac magnetic resonance imaging; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; CO, cardiac output.
We suspected that the mutation of a certain gene caused the patient to have SCA and DCM, therefore, we arranged a clinical gene test of the whole exon. Genetic screening showed the SCN5A ; NM_198056.2:c.1858C > T (p. Arg620Cys) mutation ( 10 – 13 ) and the pathogenicity of this variant has been reported; SCN5A ; NM_ 198056.2:c.1008 g > a [P. (pro336=)] mutation and there is no report on the pathogenicity of this variant. Sanger sequencing result is shown in Figure 4 and NSG data is shown in Supplementary Table S1 . The SCN5A C.1858C > T (P. arg620Cys) mutation may be associated with DCM in this patient. At the same time, APOA5 ; NM_052968.4:c.990_993delAACA (p. Asp332Valfs*5) was mutated in this patient, and its pathogenicity has been reported. According to ACMG Guidelines, this variant is considered a suspected pathogenic variant ( 14 ). The APOA5 gene mutation results in hypertriglyceridemia or hyperlipoproteinemia type 5, which was in line with the diagnosis of hypertriglyceridemia based on the patient's blood test. The relationship between SCA and DCM was not elucidated by genetic testing. There was no previous report on the absence of a RCA with DCM. According to findings of CTCA, TTE, CMR and other test results, we considered that the occurrence of DCM in this patient may not due to the absence of the RCA. Rather, we supposed that a gene mutation may cause the SCA and DCM.
Figure 4 . Sanger sequencing data. ( A ) SCN5A ; NM_198056.2; c.1858C > T; p.Arg620Cys. ( B ) SCN5A ; NM_198056.2; c.1008G > A; p.(Pro336=). ( C ) APOA5 ; NM_052968.4; c.990_993delAACA; p.Asp332Valfs*5. (a) proband (b) the son of proband (c) the daughter of proband.
Therefore, we performed family verification on the two children of the patient. The children of the proband both carried the SCN5A : c.1858C > T(p. Arg620Cys)/c.1008G > A [p.(Pro336=)] variant and APOA5 : c.990_993delAACA (p. Asp332Valfs*5) variant.
This is a rare case of congenital absence of the RCA in a patient with a DCM-related gene mutation and hyperlipidemia. Our patient had tested positive for a gene variant known to cause DCM and had 2 months of chest tightness and dyspnoea after activity along with hyperlipidemia. The son and daughter of the proband also tested positive for the same mutation. We did not perform a full pedigree of the family since other relatives refused to be tested for the relevant mutations.
3.1. Genetic DCM
The prevalence of DCM and of genetically mediated DCM is not fully known because of geographic variations, patient selection and changes in the diagnostic criteria ( 15 – 18 ). The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases presented an update of the existing classification scheme of cardiomyopathies in 2008. They grouped the cardiomyopathies into specific morphological and functional phenotypes, including hypertrophic cardiomyopathies, DCM, arrhythmogenic right ventricular cardiomyopathies (ARVC), restrictive cardiomyopathies and unclassified cardiomyopathies. Each phenotype was then subclassified into genetic and nongenetic forms, but overlaps exist between the two groups ( 6 , 8 ). Meanwhile, studies have shown that 20%–50% of non-ischemia cardiomyopathy patients have a family history ( 19 ). All of these findings suggest that genetic factors play an important role in the pathogenesis of cardiomyopathy.
Familial patterns or genetic causes have been identified in up to 35% of cases of idiopathic DCM ( 20 ). The genetic causes of DCM are diverse. An autosomal dominant trait is the most common, while autosomal recessive, X-linked and mitochondrial inheritance patterns are less common ( 21 ). TTN and LMNA are the main genes associated with the predominant cardiac phenotype, accounting for up to 25% and 5% of all cases of autosomal dominant DCM, respectively ( 22 ). RBM20 and DES are also common in clinical practice ( 23 , 24 ). Other genetic causes of a predominant DCM phenotype include mutations in sarcomere genes, Z-disc protein-encoding genes, genes encoding desmosomal proteins and genes associated with ion channel function ( 10 – 29 ).
