using case report study

Does the case report provide information about the patient's age, sex, ethnicity, race, employment status, social situation, medical history, diagnosis, prognosis, previous treatments, past and current diagnostic test results, medications, psychological tests, clinical and functional assessments, and current intervention?

Case reports should include carefully recorded, unbiased observations.

Does the case report include measurements and/or recorded observations of the case? Does it show a bias?

Case reports should explore and infer, not confirm, deduce, or prove. They cannot demonstrate causality or argue for the adoption of a new treatment approach.

Does the case report present a hypothesis that can be confirmed by another type of study?

Fictitious Example

A physician treated a young and otherwise healthy patient who came to her office reporting numbness all over her body. The physician could not determine any reason for this numbness and had never seen anything like it. After taking an extensive history the physician discovered that the patient had recently been to the beach for a vacation and had used a very new type of spray sunscreen. The patient had stored the sunscreen in her cooler at the beach because she liked the feel of the cool spray in the hot sun. The physician suspected that the spray sunscreen had undergone a chemical reaction from the coldness which caused the numbness. She also suspected that because this is a new type of sunscreen other physicians may soon be seeing patients with this numbness.

The physician wrote up a case report describing how the numbness presented, how and why she concluded it was the spray sunscreen, and how she treated the patient. Later, when other doctors began seeing patients with this numbness, they found this case report helpful as a starting point in treating their patients.

Real-life Examples

Hymes KB. Cheung T. Greene JB. Prose NS. Marcus A. Ballard H. William DC. Laubenstein LJ. (1981). Kaposi's sarcoma in homosexual men-a report of eight cases. Lancet. 2(8247), 598-600.

This case report was published by eight physicians in New York city who had unexpectedly seen eight male patients with Kaposiâ€™s sarcoma (KS). Prior to this, KS was very rare in the U.S. and occurred primarily in the lower extremities of older patients. These cases were decades younger, had generalized KS, and a much lower rate of survival. This was before the discovery of HIV or the use of the term AIDS and this case report was one of the first published items about AIDS patients.

Wu, E. B., & Sung, J. J. Y. (2003). Haemorrhagic-fever-like changes and normal chest radiograph in a doctor with SARS. Lancet, 361(9368), 1520-1521.

This case report is written by the patient, a physician who contracted SARS, and his colleague who treated him, during the 2003 outbreak of SARS in Hong Kong. They describe how the disease progressed in Dr. Wu and based on Dr. Wuâ€™s case, advised that a chest CT showed hidden pneumonic changes and facilitate a rapid diagnosis.

Related Terms

Case Series

A report about a small group of similar cases.

Preplanned Case-Observation

A case in which symptoms are elicited to study disease mechanisms. (Ex. Having a patient sleep in a lab to do brain imaging for a sleep disorder).

Now test yourself!

1. Case studies are not considered evidence-based even though the authors have studied the case in great depth.

a) True b) False

2. When are Case reports most useful?

a) When you encounter common cases and need more information b) When new symptoms or outcomes are unidentified c) When developing practice guidelines d) When the population being studied is very large

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Quantitative Study Designs: Case Studies/ Case Report/ Case Series

Quantitative study designs.

Case Study / Case Report / Case Series

Some famous examples of case studies are John Martin Marlow’s case study on Phineas Gage (the man who had a railway spike through his head) and Sigmund Freud’s case studies, Little Hans and The Rat Man. Case studies are widely used in psychology to provide insight into unusual conditions.

A case study, also known as a case report, is an in depth or intensive study of a single individual or specific group, while a case series is a grouping of similar case studies / case reports together.

A case study / case report can be used in the following instances:

The stages of a Case Study / Case Report / Case Series

Which clinical questions does Case Study / Case Report / Case Series best answer?

Emerging conditions, adverse reactions to treatments, atypical / abnormal behaviour, new programs or methods of treatment – all of these can be answered with case studies /case reports / case series. They are generally descriptive studies based on qualitative data e.g. observations, interviews, questionnaires, diaries, personal notes or clinical notes.

What are the advantages and disadvantages to consider when using Case Studies/ Case Reports and Case Series ?

What are the pitfalls to look for.

One pitfall that has occurred in some case studies is where two common conditions/treatments have been linked together with no comprehensive data backing up the conclusion. A hypothetical example could be where high rates of the common cold were associated with suicide when the cohort also suffered from depression.

Critical appraisal tools

To assist with critically appraising Case studies / Case reports / Case series there are some tools / checklists you can use.

JBI Critical Appraisal Checklist for Case Series

JBI Critical Appraisal Checklist for Case Reports

Real World Examples

Some Psychology case study / case report / case series examples

Capp, G. (2015). Our community, our schools : A case study of program design for school-based mental health services. Children & Schools, 37(4), 241–248. A pilot program to improve school based mental health services was instigated in one elementary school and one middle / high school. The case study followed the program from development through to implementation, documenting each step of the process.

Cowdrey, F. A. & Walz, L. (2015). Exposure therapy for fear of spiders in an adult with learning disabilities: A case report. British Journal of Learning Disabilities, 43(1), 75–82. One person was studied who had completed a pre- intervention and post- intervention questionnaire. From the results of this data the exposure therapy intervention was found to be effective in reducing the phobia. This case report highlighted a therapy that could be used to assist people with learning disabilities who also suffered from phobias.

Li, H. X., He, L., Zhang, C. C., Eisinger, R., Pan, Y. X., Wang, T., . . . Li, D. Y. (2019). Deep brain stimulation in post‐traumatic dystonia: A case series study. CNS Neuroscience & Therapeutics. 1-8. Five patients were included in the case series, all with the same condition. They all received deep brain stimulation but not in the same area of the brain. Baseline and last follow up visit were assessed with the same rating scale.

References and Further Reading

Greenhalgh, T. (2014). How to read a paper: the basics of evidence-based medicine. (5th ed.). New York: Wiley.

Heale, R. & Twycross, A. (2018). What is a case study? Evidence Based Nursing, 21(1), 7-8.

Himmelfarb Health Sciences Library. (2019). Study design 101: case report. Retrieved from https://himmelfarb.gwu.edu/tutorials/studydesign101/casereports.cfm

Hoffmann T., Bennett S., Mar C. D. (2017). Evidence-based practice across the health professions. Chatswood, NSW: Elsevier.

Robinson, O. C., & McAdams, D. P. (2015). Four functional roles for case studies in emerging adulthood research. Emerging Adulthood, 3(6), 413-420.

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Distinguishing case study as a research method from case reports as a publication type

The purpose of this editorial is to distinguish between case reports and case studies. In health, case reports are familiar ways of sharing events or efforts of intervening with single patients with previously unreported features. As a qualitative methodology, case study research encompasses a great deal more complexity than a typical case report and often incorporates multiple streams of data combined in creative ways. The depth and richness of case study description helps readers understand the case and whether findings might be applicable beyond that setting.

Single-institution descriptive reports of library activities are often labeled by their authors as “case studies.” By contrast, in health care, single patient retrospective descriptions are published as “case reports.” Both case reports and case studies are valuable to readers and provide a publication opportunity for authors. A previous editorial by Akers and Amos about improving case studies addresses issues that are more common to case reports; for example, not having a review of the literature or being anecdotal, not generalizable, and prone to various types of bias such as positive outcome bias [ 1 ]. However, case study research as a qualitative methodology is pursued for different purposes than generalizability. The authors’ purpose in this editorial is to clearly distinguish between case reports and case studies. We believe that this will assist authors in describing and designating the methodological approach of their publications and help readers appreciate the rigor of well-executed case study research.

Case reports often provide a first exploration of a phenomenon or an opportunity for a first publication by a trainee in the health professions. In health care, case reports are familiar ways of sharing events or efforts of intervening with single patients with previously unreported features. Another type of study categorized as a case report is an “N of 1” study or single-subject clinical trial, which considers an individual patient as the sole unit of observation in a study investigating the efficacy or side effect profiles of different interventions. Entire journals have evolved to publish case reports, which often rely on template structures with limited contextualization or discussion of previous cases. Examples that are indexed in MEDLINE include the American Journal of Case Reports , BMJ Case Reports, Journal of Medical Case Reports, and Journal of Radiology Case Reports . Similar publications appear in veterinary medicine and are indexed in CAB Abstracts, such as Case Reports in Veterinary Medicine and Veterinary Record Case Reports .

As a qualitative methodology, however, case study research encompasses a great deal more complexity than a typical case report and often incorporates multiple streams of data combined in creative ways. Distinctions include the investigator’s definitions and delimitations of the case being studied, the clarity of the role of the investigator, the rigor of gathering and combining evidence about the case, and the contextualization of the findings. Delimitation is a term from qualitative research about setting boundaries to scope the research in a useful way rather than describing the narrow scope as a limitation, as often appears in a discussion section. The depth and richness of description helps readers understand the situation and whether findings from the case are applicable to their settings.

CASE STUDY AS A RESEARCH METHODOLOGY

Case study as a qualitative methodology is an exploration of a time- and space-bound phenomenon. As qualitative research, case studies require much more from their authors who are acting as instruments within the inquiry process. In the case study methodology, a variety of methodological approaches may be employed to explain the complexity of the problem being studied [ 2 , 3 ].

Leading authors diverge in their definitions of case study, but a qualitative research text introduces case study as follows:

Case study research is defined as a qualitative approach in which the investigator explores a real-life, contemporary bounded system (a case) or multiple bound systems (cases) over time, through detailed, in-depth data collection involving multiple sources of information, and reports a case description and case themes. The unit of analysis in the case study might be multiple cases (a multisite study) or a single case (a within-site case study). [ 4 ]

Methodologists writing core texts on case study research include Yin [ 5 ], Stake [ 6 ], and Merriam [ 7 ]. The approaches of these three methodologists have been compared by Yazan, who focused on six areas of methodology: epistemology (beliefs about ways of knowing), definition of cases, design of case studies, and gathering, analysis, and validation of data [ 8 ]. For Yin, case study is a method of empirical inquiry appropriate to determining the “how and why” of phenomena and contributes to understanding phenomena in a holistic and real-life context [ 5 ]. Stake defines a case study as a “well-bounded, specific, complex, and functioning thing” [ 6 ], while Merriam views “the case as a thing, a single entity, a unit around which there are boundaries” [ 7 ].

Case studies are ways to explain, describe, or explore phenomena. Comments from a quantitative perspective about case studies lacking rigor and generalizability fail to consider the purpose of the case study and how what is learned from a case study is put into practice. Rigor in case studies comes from the research design and its components, which Yin outlines as (a) the study’s questions, (b) the study’s propositions, (c) the unit of analysis, (d) the logic linking the data to propositions, and (e) the criteria for interpreting the findings [ 5 ]. Case studies should also provide multiple sources of data, a case study database, and a clear chain of evidence among the questions asked, the data collected, and the conclusions drawn [ 5 ].

Sources of evidence for case studies include interviews, documentation, archival records, direct observations, participant-observation, and physical artifacts. One of the most important sources for data in qualitative case study research is the interview [ 2 , 3 ]. In addition to interviews, documents and archival records can be gathered to corroborate and enhance the findings of the study. To understand the phenomenon or the conditions that created it, direct observations can serve as another source of evidence and can be conducted throughout the study. These can include the use of formal and informal protocols as a participant inside the case or an external or passive observer outside of the case [ 5 ]. Lastly, physical artifacts can be observed and collected as a form of evidence. With these multiple potential sources of evidence, the study methodology includes gathering data, sense-making, and triangulating multiple streams of data. Figure 1 shows an example in which data used for the case started with a pilot study to provide additional context to guide more in-depth data collection and analysis with participants.

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Key sources of data for a sample case study

VARIATIONS ON CASE STUDY METHODOLOGY

Case study methodology is evolving and regularly reinterpreted. Comparative or multiple case studies are used as a tool for synthesizing information across time and space to research the impact of policy and practice in various fields of social research [ 9 ]. Because case study research is in-depth and intensive, there have been efforts to simplify the method or select useful components of cases for focused analysis. Micro-case study is a term that is occasionally used to describe research on micro-level cases [ 10 ]. These are cases that occur in a brief time frame, occur in a confined setting, and are simple and straightforward in nature. A micro-level case describes a clear problem of interest. Reporting is very brief and about specific points. The lack of complexity in the case description makes obvious the “lesson” that is inherent in the case; although no definitive “solution” is necessarily forthcoming, making the case useful for discussion. A micro-case write-up can be distinguished from a case report by its focus on briefly reporting specific features of a case or cases to analyze or learn from those features.

DATABASE INDEXING OF CASE REPORTS AND CASE STUDIES

Disciplines such as education, psychology, sociology, political science, and social work regularly publish rich case studies that are relevant to particular areas of health librarianship. Case reports and case studies have been defined as publication types or subject terms by several databases that are relevant to librarian authors: MEDLINE, PsycINFO, CINAHL, and ERIC. Library, Information Science & Technology Abstracts (LISTA) does not have a subject term or publication type related to cases, despite many being included in the database. Whereas “Case Reports” are the main term used by MEDLINE’s Medical Subject Headings (MeSH) and PsycINFO’s thesaurus, CINAHL and ERIC use “Case Studies.”

Case reports in MEDLINE and PsycINFO focus on clinical case documentation. In MeSH, “Case Reports” as a publication type is specific to “clinical presentations that may be followed by evaluative studies that eventually lead to a diagnosis” [ 11 ]. “Case Histories,” “Case Studies,” and “Case Study” are all entry terms mapping to “Case Reports”; however, guidance to indexers suggests that “Case Reports” should not be applied to institutional case reports and refers to the heading “Organizational Case Studies,” which is defined as “descriptions and evaluations of specific health care organizations” [ 12 ].

PsycINFO’s subject term “Case Report” is “used in records discussing issues involved in the process of conducting exploratory studies of single or multiple clinical cases.” The Methodology index offers clinical and non-clinical entries. “Clinical Case Study” is defined as “case reports that include disorder, diagnosis, and clinical treatment for individuals with mental or medical illnesses,” whereas “Non-clinical Case Study” is a “document consisting of non-clinical or organizational case examples of the concepts being researched or studied. The setting is always non-clinical and does not include treatment-related environments” [ 13 ].

Both CINAHL and ERIC acknowledge the depth of analysis in case study methodology. The CINAHL scope note for the thesaurus term “Case Studies” distinguishes between the document and the methodology, though both use the same term: “a review of a particular condition, disease, or administrative problem. Also, a research method that involves an in-depth analysis of an individual, group, institution, or other social unit. For material that contains a case study, search for document type: case study.” The ERIC scope note for the thesaurus term “Case Studies” is simple: “detailed analyses, usually focusing on a particular problem of an individual, group, or organization” [ 14 ].

PUBLICATION OF CASE STUDY RESEARCH IN LIBRARIANSHIP

We call your attention to a few examples published as case studies in health sciences librarianship to consider how their characteristics fit with the preceding definitions of case reports or case study research. All present some characteristics of case study research, but their treatment of the research questions, richness of description, and analytic strategies vary in depth and, therefore, diverge at some level from the qualitative case study research approach. This divergence, particularly in richness of description and analysis, may have been constrained by the publication requirements.

As one example, a case study by Janke and Rush documented a time- and context-bound collaboration involving a librarian and a nursing faculty member [ 15 ]. Three objectives were stated: (1) describing their experience of working together on an interprofessional research team, (2) evaluating the value of the librarian role from librarian and faculty member perspectives, and (3) relating findings to existing literature. Elements that signal the qualitative nature of this case study are that the authors were the research participants and their use of the term “evaluation” is reflection on their experience. This reads like a case study that could have been enriched by including other types of data gathered from others engaging with this team to broaden the understanding of the collaboration.

As another example, the description of the academic context is one of the most salient components of the case study written by Clairoux et al., which had the objectives of (1) describing the library instruction offered and learning assessments used at a single health sciences library and (2) discussing the positive outcomes of instruction in that setting [ 16 ]. The authors focus on sharing what the institution has done more than explaining why this institution is an exemplar to explore a focused question or understand the phenomenon of library instruction. However, like a case study, the analysis brings together several streams of data including course attendance, online material page views, and some discussion of results from surveys. This paper reads somewhat in between an institutional case report and a case study.

The final example is a single author reporting on a personal experience of creating and executing the role of research informationist for a National Institutes of Health (NIH)–funded research team [ 17 ]. There is a thoughtful review of the informationist literature and detailed descriptions of the institutional context and the process of gaining access to and participating in the new role. However, the motivating question in the abstract does not seem to be fully addressed through analysis from either the reflective perspective of the author as the research participant or consideration of other streams of data from those involved in the informationist experience. The publication reads more like a case report about this informationist’s experience than a case study that explores the research informationist experience through the selection of this case.

All of these publications are well written and useful for their intended audiences, but in general, they are much shorter and much less rich in depth than case studies published in social sciences research. It may be that the authors have been constrained by word counts or page limits. For example, the submission category for Case Studies in the Journal of the Medical Library Association (JMLA) limited them to 3,000 words and defined them as “articles describing the process of developing, implementing, and evaluating a new service, program, or initiative, typically in a single institution or through a single collaborative effort” [ 18 ]. This definition’s focus on novelty and description sounds much more like the definition of case report than the in-depth, detailed investigation of a time- and space-bound problem that is often examined through case study research.

Problem-focused or question-driven case study research would benefit from the space provided for Original Investigations that employ any type of quantitative or qualitative method of analysis. One of the best examples in the JMLA of an in-depth multiple case study that was authored by a librarian who published the findings from her doctoral dissertation represented all the elements of a case study. In eight pages, she provided a theoretical basis for the research question, a pilot study, and a multiple case design, including integrated data from interviews and focus groups [ 19 ].

We have distinguished between case reports and case studies primarily to assist librarians who are new to research and critical appraisal of case study methodology to recognize the features that authors use to describe and designate the methodological approaches of their publications. For researchers who are new to case research methodology and are interested in learning more, Hancock and Algozzine provide a guide [ 20 ].

We hope that JMLA readers appreciate the rigor of well-executed case study research. We believe that distinguishing between descriptive case reports and analytic case studies in the journal’s submission categories will allow the depth of case study methodology to increase. We also hope that authors feel encouraged to pursue submitting relevant case studies or case reports for future publication.