The SCN5A gene is associated with ion channel function caused by DCM. With the development of gene detection technology, an increasing number of individual genes have been associated with inheritance in familial DCM cases. Cheng Shen et al. performed a cross-sectional study in Chinese patients with sporadic DCM and suggested that MYBPC3 , SCN5A , MYH7 , MYPN and LDB3 are the major genes hosting the at-risk genomic variants of sporadic DCM ( 30 ).
3.2. SCN5A gene mutation-related clinical diseases
The SCN5A gene, located on chromosome 3p21 with 28 exons, encodes the alpha subunit of the main sodium channel Nav1.5, which enables the rapid influx of Na + ions (INa) ( 19 ). This alpha subunit is expressed in human cardiomyocytes as well as in many other tissues and cells, such as embryonic and denervated skeletal muscle cells in the brain, interstitial cells of Cajal in the human jejunum and colon and smooth muscle cells ( 31 – 36 ). Some studies have shown that the SCN5A splice variant is also expressed in macrophages, where it activates innate immune signalling for antiviral defence ( 37 – 39 ). Voltage-gated Na + channels are crucial in the excitation and propagation of electrical impulses in cardiomyocytes ( 40 ). Nav1.5 interacts with several proteins, including ancillary β -subunits, fascia adherens junctions, desmosomes, gap junctions and intracellular proteins that regulate the gain-of-function and loss-of-function of Nav1.5 proteins ( Figure 5 ) ( 41 ). SCN5A gene mutations are associated with a clinical spectrum, including Brugada syndrome, long-QT syndrome, progressive cardiac conduction disease, sinus node dysfunction, atrial fibrillation, DCM, multifocal ectopic Purkinje-related premature contractions, irritable bowel syndrome (IBS) and other gastrointestinal disorders, such as chronic idiopathic intestinal pseudo-obstruction ( 32 , 34 , 41 , 42 ).
Figure 5 . Genetic test results of the proband and his children, both the proband and his children had the same three genes mutation and were heterozygous. ( A ) Molecular structure of the SCN5A translated into the a-subunit (Nav1.5) of the cardiac sodium channel. ( B ) Nav1.5 consists of an N-terminus, C-terminus and 4 structurally homologous domains.
3.3. SCN5A gene mutation and DCM
The genetic background of patients with DCM is complex: 7% have a single heterozygous mutation, more than 38% have a compound heterozygous or combined mutation, and 12.8% have three or more mutations ( 43 – 45 ). Although many previous works strongly implied that the SCN5A gene mutation plays a critical role in the development of cardiomyopathy, the mechanisms remain controversial. Several mechanisms have been postulated. SCN5A gene mutations related to tachyarrhythmia or other conduction abnormalities induce DCM, especially for some patients with a long history of arrhythmia ( 41 , 46 – 49 ). A primary disruption of Nav1.5 can affect cellular pH and Ca 2+ homeostasis and result in a DCM phenotype ( 42 , 50 – 52 ). The SCN5A channel mutation disrupts the sodium channel domain to target the appropriate cytoskeletal components, such as syntrophins and dystrophins ( 48 , 53 – 57 ). In addition, the environment and common gene variants may act together with SCN5A mutations to cause DCM ( 42 , 52 , 58 , 59 ).
The proband and offspring carried the same three mutations, but they have not shown signs of DCM, and we will continue to follow the family.
3.4. SCA: absence of RCA
In 1979, Lipton et al. defined and classified SCA, which can be divided into 9 types according to origin and anatomical process. The cause of SCA is still unknown ( 60 ). Although isolated reports indicate that specific coronary abnormalities occur in families, no clear pattern of coronary inheritance has been found in humans ( 61 ). We reported a rare L-I pattern of a SCA according to the Lipton classification and summarized a review of identical types of SCA literature, in which the RCA was absent and the LCX was markedly dominant and nourished the right ventricle and atrium beyond the atrioventricular groove. A careful review of the literature revealed 59 cases with a similar anomalous coronary origin and pattern, including demographic characteristics, symptoms, complications, diagnosis and treatment strategy ( Table 2 ) ( 62 – 112 ). Of these 59 patients, 22 were male and 37 were female, and their mean age was 56 years (range 30–87 years).
Table 2 . Summary characteristics of L-1 of SCA.
3.4.1. SCA and coronary heart disease
SCA is generally considered to be a benign abnormality; however, some authors have reported that 15% of SCA patients develop myocardial ischaemia as a direct consequence of coronary artery abnormalities ( 78 ). SCA abnormalities showed a higher risk of coronary atherosclerosis in a study ( 113 ). However, the relationship between congenital abnormalities and atherosclerosis is controversial. Tanriverdi H and Rudan D suggested that atherosclerosis in patients with coronary artery abnormalities was a coincidence ( 114 , 115 ). According to Shirani's review, 15% of patients with isolated SCA have evidence of myocardial ischaemia without significant atherosclerotic stenosis ( 116 ). There were 36 (61%) patients with coronary artery absence combined with coronary atherosclerotic heart disease (CHD); of them, coronary artery bypass grafting was performed in 5 patients, and percutaneous coronary intervention was conducted in 20 patients, which was higher than the general population. SCA anomaly by itself is unlikely to induce myocardial ischaemia, and it has been considered a benign lesion ( 98 ). We consider that SCA promotes the occurrence of CHD. When evaluating clinical symptoms and the degree of myocardial area at risk, it is extremely crucial to refer patients with combined SCA and CHD for selective coronary revascularization. Previous studies have shown that interventional surgery for SCA with atherosclerosis has potentially serious consequences; thus, it is rarely performed ( 92 , 102 ). However, our report revealed that the proportion of patients undergoing interventional surgery in this condition was as high as 69% (25/36). Therefore, interventional operation can be performed successfully in a patient who have SCA with CHD when the anatomy is appropriate.
3.4.2. SCA with congenital heart disease
Congenital heart disease is uncommon in the L-I pattern of SCA, accounting for 7% (4/59). Patent foramen ovale and bicuspid aortic valve were reported in 2 patients, and one of them had annuloaortic ectasia leading to heart failure ( 101 , 105 , 107 ). Congenitally corrected transposition in a situs inversus was shown in a patient ( 1 ).
3.4.3. SCA with arrhythmia
Overall, 10% (6/59) of SCA patients have shown arrhythmia, including 3 patients with right bundle branch block ( 68 , 85 , 102 ), 2 patients with atrial fibrillation ( 30 , 43 ), 1 patient with atrioventricular block ( 72 ) and 1 patient with Brugada syndrome ( 105 ). The risk of complete atrioventricular block in patients with atrioventricular discordance has been demonstrated, and SCA anomaly likely does not present an additional risk for atrioventricular block.
3.4.4. SCA with cardiomyopathy
The present study showed that 12% (7/59) of patients had coexisting cardiomyopathy, 6 had ischaemic cardiomyopathy due to CHD, and 1 had valvular heart disease. To our knowledge, there is no case of SCA with DCM to date. There were 13 patients with hyperlipidemia.
17 patients were diagnosed with SCA by computed tomography (CT). It has been reported that CTCA is the primary method for determining the diagnosis of SCA and can help delineate the course of the proximal artery. CTCA is also an interesting new model; in addition to being noninvasive, it reveals adjacent structures to understand the origin and development of coronary arteries ( 89 ).
Guidelines regarding the management of SCA are difficult to establish, and treatment is guided by symptoms and the presence or severity of atherosclerosis stenosis or the occurrence of acute coronary syndrome. The prognosis of patients ranges from a good normal life expectancy to sudden death.