Editor’s note: In response to this invited editorial, the Journal of the Medical Library Association will consider manuscripts employing rigorous qualitative case study methodology to be Original Investigations (fewer than 5,000 words), whereas manuscripts describing the process of developing, implementing, and assessing a new service, program, or initiative—typically in a single institution or through a single collaborative effort—will be considered to be Case Reports (formerly known as Case Studies; fewer than 3,000 words).

A case report is a detailed report of the diagnosis, treatment, response to treatment, and follow-up after treatment of an individual patient. A case series is group of case reports involving patients who were given similar treatment. Case reports and case series usually contain demographic information about the patient(s), for example, age, gender, ethnic origin.

When information on more than three patients is included, the case series is considered to be a systematic investigation designed to contribute to generalizable knowledge (i.e., research ), and therefore submission is required to the IRB.

For all case reports and case series, a signed HIPAA authorization should be obtained from the patients or their legally authorized representatives for the use and disclosure of their Protected Health Information. The only exception to the requirement for obtaining authorization is if the author of a case report or case series believes that the information is not identifiable; in this case, the author must consult with the Privacy Officer at Boston Medical Center ( [email protected] ) or the HIPAA Privacy Officer of Boston University ( [email protected] ) to seek an expert opinion about the magnitude of the risk of identifying an individual.

For case reports or case series containing more than three patients, the HIPAA authorization should be part of the consent form that is reviewed by the IRB.

For case reports or case series containing three or fewer patients, authors should prepare an authorization form using the following templates and arrange for review as indicated below. The red text in the template should be customized for the specific case report or case series. Please note that for deceased patients, authorization must be obtained from the personal representative, who is the administrator or executor of the patient’s estate.

Writing a Case Report

This page is intended for medical students, residents or others who do not have much experience with case reports, but are planning on writing one.

What is a case report? A medical case report, also known as a case study, is a detailed description of a clinical encounter with a patient. The most important aspect of a case report, i.e. the reason you would go to the trouble of writing one, is that the case is sufficiently unique, rare or interesting such that other medical professionals will learn something from it.

Case reports are commonly of the following categories :

- Rare diseases

- Unusual presentation of disease

- Unexpected events

- Unusual combination of diseases or conditions

- Difficult or inconclusive diagnosis

- Treatment or management challenges

- Personal impact

- Observations that shed new light on a disease or condition

- Anatomical variations

It is important that you recognize what is unique or interesting about your case, and this must be described clearly in the case report.

Case reports generally take the format of :

1. Background

2. Case presentation

3. Observations and investigation

4. Diagnosis

5. Treatment

7. Discussion

Does a case report require IRB approval?

Case reports typically discuss a single patient. If this is true for your case report, then it most likely does not require IRB approval because it not considered research. If you have more than one patient, your study could qualify as a Case Series, which would require IRB review. If you have questions, you chould check your local IRB's guidelines on reviewing case reports.

Are there other rules for writing a case report?

First, you will be collecting protected health information, thus HIPAA applies to case reports. Spectrum Health has created a very helpful guidance document for case reports, which you can see here: Case Report Guidance - Spectrum Health

While this guidance document was created by Spectrum Health, the rules and regulations outlined could apply to any case report. This includes answering questions like: Do I need written HIPAA authorization to publish a case report? When do I need IRB review of a case report? What qualifies as a patient identifier?

How do I get started?

1. We STRONGLY encourage you to consult the CARE Guidelines, which provide guidance on writing case reports - https://www.care-statement.org/

Specifically, the checklist - https://www.care-statement.org/checklist - which explains exactly the information you should collect and include in your case report.

2. Identify a case. If you are a medical student, you may not yet have the clinical expertise to determine if a specific case is worth writing up. If so, you must seek the help of a clinician. It is common for students to ask attendings or residents if they have any interesting cases that can be used for a case report.

3. Select a journal or two to which you think you will submit the case report. Journals often have specific requirements for publishing case reports, which could include a requirement for informed consent, a letter or statement from the IRB and other things. Journals may also charge publication fees (see Is it free to publish? below)

4. Obtain informed consent from the patient (see " Do I have to obtain informed consent from the patient? " below). Journals may have their own informed consent form that they would like you to use, so please look for this when selecting a journal.

Once you've identified the case, selected an appropriate journal(s), and considered informed consent, you can collect the required information to write the case report.

How do I write a case report?

Once you identify a case and have learned what information to include in the case report, try to find a previously published case report. Finding published case reports in a similar field will provide examples to guide you through the process of writing a case report.

One journal you can consult is BMJ Case Reports . MSU has an institutional fellowship with BMJ Case Reports which allows MSU faculty, staff and students to publish in this journal for free. See this page for a link to the journal and more information on publishing- https://lib.msu.edu/medicalwriting_publishing/

There are numerous other journals where you can find published case reports to help guide you in your writing.

Do I have to obtain informed consent from the patient?

The CARE guidelines recommend obtaining informed consent from patients for all case reports. Our recommendation is to obtain informed consent from the patient. Although not technically required, especially if the case report does not include any identifying information, some journals require informed consent for all case reports before publishing. The CARE guidelines recommend obtaining informed consent AND the patient's perspective on the treatment/outcome (if possible). Please consider this as well.

If required, it is recommended you obtain informed consent before the case report is written.

An example of a case report consent form can be found on the BMJ Case Reports website, which you can access via the MSU library page - https://lib.msu.edu/medicalwriting_publishing/ . Go to "Instructions for Authors" and then "Patient Consent" to find the consent form they use. You can create a similar form to obtain consent from your patient. If you have identified a journal already, please consult their requirements and determine if they have a specific consent form they would like you to use.

Seek feedback

Once you have written a draft of the case report, you should seek feedback on your writing, from experts in the field if possible, or from those who have written case reports before.

Selecting a journal

Aside from BMJ Case Reports mentioned above, there are many, many journals out there who publish medical case reports. Ask your mentor if they have a journal they would like to use. If you need to select on your own, here are some strategies:

1. Do a PubMed search. https://pubmed.ncbi.nlm.nih.gov/

a. Do a search for a topic, disease or other feature of your case report

b. When the results appear, on the left side of the page is a limiter for "article type". Case reports are an article type to which you can limit your search results. If you don't see that option on the left, click "additional filters".

c. Review the case reports that come up and see what journals they are published in.

2. Use JANE - https://jane.biosemantics.org/

3. Check with specialty societies. Many specialty societies are affiliated with one or more journal, which can be reviewed for ones that match your needs

4. Search through individual publisher journal lists. Elsevier publishes many different medical research journals, and they have a journal finder, much like JANE ( https://journalfinder.elsevier.com/ ). This is exclusive to Elsevier journals. There are many other publishers of medical journals for review, including Springer, Dove Press, BMJ, BMC, Wiley, Sage, Nature and many others.

Is it free to publish ?

Be aware that it may not be free to publish your case report. Many journals charge publication fees. Of note, many open access journals charge author fees of thousands of dollars. Other journals have smaller page charges (i.e. $60 per page), and still others will publish for free, with an "open access option". It is best practice to check the journal's Info for Authors section or Author Center to determine what the cost is to publish. MSU-CHM does NOT have funds to support publication costs, so this is an important step if you do not want to pay out of pocket for publishing

*A more thorough discussion on finding a journal, publication costs, predatory journals and other publication-related issues can be found here: https://research.chm.msu.edu/students-residents/finding-a-journal

Gagnier JJ, Kienle G, Altman DG, Moher D, Sox H, Riley D. 2013. The CARE guidelines: Consensus-based clinical case reporting guideline development. Glob Adv Health Med . 2:38-43. doi: 10.7453/gahmj.2013.008

Riley DS, Barber MS, Kienle GS, AronsonJK, von Schoen-Angerer T, Tugwell P, Kiene H, Helfand M, Altman DG, Sox H, Werthmann PG, Moher D, Rison RA, Shamseer L, Koch CA, Sun GH, Hanaway P, Sudak NL, Kaszkin-Bettag M, Carpenter JE, Gagnier JJ. 2017. CARE guidelines for case reports: explanation and elaboration document . J Clin Epidemiol . 89:218-234. doi: 10.1016/j.jclinepi.2017.04.026

Guidelines to writing a clinical case report. 2017. Heart Views . 18:104-105. doi: 10.4103/1995-705X.217857

Ortega-Loubon C, Culquichicon C, Correa R. The importance of writing and publishing case reports during medical education. 2017. Cureus. 9:e1964. doi: 10.7759/cureus.1964

Writing and publishing a useful and interesting case report. 2019. BMJ Case Reports. https://casereports.bmj.com/pages/wp-content/uploads/sites/69/2019/04/How-to-write-a-Case-Report-DIGITAL.pdf

Camm CF. Writing an excellent case report: EHJ Case Reports , Case of the Year 2019. 2020. European Heart Jounrnal. 41:1230-1231. https://doi.org/10.1093/eurheartj/ehaa176

*content developed by Mark Trottier, PhD

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Study protocol article, a protocol for the use of case reports/studies and case series in systematic reviews for clinical toxicology.

Introduction: Systematic reviews are routinely used to synthesize current science and evaluate the evidential strength and quality of resulting recommendations. For specific events, such as rare acute poisonings or preliminary reports of new drugs, we posit that case reports/studies and case series (human subjects research with no control group) may provide important evidence for systematic reviews. Our aim, therefore, is to present a protocol that uses rigorous selection criteria, to distinguish high quality case reports/studies and case series for inclusion in systematic reviews.

Methods: This protocol will adapt the existing Navigation Guide methodology for specific inclusion of case studies. The usual procedure for systematic reviews will be followed. Case reports/studies and case series will be specified in the search strategy and included in separate sections. Data from these sources will be extracted and where possible, quantitatively synthesized. Criteria for integrating cases reports/studies and case series into the overall body of evidence are that these studies will need to be well-documented, scientifically rigorous, and follow ethical practices. The instructions and standards for evaluating risk of bias will be based on the Navigation Guide. The risk of bias, quality of evidence and the strength of recommendations will be assessed by two independent review teams that are blinded to each other.

Conclusion: This is a protocol specified for systematic reviews that use case reports/studies and case series to evaluate the quality of evidence and strength of recommendations in disciplines like clinical toxicology, where case reports/studies are the norm.

Introduction

Systematic reviews are routinely relied upon to qualitatively synthesize current knowledge in a subject area. These reviews are often paired with a meta-analysis for quantitative syntheses. These qualitative and quantitative summaries of pooled data, collectively evaluate the quality of the evidence and the strength of the resulting research recommendations.

There currently exist several guidance documents to instruct on the rigors of systematic review methodology: (i) the Cochrane Collaboration, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and PRISMA-P (for protocols) that offer directives on data synthesis; and (ii) the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines that establish rules for the development of scientific recommendations ( 1 – 5 ). This systematic review guidance is based predominantly on clinical studies, where randomized controlled trials (RCTs) are the gold standard. For that reason, a separate group of researchers has designed the Navigation Guide, specific to environmental health studies that are often observational ( 6 , 7 ). To date, systematic review guidelines (GRADE, PRISMA, PRISMA-P, and Navigation Guide) remove case reports/studies and case series (human subjects research with no control group) from consideration in systematic reviews, in part due to the challenges in evaluating the internal validity of these kinds of study designs. We hypothesize, however, that under certain circumstances, such as in rare acute poisonings, or preliminary reports of new drugs, some case reports and case series may contribute relevant knowledge that would be informative to systematic review recommendations. This is particularly important in clinical settings, where such evidence could potentially change our understanding of the screening, presentation, and potential treatment of rare conditions, such as poisoning from obscure toxins. The Cochrane Collaboration handbook states that “ for some rare or delayed adverse outcomes only case series or case-control studies may be available. Non-randomized studies of interventions with some study design features that are more susceptible to bias may be acceptable for evaluation of serious adverse events in the absence of better evidence, but the risk of bias must still be assessed and reported ” ( 8 ). In addition, the Cochrane Adverse Effects group has shown that case studies may be the best settings in which to observe adverse effects, especially when they are rare and acute ( 9 ). We believe that there may be an effective way to consider case reports/studies and case series in systematic reviews, specifically by developing specific criteria for their inclusion and accounting for their inherent bias.

We propose here a systematic review protocol that has been specifically developed to consider the inclusion and integration of case reports/studies and case series. Our main objective is to create a protocol that is an adaptation of the Navigation Guide ( 6 , 10 ) that presents methodology to examine high quality case reports/studies and case series through cogent inclusion and exclusion criteria. This methodology is in concordance with the Cochrane Methods for Adverse Effects for scoping reviews ( 11 ).

This protocol was prepared in accordance with the usual structured methodology for systematic reviews (PRISMA, PRISMA-P, and Navigation guide) ( 3 – 7 , 10 ). The protocol will be registered on an appropriate website, such as one of the following:

(i) The International Prospective Register of Systematic Reviews (PROSPERO) database ( https://www.crd.york.ac.uk/PROSPERO/ ) is an international database of prospectively registered systematic reviews in health and social welfare, public health, education, crime, justice, and international development, where there is a health-related outcome. It aims to provide a comprehensive listing of systematic reviews registered at inception to help avoid duplication and reduce opportunity for reporting bias by enabling comparison of the completed review with what was planned in the protocol. PROSPERO accepts registrations for systematic reviews, rapid reviews, and umbrella reviews. Key elements of the review protocol are permanently recorded and stored.

(ii) The Open Science Framework (OSF) platform ( https://osf.io/ ) is a free, open, and integrated platform that facilitates open collaboration in research science. It allows for the management and sharing of research project at all stages of research for broad dissemination. It also enables capture of different aspects and products of the research lifecycle, from the development of a research idea, through the design of a study, the storage and analysis of collected data, to the writing and publication of reports or research articles.

(iii) The Research Registry (RR) database ( https://www.researchregistry.com/ ) is a one-stop repository for the registration of all types of research studies, from “first-in-man” case reports/studies to observational/interventional studies to systematic reviews and meta-analyses. The goal is to ensure that every study involving human participants is registered in accordance with the 2013 Declaration of Helsinki. The RR enables prospective or retrospective registrations of studies, including those types of studies that cannot be registered in existing registries. It specifically publishes systematic reviews and meta-analyses and does not register case reports/studies that are not first-in-man or animal studies.

Any significant future changes to the protocol resulting from knowledge gained during the development stages of this project will be documented in detail and a rationale for all changes will be proposed and reported in PROSPERO, OSF, or RR.

The overall protocol will differentiate itself from other known methodologies, by defining two independent teams of reviewers: a classical team and a case team. The classical team will review studies with control groups and an acceptable comparison group (case reports/studies and case series will be excluded). In effect, this team will conduct a more traditional systematic review where evidence from case reports/studies and case series are not considered. The case team will review classical studies, case reports, and case series. This case team will act as a comparison group to identify differences in systematic review conclusions due to the inclusion of evidence from case reports/studies and case series. Both teams will identify studies that meet specified inclusion criteria, conduct separate analyses and risk of bias evaluations, along with overall quality assessments, and syntheses of strengths of evidence. Each team will be blinded to the results of the other team throughout the process. Upon completion of the systematic review, results from each team will be presented, evaluated, and compared.

Patient and Public Involvement

No patient involved.

Eligibility Criteria

Studies will be selected according to the criteria outlined below.

Study Designs

Studies of any design reported in any translatable language to English by online programs (e.g., Google Translate) will be included at the beginning. These studies will span interventional studies with control groups (Randomized Controlled Trials: RCTs), as well as observational studies with and without exposed groups. All observational studies will be eligible for inclusion in accordance with the objectives of this systematic review. Thereafter, only the case team will include cases reports/studies and case series, as specified in their search strategy. The case team will include a separate section for human subjects research that has been conducted with no control groups.

Type of Population

All types of studies examining the general adult human population or healthy adult humans will be included. Studies that involve both adults and children will also be included if data for adults are reported separately. Animal studies will be excluded for the methodological purpose of this (case reports/studies and case series) protocol given that the framework for systematic reviews in toxicology already adequately retrieves this type of toxin data on animals.

Inclusion/Exclusion Criteria

Studies of any design will be included if they fulfill all the eligibility criteria. To be integrated into the overall body of evidence, cases reports/studies and case series must meet pre-defined criteria indicating that they are well-documented, scientifically rigorous, and follow ethical practices, under the CARE guidelines (for Ca se Re ports) ( 12 , 13 ) and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case reports/studies and for Case Series ( 14 , 15 ) that classify case reports/studies in terms of completeness, transparency and data analysis. Studies that were conducted using unethical practices will be excluded.

Type of Exposure/Intervention

Either the prescribed treatment or described exposure to a chemical substance (toxin/toxicant) will be detailed here.

Type of Comparators

In this protocol we plan to compare two review methodologies: one will include and the other will exclude high quality case reports/studies and case series; these two review methodologies will be compared. The comparator will be (the presence or absence of) an available control group that has been specified and is acceptable scientifically and ethically.

Type of Outcomes

The outcome of mortality or morbidity related to the toxicological exposure, will be detailed here.

Information Sources and Search Strategy

There will be no design, date or language limitations applied to the search strategy. A systematic search in electronic academic databases, electronic grey literature, organizational websites, and internet search engines will be performed. We will search at least the following major databases:

- Electronic academic databases : Pubmed, Web of Sciences, Toxline, Poisondex, and databases specific to case reports/studies and case series (e.g., PMC, Scopus, Medline) ( 13 )

- Electronic grey literature databases : OpenGrey ( http://www.opengrey.eu/ ), grey literature Report ( http://greylit.org/ )

- Organizational websites : AHRQ Patient Safety Network ( https://psnet.ahrq.gov/webmm ), World Health Organization ( www.who.int )

- Internet search engines : Google ( https://www.google.com/ ), GoogleScholar ( https://scholar.google.com/ ).

Study Records

Following a systematic search in all the databases above, each of the two independent teams of reviewers (the classical team and the case team) will, respectively, upload separately and in accordance with the eligibility criteria, the literature search results to the systematic review management software, “Covidence,” a primary screening and data extraction tool ( 16 ).