According to the clinical symptoms and examination results of the patient, we believe that the patient's SCA was benign and was not the cause of his DCM. Another case of absence of the RCA with coexistence of the SCN5A gene mutation was previously reported by Katsaras D et al. ( 106 ). In this case, a patient with familial Brugada syndrome with absence of the RCA tested positive for a SCN5A gene C.664C. > T variant and presented with patent foramen ovale. In contrast, our case did not show Brugada syndrome rather than demonstrating DCM. As we discussed above, the SCN5A gene variant is associated with a spectrum of clinical diseases, and loss of sodium channel function has a critical role in the development of cardiomyopathy ( 48 ). The proband and his children carried the same three mutations. His children refused echocardiography but currently have no symptoms of DCM. The genetic background of patients presenting with DCM is complex; some studies have shown that more than 38% have a compound heterozygous or combined mutation, and 12.8% have three or more mutations ( 43 – 45 ). It is unclear whether the SCN5A gene mutation correlated with RCA absence and DCM in the present case. Meanwhile, the proband and his children carried an APOA5 gene mutation, which is considered a suspected pathogenic variant resulting in hypertriglyceridemia or hyperlipoproteinemia independent of the SCN5A mutation.
This is the first case of SCA combined with DCM of the SCN5A C.1858C > T (P.arg620Cys) mutation, which is the cause of DCM and Brugada syndrome. We should carefully identify and reduce life-threatening events in clinical practice to improve the survival rate. As with many other coronary artery abnormalities, coronary angiography is the gold standard method of diagnosis; importantly, CTCA plays a crucial role in diagnosis when considered as a noninvasive operation. Moreover, the underlying aetiological and pathological link between SCA and DCM remains to be explored.
Material preparation, data collection and analysis were performed by JY and XH. The first draft of the manuscript was written by JY and XH. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcvm.2023.1113886/full#supplementary-material .
SCA, single coronary artery; DCM, dilated cardiomyopathy; RCA, right coronary artery; CCTA, computed tomography coronary angiogram; CMR, cardiac magnetic resonance imaging; TTE, transthoracic echocardiography; LVEF, left ventricular systolic function; LVEDD, left ventricular end-diastole diameter; LVEDV, left ventricular end-diastole volume; LAD, left anterior descending; LCX, left circumflex.
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Keywords: SCN5A , single coronary artery, dilated cardiomyopathy, genetic mutation, hyperlipidemia
Citation: Hu X, Kong J, Niu T, Chen L and Yang J (2023) Single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with the SCN5A and APOA5 gene mutation: A case report and review of the literature. Front. Cardiovasc. Med. 10:1113886. doi: 10.3389/fcvm.2023.1113886
Received: 1 December 2022; Accepted: 23 March 2023; Published: 22 May 2023.
© 2023 Hu, Kong, Niu, Chen and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jingjing Yang [email protected]
Specialty Section: This article was submitted to Coronary Artery Disease, a section of the journal Frontiers in Cardiovascular Medicine
- Open Access
- Published: 19 May 2023
Headache following vaccination against COVID-19 among healthcare workers with a history of COVID-19 infection: a cross-sectional study in Iran with a meta-analytic review of the literature
- Somayeh Nasergivehchi 1 , 2 ,
- Mansoureh Togha ORCID: orcid.org/0000-0002-9368-6835 1 , 3 ,
- Elham Jafari 1 ,
- Mehrdad Sheikhvatan 4 , 5 &
- Donya Shahamati 6
Head & Face Medicine volume 19 , Article number: 19 ( 2023 ) Cite this article
There is evidence of the occurrence of headache after vaccination against COVID-19. However, only a few studies have examined the headache characteristics and related determinants, especially among healthcare workers with a history of COVID-19 infection.