All study records identified during the search will be downloaded and duplicate records will be identified and deleted. Thereafter, two research team members will independently screen the titles and abstracts (step 1) and then the full texts (step 2) of potentially relevant studies for inclusion. If necessary, information will be requested from the publication authors to resolve questions about eligibility. Finally, any disagreements that may potentially exist between the two research team members will be resolved first by discussion and then by consulting a third research team member for arbitration.

If a study record identified during the search was authored by a reviewing research team member, or that team member participated in the identified study, that study record will be re-assigned to another reviewing team member.

Data Collection Process, Items Included, and Prioritization if Needed

All reviewing team members will use standardized forms or software (e.g., Covidence), and each review member will independently extract the data from included studies. If possible, the extracted data will be synthesized numerically. To ensure consistency across reviewers, calibration exercises (reviewer training) will be conducted prior to starting the reviews. Extracted information will include the minimum study characteristics (study authors, study year, study country, participants, intervention/exposure, outcome), study design (summary of study design, comparator, models used, and effect estimate measure) and study context (e.g., data on simultaneous exposure to other risk factors that would be relevant contributors to morbidity or mortality). As specified in the section on study records, a third review team member will resolve any conflicts that arise during data extraction that are not resolved by consensus between the two initial data extractors.

Data on potential conflict of interest for included studies, as well as financial disclosures and funding sources, will also be extracted. If no financial statement or conflict of interest declaration is available, the names of the authors will be searched in other studies published within the previous 36 months and in other publicly available declarations of interests, for funding information ( 17 , 18 ).

Risk of Bias Assessment

To assess the risk of bias within included studies, the internal validity of potential studies will be assessed by using the Navigation Guide tool ( 6 , 19 ), which covers nine domains of bias for human studies: (a) source population representation; (b) blinding; (c) exposure or intervention assessment; (d) outcome assessment; (e) confounding; (f) incomplete outcome data; (g) selective outcome reporting; (h) conflict of interest; and (i) other sources of bias. For each section of the tool, the procedures undertaken for each study will be described and the risk of bias will be rated as “ low risk”; “probably low risk”; “probably risk”; “high risk”; or “not applicable.” Risk of bias on the levels of the individual study and the entire body of evidence will be assessed. Most of the text from these instructions and criteria for judging risk of bias has been adopted verbatim or adapted from one of the latest Navigation Guide systematic reviews used by WHO/ILO ( 6 , 19 , 20 ).

For case reports/studies and case series, the text from these instructions and criteria for judging risk of bias has been adopted verbatim or adapted from one of the latest Navigation Guide systematic reviews ( 21 ), and is given in Supplementary Material . Specific criteria are listed below. To ensure consistency across reviewers, calibration exercises (reviewer training) will be conducted prior to starting the risk of bias assessments for case reports/studies and case series.

Are the Study Groups at Risk of Not Representing Their Source Populations in a Manner That Might Introduce Selection Bias?

The source population is viewed as the population for which study investigators are targeting their study question of interest.

Examples of considerations for this risk of bias domain include: (1) the context of the case report; (2) level of detail reported for participant inclusion/exclusion (including details from previously published papers referenced in the article), with inclusion of all relevant consecutive patients in the considered period; ( 14 , 15 ) (3) exclusion rates, attrition rates and reasons.

Were Exposure/Intervention (Toxic, Treatment) Assessment Methods Lacking Accuracy?

The following list of considerations represents a collection of factors proposed by experts in various fields that may potentially influence the internal validity of the exposure assessment in a systematic manner (not those that may randomly affect overall study results). These should be interpreted only as suggested considerations and should not be viewed as scoring or a checklist . Considering there are no controls in such designs, this should be evaluated carefully to be sure the report really contributes to the actual knowledge .

List of Considerations :

Possible sources of exposure assessment metrics:

1) Identification of the exposure

2) Dose evaluation

3) Toxicological values

4) Clinical effects *

5) Biological effects *

6) Treatments given (dose, timing, route)

* Some clinical and biological effects might be related to exposure

For each, overall considerations include:

1) What is the quality of the source of the metric being used?

2) Is the exposure measured in the study a surrogate for the exposure?

3) What was the temporal coverage (i.e., short or long-term exposure)?

4) Did the analysis account for prediction uncertainty?

5) How was missing data accounted for, and any data imputations incorporated?

6) Were sensitivity analyses performed?

Were Outcome Assessment Methods Lacking Accuracy?

Was Potential Confounding Inadequately Incorporated?

This is a very important issue for case reports/studies and case series. Case reports/studies and case series do not include controls and so, to be considered in a systematic review, these types of studies will need to be well-documented with respect to treatment or other contextual factors that may explain or influence the outcome. Prior to initiating the study screening, review team members should collectively generate a list of potential confounders that are based on expert opinion and knowledge gathered from the scientific literature:

Tier I: Important confounders

• Other associated treatment (i.e., intoxication, insufficient dose, history, or context)

• Medical history

Tier II: Other potentially important confounders and effect modifiers:

• Age, sex, country.

Were Incomplete Outcome Data Inadequately Addressed?

Does the Study Report Appear to Have Selective Outcome Reporting?

Did the Study Receive Any Support From a Company, Study Author, or Other Entity Having a Financial Interest?

Did the Study Appear to Have Other Problems That Could Put It at a Risk of Bias?

Data synthesis criteria and summary measures if feasible.

Meta-analyses will be conducted using a random-effects model if studies are sufficiently homogeneous in terms of design and comparator. For dichotomous outcomes, effects of associations will be determined by using risk ratios (RR) or odds ratios (OR) with 95% confidence intervals (CI). Continuous outcomes will be analyzed using weighted mean differences (with 95% CI) or standardized mean differences (with 95% CI) if different measurement scales are used. Skewed data and non-quantitative data will be presented descriptively. Where data are missing, a request will be made to the original authors of the study to obtain the relevant missing data. If these data cannot be obtained, an imputation method will be performed. The statistical heterogeneity of the studies using the Chi Squared test (significance level: 0.1) and I 2 statistic (0–40%: might not be important; 30–60%: may represent moderate heterogeneity; 50–90%: may represent substantial heterogeneity; 75–100%: considerable heterogeneity). If there is heterogeneity, an attempt will be made to explain the source of this heterogeneity through a subgroup or sensitivity analysis.

Finally, the meta-analysis will be conducted in the latest version of the statistical software RevMan. The Mantel-Haenszel method will be used for the fixed effects model if tests of heterogeneity are not significant. If statistical heterogeneity is observed ( I 2 ≥ 50% or p < 0.1), the random effects model will be chosen. If quantitative synthesis is not feasible (e.g., if heterogeneity exists), a meta-analysis will not be performed and a narrative, qualitative summary of the study findings will be done.

Separate analyses will be conducted for the studies that contain control groups using expected mortality/morbidity, in order to include them in the quantitative synthesis of case reports/studies and case series.

If quantitative synthesis is not appropriate, a systematic narrative synthesis will be provided with information presented in the text and tables to summarize and explain the characteristics and findings of the included studies. The narrative synthesis will explore the relationship and findings both within and between the included studies.

Possible Additional Analyses

If feasible, subgroup analyses will be used to explore possible sources of heterogeneity, if there is evidence for differences in effect estimates by country, study design, or patient characteristics (e.g., sex and age). In addition, sensitivity analysis will be performed to explore the source of heterogeneity as for example, published vs. unpublished data, full-text publications vs. abstracts, risk of bias (by omitting studies that are judged to be at high risk of bias).

Overall Quality of Evidence Assessment

The quality of evidence will be assessed using an adapted version of the Evidence Quality Assessment Tool in the Navigation Guide. This tool is based on the GRADE approach ( 1 ). The assessment will be conducted by two teams, again blinded to each other, one that has the results of the case reports/studies and case series/control synthesis, the other without.

Data synthesis will be conducted independently by the classical and case teams. Evidence ratings will start at “high” for randomized control studies, “moderate” for observational studies, and “low” for case reports/studies and case series . It is important to be clear that sufficient levels of evidence cannot be achieved without study comparators. With regards to case reports/studies and case series, we classify these as starting at the lowest point of evidence and therefore we cannot consider evidence higher than low for these kinds of studies. Complete instructions for making quality of evidence judgments are presented in Supplementary Material .

Synthesis of Strength of Evidence

The standard Navigation Guide methodology will be applied to rate the strength of recommendations. The classical and case teams, blinded to the results from each other during the process, will independently assess the strength of evidence. The evidence quality ratings will be translated into strength of evidence for each population based on a combination of four criteria: (a) Quality of body of evidence; (b) Direction of effect; (c) Confidence in effect; and (d) Other compelling attributes of the data that may influence certainty. The ratings for strength of evidence will be “sufficient evidence of harmfulness,” “limited of harmfulness,” “inadequate of harmfulness” and “evidence of lack of harmfulness.”

Once we complete the synthesis of case reports/studies and case series, findings of this separate evidence stream will only be considered if RCTs and observational studies are not available. They will not be used to upgrade or downgrade the strength of other evidence streams.