We evaluated the incidence of headaches after injection of different types of COVID-19 vaccine to determine factors relating to the incidence of headache after vaccination among the Iranian healthcare workers who had previously contracted COVID-19. A group of 334 healthcare workers with a history of COVID-19 infection were included and vaccinated (at least one month after recovery without any COVID-19 related symptoms) with different COVID-19 vaccines. The baseline information, headache characteristics and vaccine specifications were recorded.
Overall, 39.2% reported experiencing a post-vaccination headache. Of those with a previous history of headache, 51.1% reported migraine-type, 27.4% tension-type and 21.5% other types. The mean time between vaccination and headache appearance was 26.78 ± 6.93 h, with the headache appearing less than 24 h after vaccination in most patients (83.2%). The headaches reached its peak within 8.62 ± 2.41 h. Most patients reported a compression-type headache. The prevalence of post-vaccination headaches was significantly different according to the type of vaccine used. The highest rates were reported for AstraZeneca, followed by Sputnik V. In regression analysis, the vaccine brand, female gender and initial COVID-19 severity were the main determinants for predicting post-vaccination headache.
Participants commonly experienced a headache following vaccination against COVID-19. Our study results indicated that this was slightly more common in females and in those with a history of severe COVID-19 infection.
Peer Review reports
With the onset of the COVID-19 pandemic in December 2019, efforts began to provide effective and safe drugs to treat the disease and prevent its development. In line with what has been observed in previous pandemics, the efforts to produce effective vaccines increased rapidly. A few months after the start of such efforts and with the rapid spread of COVID-19 and its variants, the first generations of effective immunogenic vaccines were introduced and gradually approved by international scientific reference committees, including the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) [ 1 , 2 ].
It did not take long to generate various brands of vaccines in countries such as the United States, China, Germany, Japan, India, Russia, and even in developing countries such as Iran and Cuba, and introduce them to the world [ 3 , 4 , 5 ]. However, as the production and commercialization of these vaccines accelerated, concerns arose. First, with the emergence of COVID-19 variants, especially the Delta strain, concern increased about reduced immunogenicity against the virus variants. The protective effects of some vaccines initially having an immunogenicity level of over 90% were seen to decrease to less than 70% [ 6 , 7 ]. More importantly, following inoculation with various vaccine brands against COVID-19, potential and, rarely, life-threatening side effects were reported. Common side effects for the COVID-19-vaccines included local inflammation, headache, muscle pain, nausea, fatigue, fever and chills . Anaphylaxis, thromboembolic events, myocarditis, pericarditis and even death were rarely reported, but seriously called into question the safety of some brands [ 9 ].
One of the most common side effects following injection of the different brands of COVID-19 vaccine has been headache. According to the Zoe Health Study, the overall prevalence of headache after vaccination by Pfizer-BioNTech vaccine ranged from 25 to 42% [ 10 ]. The CDC Trusted Source page reported that approximately one-third of people experienced severe post-vaccination headache, regardless of the type or brand of vaccine, at a rate of 1% after the first dose and 3% after the second dose [ 11 ].
One study in Italy reported on the increased likelihood of headache after vaccination by AstraZeneca vaccine, followed by the Pfizer vaccine [ 12 ]. Ekizoglu et al. assessed the history of headache following influenza vaccination and during Covid-19. They found that 30.6% healthcare personnel had experienced headache following Covid vaccination that was more common in females with pre-existing primary headaches, thyroid disorders, headache during COVID-19, or headache related to the influenza vaccine [ 15 ]. Sekiguchi et al. in their study in Japan performed a survey on nursing staff. Their result demonstrated that participants with the history of headache (migraineurs and non-migraineurs) will develop more headache compare to the healthy controls [ 13 ].
However, overall information about headache following those brands, as well as others, has been limited and requires further evaluation. This is especially important for individuals who have experienced COVID-19 infection prior to vaccination. This study evaluated and compared the incidence of headache following inoculation with different types of commonly used COVID-19 vaccines and determined the factors related to the incidence of headache following vaccination among selected Iranian healthcare workers who had previously recovered from COVID-19.
Materials and methods
The participants in this cross-sectional study comprised 334 healthcare personnel who had initially recovered from COVID-19 infections of different intensities. According to our institutional protocol, these individuals were vaccinated at least one month after recovery with one of the brands of COVID-19 vaccine mentioned above between April and September 2021. The brands of corona vaccine that were commonly used among healthcare workers in this study included AstraZeneca, Sinopharm (China), Sputnik V (Russia), Bharat (India) and COVIran Barekat (Iran).
An online questionnaire designed to cover all the necessary data. This questionnaire included the demographics characteristics, the brand of vaccine administered, severity of initial COVID-19 infection (defined as quarantine at home, hospitalization in an isolated ward or ICU), concomitant clinical symptoms, PCR positivity after vaccination, rate of analgesic use after vaccination and COVID-19 positivity between two vaccine doses. In addition, information related to the post-vaccination headache, including time duration between vaccination and headache occurrence, time to reaching peak intensity after onset, pattern and location of the headache and medication used for headache relief also were assessed.
All patients were reassured about the privacy of their information and, after explaining the objectives of the project, verbal consent was obtained from all. The study endpoint was to determine the prevalence of headache and its characteristics following the use of each vaccine brand and then to determine the effect of vaccination of the different brands while adjusting for gender, initial COVID-19 severity and previous history of headache. In this regard, the severity of the COVID-19 was determined based on the Criteria for Clinical Severity of Confirmed COVID-19 as released by WHO [ 1 , 2 ].
For statistical analysis, results were presented as mean ± standard deviation (SD) for the quantitative variables and were summarized by frequency (percentage) for categorical variables. Continuous variables were compared using the t -test or Mann-Whitney test whenever the data did not appear to have a normal distribution or when the assumption of equal variance was violated across the study groups. The multivariable logistic regression model was employed to examine the effect of type of vaccine on post-vaccination headache as adjusted for gender, history of headache and COVID-19 severity. P-values of ≤ 0.05 were considered statistically significant. The statistical software SPSS (version 23.0) for Windows (IBM; USA) was used for statistical analysis.
A total of 334 hospital staff members who had a history of COVID-19 infection and had subsequently been vaccinated with different brands of vaccines in Iran were assessed (Table 1 ). The average age of participants was 36.62 ± 4.36 year. of which 72.8% were female and 27.2% were male. Of the vaccines used, 12.9% were vaccinated with AstraZeneca, 16.2% with Sinopharm, 62.3% with Sputnik V, 6.9% with Bharat and 1.8% with other brands. The initial COVID-19 severity of the participants was assessed and it was determined that 62.6% had quarantined at home, 32.3% had been hospitalized in a general ward and 5.1% had been admitted to an ICU.
Overall, 39.2% of participants reported experiencing post-vaccination headache and 30.8% of participants reported a history of headache. Of those, 51.1% characterized their previous headaches as of the migraine type, 27.4% as tension type and 21.5% as other types. The mean time between injection of the vaccine and the onset of headache was 26.78 ± 6.93 h. Most participants (83.2%) reported the onset of headache to be less than 24 h after vaccination. They reported the headache reaching a peak within about 8.62 ± 2.41 h after the onset and the overall duration of the headache to be 4.22 ± 1.26 h. In 50% of participants, the headache duration was less than 6 h.
With respect to the symptoms accompanying the post-vaccination headache, the most frequent was nausea (9.2%), followed by sensitivity to noise (6.9%) and photophobia (4.6%). In most patients, the headache was of the compression type and most reported that the headache was felt diffusely in various parts of the head. The severity of headache in most participants (93.0%) was such that they resorted to the use of some type of analgesic (Table 2 ).