To the best of our knowledge, this protocol is one of the first to specifically address the incorporation of case reports/studies and case series in a systematic review ( 9 ). The protocol was adapted from the Navigation Guide with the intent of integrating the case reports/studies and case series in systematic review recommendations, while following traditional systematic review methodology to the greatest extent possible. To be included, these case report/studies and case series will need to be well-documented, scientifically rigorous, and follow ethical practices. In addition, we believe that some case reports/studies and case series might bring relevant knowledge that should be considered in systematic review recommendations when data from RCT's and observational studies are not available, especially when even a small number of studies report an important and possibly causal association in an epidemic or a side effect of a newly marketed medicine. Our methodology will be the first to effectively incorporate case reports/studies and case series in systematic reviews that synthesize evidence for clinicians, researchers, and drug developers. These types of studies will be incorporated mostly through paper selection and risk of bias assessments. In addition, we will conduct meta-analyses if the eligible studies provide sufficient data.

This protocol has limitations related primarily to the constraints of case reports/studies and case series. These are descriptive studies. In addition, a case series is subject to selection bias because the clinician or researcher selects the cases themselves and may represent outliers in clinical practice. Furthermore, this kind of study does not have a control group, so it is not possible to compare what happens to other people who do not have the disease or receive treatment. These sources of bias mean that reported results may not be generalizable to a larger patient population and therefore cannot generate information on incidences or prevalence rates and ratios ( 22 , 23 ). However, it is important to note that promoting the need to synthesize these types of studies (case reports/studies and case series) in a formal systematic review, should not deter or delay immediate action from being taken when a few small studies report a plausible causal association between exposure and disease, such as, in the event of an epidemic or a side effect of a newly marketed medicine ( 23 ). In this study protocol, we will not consider animal studies that might give relevant toxicological information because we are focusing on study areas where a paucity of information exists. Finally, we must note that, case reports/studies and case series do not provide independent proof, and therefore, the findings of this separate evidence stream (case reports/studies and case series) will only be considered if evidence from RCTs and observational studies is not available. Case reports/studies and case series will not be used to upgrade or downgrade the strength of other evidence streams. In any case, it is very important to remember that these kinds of studies (case reports/studies and case series) are there to quickly alert agencies of the need to take immediate action to prevent further harm.

Despite these limitations, case reports/studies and case series are a first line of evidence because they are where new issues and ideas emerge (hypothesis-generating) and can contribute to a change in clinical practice ( 23 – 25 ). We therefore believe that data from case reports/studies and case series, when synthesized and presented with completeness and transparency, may provide important details that are relevant to systematic review recommendations.

Author Contributions

AD and GS the protocol study was designed. JL, TW, and DM reviewed. MF, ALG, RV, NC, CB, GLR, MD, ML, and AN significant improvement was made. AN and AD wrote the manuscript. GS improved the language. All authors reviewed and commented on the final manuscript, read and approved the final manuscript to be published.

This project was supported by the French Pays de la Loire region and Angers Loire Métropole, University of Angers and Centre Hospitalo-Universitaire CHU Angers. The project is entitled TEC-TOP (no award/grant number).

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.

Publisher's Note

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.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.708380/full#supplementary-material

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Keywords: toxicology, epidemiology, public health, protocol, systematic review, case reports/studies, case series

Citation: Nambiema A, Sembajwe G, Lam J, Woodruff T, Mandrioli D, Chartres N, Fadel M, Le Guillou A, Valter R, Deguigne M, Legeay M, Bruneau C, Le Roux G and Descatha A (2021) A Protocol for the Use of Case Reports/Studies and Case Series in Systematic Reviews for Clinical Toxicology. Front. Med. 8:708380. doi: 10.3389/fmed.2021.708380

Received: 19 May 2021; Accepted: 11 August 2021; Published: 06 September 2021.

Reviewed by:

Copyright © 2021 Nambiema, Sembajwe, Lam, Woodruff, Mandrioli, Chartres, Fadel, Le Guillou, Valter, Deguigne, Legeay, Bruneau, Le Roux and Descatha. 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: Aboubakari Nambiema, aboubakari.nambiema@univ-angers.fr ; orcid.org/0000-0002-4258-3764

How to review a case report

Journal of Medical Case Reports volume 10 , Article number: 88 ( 2016 ) Cite this article

Introduction

Sharing individual patient experiences with clinical colleagues is an essential component of learning from each other. This sharing of information may be made global by reporting in a scientific journal. In medicine, patient management decisions are generally based on the evidence available for use of a particular investigation or technology [ 1 ]. The hierarchical rank of the evidence signifies the probability of bias. The higher up the hierarchy, the better its reliability and thus its clinical acceptance (Table 1 ). Though case reports remain lowest in the hierarchy of evidence, with meta-analysis representing the highest level, they nevertheless constitute important information with regard to rare events and may be considered as anecdotal evidence [ 2 ] (Table 1 ). Case reports may stimulate the generation of new hypotheses, and thus may support the emergence of new research.

The definition of a case report or a case series is not well defined in the literature and has been defined variously by different journals and authors. However, the basic definition of a case report is the detailed report of an individual including aspects like exposure, symptoms, signs, intervention, and outcome. It has been suggested that a report with more than four cases be called a case series and those with fewer than four a case report [ 3 ]. A case series is descriptive in design. Other authors describe “a collection of patients” as a case series and “a few patients” as a case report [ 4 ]. We suggest that should more than one case be reported, it may be defined as a case series—a concept proposed by other authors [ 5 ].

The importance of case reports

A case report may describe an unusual etiology, an unusual or unknown disorder, a challenging differential diagnosis, an unusual setting for care, information that can not be reproduced due to ethical reasons, unusual or puzzling clinical features, improved or unique technical procedures, unusual interactions, rare or novel adverse reactions to care, or new insight into the pathogenesis of disease [ 6 , 7 ]. In recent years, the publication of case reports has been given low priority by many high impact factor journals. However, the need for reporting such events remains. There are some journals dedicated purely to case reports, such as the Journal of Medical Case Reports , emphasizing their importance in modern literature. In the past, isolated case reports have led to significant advancements in patient care. For example, case reports concerning pulmonary hypertension and anorexic agents led to further trials and the identification of the mechanism and risk factors associated with these agents [ 2 , 8 ].

Reporting and publishing requirements

The reporting of cases varies for different journals. The authors need to follow the instructions for the intended publication. Owing to significant variability, it would be difficult to have uniform publication guidelines for case reports. A checklist called the CARE guidelines is useful for authors writing case reports [ 9 , 10 ]. However, it would be universally prudent to include a title, keywords, abstract, introduction, patient information, clinical findings, timeline, diagnostic assessment, therapeutic interventions, follow-up and outcomes, discussion, patient perspective, and informed consent.

Peer review process

The peer review process is an essential part of ethical and scientific writing. Peer review ultimately helps improve articles by providing valuable feedback to the author and helps editors make a decision regarding publication. The peer reviewer should provide unbiased, constructive feedback regarding the manuscript. They may also highlight the strengths and weaknesses of the report. When reviewing an article, it is prudent to read the entire manuscript first to understand the overall content and message. The reviewer than may read section-wise and provide comments to the authors and editorial team accordingly. The reviewer needs to consider the following important points when reviewing a case for possible publication [ 8 , 9 ] (summarized in Table 2 ).

Novelty remains the foremost important aspect of a case. The case report should introduce novel aspects of patient evaluation, investigation, treatment, or any other aspect related to patient care. The relevant information becomes a hypothesis generator for further study. The novelty may at times be balanced with some important information like severe adverse effects, even if they have been reported earlier. Reporting adverse events remains important so that information on cumulative adverse effects can be gathered globally, which helps in preparing a policy or guideline or a warning note for its use in patients. The data related to adverse effects include not only the impact but also the number of patients affected. This becomes more important for serious adverse effects. In the absence of an international registry for adverse effects, published case reports are important pieces of information. Owing to ethical concerns, formal evaluation may not be feasible in the format of prospective study.

Essential description

The case needs to have all essential details to allow a useful conclusion to emerge. For example, if a case is being reported for hemodynamic variability due to a drug, then the drug dose and timing along with timed vital signs need to be described.

Authenticity and genuineness

Honesty remains the most important basic principle of all publications. This remains a primary responsibility of the authors. However, if there is any doubt, reviewers may seek clarification. This doubt may result from some discordance in the case description. At times, a lack of correlation between the figures and description may act as “red flags.” For instance, authors may discuss a technique for dealing with a difficult airway, but the figure is of a normal-appearing airway. Another example would be where the data and figure do not correlate in a hemodynamic response related to a drug or a technique, with the graphical picture or screenshot of hemodynamics acting as an alert sign. Such cause for concern may be communicated in confidence to the editor.

Ethical or competing interests

Ethical issues need to be cautiously interpreted and communicated. The unethical use of a drug or device is not desirable and often unworthy of publication. This may relate to the route or dose of the drug administered. The off-label use of drugs where known side effects are greater than potential benefit needs to be discouraged and remains an example of unethical use. This use may be related to the drug dose, particularly when the drug dose exceeds the routine recommended dose, or to the route of administration. As an example, the maximal dose of acetaminophen (paracetamol) is 4g/day, and if an author reports exceeding this dose, it should be noted why a greater than recommended dose was used. Ultimately, the use of a drug or its route of administration needs to be justified in the manuscript. The reviewers need to serve as content experts regarding the drugs and other technologies used in the case. A literature search by the reviewer provides the data to comment on this aspect.