Figure 1 shows that the prevalence of post-vaccination headache was significantly different according to the brand of vaccine administered. The prevalence of post-vaccination headache was highest for AstraZeneca (62.8%), followed by Sputnik V (40.4%) and Bharat (30.4%) (p < 0.001). Post-vaccine headache was found to be significantly higher in females than in males (43.6% versus 27.5%; p = 0.001). Table 3 reveals that, although the onset of headache (early or delayed) did not differ across vaccine brands, the pattern of headache did differ. Compression headache was reported more often by those vaccinated with AstraZeneca or Sputnik V. Pulsatile headaches were reported to occur most often following vaccination with Sinopharm.
Prevalence of post-vaccine headache according to type of vaccine used (p = 0.001)
Table 4 indicates that, in multivariate logistic regression analysis, the brand of vaccine (OR = 1.328; p = 0.040), female gender (OR = 1.934; p = 0.017) and COVID-19 severity (OR = 3.541; p = 0.001) were the main determinants for prediction of post-vaccination headache. It was noted that a history of headache before vaccination was not significantly associated with the occurrence of post-vaccination headache.
Recent studies have reported on the occurrence of headache after inoculation with COVID-19 vaccines; however, the present study is the first to evaluate this event in individuals who have been vaccinated after initial infection by and recovery from COVID-19 and who experienced post-vaccination headaches. It should be noted that, post-vaccination, there were no signs of re-infection among participants.
The predominant finding of the present study has been that about one-third of the vaccinated individuals in the study group reported various types of post-vaccination headache. A review of the literature (Table 5 ) showed that the incidence of post-vaccination headache ranged from 19.5 to 49.4% regardless of the type of vaccine used or the target population (general population or healthcare workers). In a meta-analysis of these studies, we found an overall prevalence of 31.2% (95% CI: 25.3–37.9%) for headache, with a prevalence of 34.6% (95% CI: 27.4–42.5%) among healthcare workers, but with considerable heterogeneity across the studies (I 2 = 99.037 (Figs. 2 ) and 98.343 (Fig. 3 ), respectively; p < 0.001) [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. These divergent results could relate to the different brands of vaccine used as well as differences in the study populations. It could be concluded that about one-third of individuals who have been vaccinated against COVID-19 experienced various degrees of headache, with a slightly higher incidence rate among healthcare personnel.
Prevalence of post-vaccine headache among total population in different studies
Prevalence of post-vaccine headache among healthcare workers in different studies
More interestingly, most headaches occurred within the first 24 h after vaccination (83.2%) with the mean time between vaccination and headache onset to be 26.78 ± 6.93 h. As indicated by Göbel et al. [ 34 ], the latency between vaccination against COVID-19 and the occurrence of headache was on average 18.0 ± 27.0 h. More than half of their participants perceived the headache in less than 10 h and 80% within 24 h after vaccination, which is similar to our findings. Koji Sekiguchi et al. [ 35 ] also reported that the median onset of headache after the first and second vaccine doses were 10 and 12 h, respectively, and mean duration of headache was 4.5 and 8.0 h, respectively. In that study, the mean time to onset of headache after vaccination was 4.22 ± 1.26 h. In 50% of their participants, the headache duration was less than 6 h and in 80% was less than 22 h. Göbel et al. [ 34 ] reported a mean headache duration of 14.2 + 21.4 h.
About one-third of participants reported generalized headache. Göbel et al. [ 34 ] reported bilateral headache in 73.1% of their subjects, with the most prominent zones being the forehead (38.0%) followed by the temple (32.2%). Sekiguchi et al. [ 35 ] reported the rate of bilateral headache in healthy controls having no history of headache, and history of migraine and non-migraine headaches as being 78.8%, 62.5% and 75.9%, respectively. The participants in the present study primarily reported compression-type headaches. Göbel et al. [ 34 ] reported compression headache and dull pain in 49.2% and 40.7% of participants, respectively. Ekizoglu et al. [ 15 ] reported throbbing headaches in 40.1% of participants and compression headache in 30.4%.