Competing interests (or conflicts of interest) are concerns that interfere or potentially interfere with presentation, review, or publication. They must be declared by the authors. Conflicts can relate to patient-related professional attributes (like the use of a particular procedure, drug, or instrument) being affected by some secondary gains (financial, non-financial, professional, personal). Financial conflict may be related to ownership, paid consultancy, patents, grants, honoraria, and gifts. Non-financial conflicts may be related to memberships, relationships, appearance as an expert witness, or personal convictions. At times, the conflict may be related to the author’s relationship with an organization or another person. A conflict may influence the interpretation of the outcome in an inappropriate and unscientific manner. Although conflicts may not be totally abolished, they must be disclosed when they reasonably exist. This disclosure should include information such as funding sources, present membership, and patents pending. Reviewers should cautiously interpret any potential bias regarding the outcome of the case based on the reported conflicts. This is essential for transparent reporting of research. At times, competing interests may be discovered by a reviewer and should be included in comments to the editorial team. Such conflicts may again be ascertained when the reviewer reviews the literature during the peer review process. The reviewer should also disclose their own conflicts related to the manuscript review when sending their report to the editorial team.

Impact on clinical practice

This is an important aspect for the final decision of whether to publish a case report. The main thrust or carry-home message needs to be emphasized clearly. It needs to be elaborated upon in concluding remarks.

Patient anonymity, consent, and ethical approval

When reviewing the manuscript of a case report, reviewers should ensure that the patient’s anonymity and confidentiality is protected. The reviewers should check that patient identifiers have been removed or masked from all aspects of the manuscript, whether in writing or within photograph. Identifiers can include things like the name of the patient, geographical location, date of birth, phone numbers, email of the patient, medical record numbers, or biometric identifiers. Utmost care needs to be taken to provide full anonymity for the patient.

Consent is required to participate in research, receive a certain treatment, and publish identifiable details. These consents are for different purposes and need to be explained separately to the patient. A patient’s consent to participate in the research or for use of the drug may not extend to consent for publication. All these aspects of consent must be explained to the patient, written explicitly in the patient’s own language, understood by the patient, and signed by the patient. For the purpose of the case, the patient must understand and consent for any new technique or drug (its dose, route, and timing) being used. In the case of a drug being used for a non-standard indication or route, consent for use must also be described. Patient consent is essential for the publication of a case if patient body parts are displayed in the article. This also includes any identifiers that can reveal the identity of the patient, such as the patient’s hospital identification number, address, and any other unique identifier. In situations where revealing the patient’s identity cannot be fully avoided, for example if the report requires an image of an identifiable body part like the face, then this should be explained to the patient, the image shown to them, and consent taken. Should the patient die, then consent must be obtained from next of kin or legal representative.

With case series, securing individual patient consent is advised and preferable. The authors may also need institutional review board (IRB) approval to publish a case series. IRBs can waive the need for consent if a study is conducted retrospectively and data are collected from patient notes for the purpose of research, usually in an anonymized way. However, wherever possible, individual patient consent is preferable, even for a retrospective study. Consent is mandatory for any prospective data collection for the purpose of publication as a case series. Consent and/or IRB approval must be disclosed in the case report and reasons for not obtaining individual consent may be described, if applicable.

There may be situations in which publishing patient details without their consent is justified, but this is a decision that should be made by the journal editor, who may decide to discuss the case with the Committee on Publication Ethics. Reviewers need to emphasize the issue to the editor when submitting their comments.

Manuscript writing

The CARE guidelines provide a framework that supports transparency and accuracy in the publication of case reports and the reporting of information from patient encounters. The acronym CARE was created from CA (the first two letters in “case”) and RE (the first two letters in “reports”). The initial CARE tools are the CARE checklist and the Case Report Writing Templates. These tools support the writing of case reports and provide data that inform clinical practice guidelines and provide early signals of effectiveness, harms, and cost [ 10 ].

The presentation of the case and its interpretation should be comprehensive and related. The various components of the manuscript should have sufficient information for understanding the key message of the case. The reviewer needs to comment on the relevant components of the manuscript. The reviewer should ascertain that the title of the case manuscript is relevant and includes keywords related to the case. The title should be short, descriptive, and interesting. The abstract should be brief, without any abbreviations, and include keywords. It is preferable to use Medical Subject Headings (MeSH) keywords. Reviewers must ensure that the introduction emphasizes the context of the case and describes the relevance and its importance in a concise and comprehensive manner. The case description should be complete and should follow basic rules of medical communication. The details regarding patient history, physical examination, investigations, differential diagnosis, management, and outcome should be described in chronological order. If repeated observations are present, then they may be tabulated. The use of graphs and figures helps the readers to better understand the case. Interpretation or inferences based on the outcomes should be avoided in this section and should be considered a part of the discussion. The discussion should highlight important aspects of the case, with its interpretation within the context of the available literature. References should be formatted as per the journal style. They should be complete and preferably of recent publications.

Reviewer responsibility

The reviewer’s remarks are essential not only for the editorial team but also for authors. A good peer review requires honesty, sincerity, and punctuality. Even if a manuscript is rejected, the authors should receive learning points from peer review commentary. The best way to review a manuscript is to read the manuscript in full for a gross overview and develop general comments. Thereafter, the reviewer should address each section of the manuscript separately and precisely. This may be done after a literature search if the reviewer needs to substantiate his/her commentary.

Constructive criticism

The reviewer’s remarks should be constructive to help the authors improve the manuscript for further consideration. If the manuscript is rejected, the authors should have a clear indication for the rejection. The remarks may be grouped as major and minor comments. Major comments likely suggest changes to the whole presentation, changing the primary aim of the case report, or adding images. Minor comments may include grammatical errors or getting references for a statement. The editorial team must be able to justify their decision on whether or not to accept an article for publication, often by citing peer review feedback. It is also good style to tabulate a list of the strengths and weaknesses of the manuscript.

Fixed time for review

Reviewer remarks should be submitted within a specified timeframe. If any delay is expected, it should be communicated to the editorial team. Reviewers should not rush to submit feedback without sufficient time to adequately review the paper and perform any necessary literature searches. Should a reviewer be unable to submit the review within the specified timeframe, they should reply to the review invitation to decline at their earliest convenience. If, after accepting a review invitation, the reviewer realizes they do not have time to perform the review, this must be communicated to the editorial team.

Conflict of interest

The reviewer’s conflicts of interest should be included along with the review. The conflicts may be related to the contents of the case, drugs, or devices pertaining to the case; the author(s); or the affiliated institution(s) of the author(s).

Lack of expertise

The reviewer may decline to review the manuscript if they think the topic is out of their area of expertise. If, after accepting an invitation to review, the reviewer realizes they are unable to review the manuscript owing to a lack of expertise in that particular field, they should disclose the fact to the editorial team.

Confidentiality

The reviewer should keep the manuscript confidential and should not use the contents of the unpublished manuscript in any form. Discussing the manuscript among colleagues or any scientific forum or meetings is inappropriate.

Review of revised manuscript

At times, a manuscript is sent for re-review to the reviewer. The reviewer should read the revised manuscript, the author’s response to the previous round of peer review, and the editorial comments. Sometimes, the authors may disagree with the reviewer’s remarks. This issue needs to be elaborated on and communicated with the editor. The reviewer should support their views with appropriate literature references. If the authors justify their reason for disagreeing with the viewer, then their argument should be considered evidence-based. However, if the reviewer still requests the revision, this may be politely communicated to the author and editor with justification for the same. In response to reviewers remarks, authors may not agree fully and provide certain suggestion in the form of clarification related to reviewers remarks. The reviewers should take these clarifications judiciously and comment accordingly with the intent of improving the manuscript further.

Peer reviewers have a significant role in the dissemination of scientific literature. They act as gatekeepers for science before it is released to society. Their sincerity and dedication is paramount to the success of any journal. The reviewers should follow a scientific and justifiable methodology for reviewing a case report for possible publication. Their comments should be constructive for the overall improvement of the manuscript and aid the editorial team in making a decision on publication. We hope this article will help reviewers to perform their important role in the best way possible. We send our best wishes to the reviewer community and, for those who are inspired to become reviewers after reading this article, our warm welcome to the reviewers’ club.

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Department of Anaesthesiology, Pain and Palliative Care, DR BRAIRCH, AIIMS, Ansari Nagar, New Delhi, 110029, India

Rakesh Garg

Neurology and Medical Education, California University of Science and Medicine - School of Medicine, Colton, CA, USA

Shaheen E. Lakhan

Sandwell & West Birmingham Hospitals, NHS Trust, Birmingham, UK

Ananda K. Dhanasekaran

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Correspondence to Rakesh Garg .

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The authors declare that they have no competing interests.

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All authors read and approved the final manuscript.

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Garg, R., Lakhan, S.E. & Dhanasekaran, A.K. How to review a case report. J Med Case Reports 10 , 88 (2016). https://doi.org/10.1186/s13256-016-0853-3

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DOI : https://doi.org/10.1186/s13256-016-0853-3

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epidemiology

In 1904, Dr James Herrick evaluated a 20-year-old patient from Grenada who was studying in Chicago and suffered from anaemia and a multisystem illness. The patient was found to have ‘freakish’ elongated red cells that resembled a crescent or a sickle. Dr Herrick concluded that the red cells were not artefacts because the appearance of the cells was maintained regardless of how the smear slide was prepared. He followed the patient who had subsequently received care from other physicians until 1907 and questioned whether this was syphilis or a parasite from the tropics. Then in 1910, in a published case report, he concluded that this presentation strongly suggested a previously unrecognised change in the composition of the corpuscle itself. 1 Sickle cell disease became a diagnosis thereafter.