Another important finding was the occurrence of post-vaccination headache as being potentially influenced by the factors of the female gender and severity of the initial COVID-19 infection. Research released by the CDC on the safety of COVID-19 vaccinations indicated post-vaccination side-effects occurred among 79.1% of women but only in 61.2% of men [ 36 ]. As migraine and tension headaches are more prevalent in women than in men [ 37 , 38 ], such a difference may affect the likelihood of post-vaccination headache among women compared to men.
The current study found a significant difference in the prevalence of headache according to vaccine brand used among different countries. As shown, the highest rate of headache was after AstraZeneca vaccination, followed by Sputnik V; however, the literature reviewed (Table 5 ) did not differentiate between vaccines in relation to post-vaccination headache. For example, the rate of post-vaccination headache following vaccination by Pfizer-BioNTech ranged from 6.0 to 48.7%. Additionally, information about the incidence of side-effects of brands such as Sinopharm and Sputnik V vaccines has been limited.
There is no documented and comprehensive explanation of the pathomechanisms of headache following vaccination against COVID-19. Some believe that such a headache may originate from the spike protein of the virus used to produce the vaccine [ 39 ]. Others have speculated that the immune response triggered by such proteins plays a significant role [ 40 ]. This means that flaring pro-inflammatory cascades and secretion of cytokines and prostaglandins may be responsible for vaccination-related headache and other concurrent symptoms [ 41 , 41 ]. It should be noted that the technologies and materials used for creating the vaccines could play a role in post-vaccination headache. This should be evaluated in further studies.
One limitation of the study was that some of the most commonly used brands globally, such as Pfizer, were not widely available in Iran; thus was not possible to evaluate the post-vaccination headache for these brands. Additionally, the pattern of headache among the healthcare workers as participants was not evaluated during the first exposure to COVID-19.
The current study examined the incidence of post-vaccination headache among healthcare workers who were vaccinated against COVID-19 after recovering from a previous bout of the virus. Different brands of vaccine were examined and it was found that 39.2% of participants experienced post-vaccination headache. This incidence was greater among females than males as well as those who had experienced more severe cases of COVID-19 before vaccination. Among the brands used in our population, the highest rate of post-vaccination headache was for the AstraZeneca, followed by Sputnik V. Considering that COVID-19 will continue to infect the global population in the future, vaccination, as well as identification and classification of post-vaccination headache, can improve appropriate management of the virus. The differentiation of such headaches from other post-vaccination side-effects, such as cerebrovascular thrombotic events, can be vital to the targeted management of these events.
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Department of Headache, Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
Somayeh Nasergivehchi, Mansoureh Togha & Elham Jafari
Department of Neurology, Baharloo University Hospital, Tehran University of Medical Sciences, Tehran, Iran
Department of Headache, Neurology Ward, School of Medicine, Sina University Hospital, Tehran University of Medical Sciences, Tehran, Iran
Tehran University of Medical Sciences, Tehran, Iran
Heidelberg University Hospital, Heidelberg, Germany
Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Behehshti University of Medical Sciences Tehran, Tehran, Iran
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Somayeh Nasergivehchi contributed to the study conception and design, acquisition of data and drafting of the manuscript. Mansoureh Togha contributed to the study conception and design and the critical revision of the manuscript. Elham Jafari contributed to the study conception and design, acquisition of data and revision of the manuscript. Mehrdad Sheikhvatan contributed to analysis and statistics of the data. Donya Shahamati contributed to data entry and processing.
Correspondence to Mansoureh Togha .
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Nasergivehchi, S., Togha, M., Jafari, E. et al. Headache following vaccination against COVID-19 among healthcare workers with a history of COVID-19 infection: a cross-sectional study in Iran with a meta-analytic review of the literature. Head Face Med 19 , 19 (2023). https://doi.org/10.1186/s13005-023-00363-4
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Accepted : 08 May 2023
Published : 19 May 2023
DOI : https://doi.org/10.1186/s13005-023-00363-4
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