Case reports and case series have profoundly influenced the medical literature and continue to advance our knowledge in the present time. In 1985, the American Medical Association reprinted 51 papers from its journal that had significantly changed the science and practice of medicine over the past 150 years, and five of these papers were case reports. 2 However, concerns about weak inferences and the high likelihood of bias associated with such reports have resulted in minimal attention being devoted to developing frameworks for approaching, appraising, synthesising and applying evidence derived from case reports/series. Nevertheless, such observations remain the bread and butter of learning by pattern recognition and integral to advancing medical knowledge.

Guidance on how to write a case report is available (ie, a reporting guideline). The Case Report (CARE) guidelines 3 were developed following a three-phase consensus process and provide a 13-item checklist that can assist researchers in publishing complete and meaningful exposition of medical information. This checklist encourages the explicit presentation of patient information, clinical findings, timeline, diagnostic assessment, therapeutic interventions, follow-up and outcomes. 3 Yet, systematic reviewers appraising the evidence for decision-makers require tools to assess the methodological quality (risk of bias assessment) of this evidence.

In this guide, we present a framework to evaluate the methodological quality of case reports/series and synthesise their results, which is particularly important when conducting a systematic review of a body of evidence that consists primarily of uncontrolled clinical observations.

Definitions

In the biomedical published literature, a case report is the description of the clinical course of one individual, which may include particular exposures, symptoms, signs, interventions or outcomes. A case report is the smallest publishable unit in the literature, whereas case series report aggregates individual cases in one publication. 4

If a case series is prospective, differentiating it from a single-arm uncontrolled cohort study becomes difficult. In one clinical practice guideline, it was proposed that studies without internal comparisons can be labelled as case series unless they explicitly report having a protocol before commencement of data collection, a definition of inclusion and exclusion criteria, a standardised follow-up and clear reporting of the number of excluded patients and those lost to follow-up. 6

Evaluating methodological quality

Pierson 7 provided an approach to evaluate the validity of a case report based on five components: documentation, uniqueness, objectivity, interpretation and educational value, resulting in a score with a maximum of 10 (a score above 5 was suggested indicate a valid case report). This approach, however, was rarely used in subsequent work and seems to conflate methodological quality with other constructs. For case reports of adverse drug reactions, other systems classify an association as definite, probable, possible or doubtful based on leading questions. 8 9 These questions are derived from the causality criteria that was established in 1965 by the English epidemiologist Bradford Hills. 10 Lastly, we have adapted the Newcastle Ottawa scale 11 for cohort and case–control studies by removing items that relate to comparability and adjustment (which are not relevant to non-comparative studies) and retained items that focused on selection, representativeness of cases and ascertainment of outcomes and exposure. This tool was applied in several published systematic reviews with good inter-rater agreement. 12–16

Proposed tool

The previous criteria from Pierson, 7 Bradford Hills 10 and Newcastle Ottawa scale modifications 11 converge into eight items that can be categorised into four domains: selection, ascertainment, causality and reporting. The eight items with leading explanatory questions are summarised in table 1 .

View inline

Tool for evaluating the methodological quality of case reports and case series

For example, a study that explicitly describes all the cases who have presented to a medical centre over a certain period of time would satisfy the selection domain. In contrast, a study that reports on several individuals with unclear selection approach leaves the reader with uncertainty to whether this is the whole experience of the researchers and suggests possible selection bias. For the domain of ascertainment, self-report (of the exposure or the outcome) is less reliable than ascertainment using administrative and billing codes, which in turn is less reliable than clinical records. For the domain of causality, we would have stronger inference in a case report of an adverse drug reaction that has resolved with cessation of the drug and reoccurred after reintroduction of the drug. Lastly, for the domain of reporting, a case report that is described with sufficient details may allow readers to apply the evidence derived from the report in their practice. On the other hand, an inadequately reported case will likely be unhelpful in the course of clinical care.

We suggest using this tool in systematic reviews of case reports/series. One option to summarise the results of this tool is to sum the scores of the eight binary responses into an aggregate score. A better option is not to use an aggregate score because numeric representation of methodological quality may not be appropriate when one or two questions are deemed most critical to the validity of a report (compared with other questions). Therefore, we suggest making an overall judgement about methodological quality based on the questions deemed most critical in the specific clinical scenario.

Synthesis of case reports/series

A single patient case report does not allow the estimation of an effect size and would only provide descriptive or narrative results. Case series of more than one patient may allow narrative or quantitative synthesis.

Narrative synthesis

A systematic review of the cases with the rare syndrome of lipodystrophy was able to suggest core and supportive clinical features and narratively summarised data on available treatment approaches. 17 Another systematic review of 172 cases of the infrequently encountered glycogenic hepatopathy was able to characterise for the first time patterns of liver enzymes and hepatic injury in this disease. 18

Quantitative synthesis

Quantitative analysis of non-comparative series does not produce relative association measures such as ORs or relative risks but can provide estimates of prevalence or event rates in the form of a proportion (with associated precision). Proportions can be pooled using fixed or random effects models by means of the various available meta-analysis software. For example, a meta-analysis of case series of patients presenting with aortic transection showed that mortality was significantly lower in patients who underwent endovascular repair, followed by open repair and non-operative management (9%, 19% and 46%, respectively, P<0.01). 19

A common challenge, however, occurs when proportions are too large or too small (close to 0 or to 1). In this situation, the variance of the proportion becomes very small leading to an inappropriately large weight in meta-analysis. One way to overcome this challenge is to transform prevalence to a variable that is not constrained to the 0–1 range and has approximately normal distribution, conduct the meta-analysis and then transform the estimate back to a proportion. 20 This is done using logit transformation or using the Freeman-Tukey double arcsine transformation, 21 with the latter being often preferred. 20

Another type of quantitative analysis that may be utilised is regression. A meta-analysis of 47 published cases of hypocalcaemia and cardiac dysfunction used univariate linear regression analysis to demonstrate that both QT interval and left ventricular ejection fraction were significantly correlated with corrected total serum calcium level. 22 Meta-regression, which is a regression in which the unit of analysis is a study, not a patient, can also be used to synthesise case series and control for study-level confounders. A meta-regression analysis of uncontrolled series of patients with uveal melanoma treated with proton beam therapy has shown that this treatment was associated with better outcomes than brachytherapy. 23 It is very important, however, to recognise that meta-regression results can be severely affected by ecological bias.

From evidence to decision

Several authors have described various important reasons to publish case reports/series ( table 2 ). 7 24 25

Role of case reports/series in the medical literature

It is paramount to recognise that a systematic review and meta-analysis of case reports/series should not be placed at the top of the hierarchy in a pyramid that depicts validity. 26 The certainty of evidence derived from a meta-analysis is contingent on the design of included studies, their risk of bias, as well as other factors such as imprecision, indirectness, inconsistency and likelihood of publication bias. 27 Commonly, certainty in evidence derived from case series/reports will be very low. Nevertheless, inferences from such reports can be used for decision-making. In the example of case series of aortic transection showing lower mortality with endovascular repair, a guideline recommendation was made stating ‘We suggest that endovascular repair be performed preferentially over open surgical repair or non-operative management’. This was graded as a weak recommendation based on low certainty evidence. 28 The strength of this recommendation acknowledged that the recommendation might not universally apply to everyone and that variability in decision-making was expected. The certainty in evidence rating of this recommendation implied that future research would likely yield different results that may change the recommendation. 28

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach clearly separates the certainty of evidence from the strength of recommendation. This separation allows decision-making based on lower levels of evidence. For example, despite low certainty evidence (derived from case series) regarding the association between aspirin and Reye’s syndrome in febrile children, a strong recommendation for using acetaminophen over aspirin is possible. 29 GRADE literature also describes five paradigmatic situations in which a strong recommendation can be made based on low quality evidence. 30 One of which is when the condition is life threatening. An example of which would be using hyperbaric oxygen therapy for purpura fulminans, which is only based on case reports. 31

Guideline developers and decision-makers often struggle when dealing with case reports/case series. On occasions, they ignore such evidence and focus the scope of guidelines on areas with higher quality evidence. Sometimes they label recommendations based on case reports as expert opinion. 32 We propose an approach to evaluate the methodological quality of case reports/series based on the domains of selection, ascertainment, causality and reporting and provide signalling questions to aid evidence-based practitioners and systematic reviewers in their assessment. We suggest the incorporation of case reports/series in decision-making based on the GRADE approach when no other higher level of evidence is available.

In this guide, we have made the case for publishing case reports/series and proposed synthesis of their results in systematic reviews to facilitate using this evidence in decision-making. We have proposed a tool that can be used to evaluate the methodological quality in systematic reviews that examine case reports and case series.

Contributors MHM drafted the paper and all coauthors critically revised the manuscript. All the authors contributed to conceive the idea and approved the final submitted version.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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