case study for therapy

How to Write a Case Conceptualization: 10 Examples (+ PDF)

Such understanding can be developed by reading relevant records, meeting with clients face to face, and using assessments such as a mental status examination.

As you proceed, you are forming a guiding concept of who this client is, how they became who they are, and where their personal journey might be heading.

Such a guiding concept, which will shape any needed interventions, is called a case conceptualization, and we will examine various examples in this article.

Before you continue, we thought you might like to download our three Positive CBT Exercises for free . These science-based exercises will provide you with detailed insight into positive Cognitive-Behavioral Therapy (CBT) and give you the tools to apply it in your therapy or coaching.

This Article Contains:

What is a case conceptualization or formulation, 4 things to include in your case formulation, a helpful example & model, 3 samples of case formulations, 6 templates and worksheets for counselors, relevant resources from positivepsychology.com, a take-home message.

In psychology and related fields, a case conceptualization summarizes the key facts and findings from an evaluation to provide guidance for recommendations.

This is typically the evaluation of an individual, although you can extend the concept of case conceptualization to summarizing findings about a group or organization.

Based on the case conceptualization, recommendations can be made to improve a client’s self-care , mental status, job performance, etc (Sperry & Sperry, 2020).

• Summary of the client’s identifying information, referral questions, and timeline of important events or factors in their life . A timeline can be especially helpful in understanding how the client’s strengths and limitations have evolved.
• Statement of the client’s core strengths . Identifying core strengths in the client’s life should help guide any recommendations, including how strengths might be used to offset limitations.
• Statement concerning a client’s limitations or weaknesses . This will also help guide any recommendations. If a weakness is worth mentioning in a case conceptualization, it is worth writing a recommendation about it.

Note: As with mental status examinations , observations in this context concerning weaknesses are not value judgments, about whether the client is a good person, etc. The observations are clinical judgments meant to guide recommendations.

• A summary of how the strengths, limitations, and other key information about a client inform diagnosis and prognosis .

You should briefly clarify how you arrived at a given diagnosis. For example, why do you believe a personality disorder is primary, rather than a major depressive disorder?

Many clinicians provide diagnoses in formal psychiatric terms, per the International Classification of Diseases (ICD-10) or Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Some clinicians will state a diagnosis in less formal terms that do not coincide exactly with ICD-10 or DSM-5 codes. What is arguably more important is that a diagnostic impression, formal or not, gives a clear sense of who the person is and the support they need to reach their goals.

Prognosis is a forecast about whether the client’s condition can be expected to improve, worsen, or remain stable. Prognosis can be difficult, as it often depends on unforeseeable factors. However, this should not keep you from offering a conservative opinion on a client’s expected course, provided treatment recommendations are followed.

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Based on the pointers for writing a case conceptualization above, an example for summarizing an adolescent case (in this instance, a counseling case for relieving depression and improving social skills) might read as follows.

Background and referral information

This is a 15-year-old Haitian–American youth, referred by his mother for concerns about self-isolation, depression, and poor social skills. He reportedly moved with his mother to the United States three years ago.

He reportedly misses his life and friends in Haiti. The mother states he has had difficulty adjusting socially in the United States, especially with peers. He has become increasingly self-isolating, appears sad and irritable, and has started to refuse to go to school.

His mother is very supportive and aware of his emotional–behavioral needs. The youth has been enrolled in a social skills group at school and has attended three sessions, with some reported benefit. He is agreeable to start individual counseling. He reportedly does well in school academically when he applies himself.

Limitations

Behavioral form completed by his mother shows elevated depression scale (T score = 80). There is a milder elevation on the inattention scale (T score = 60), which suggests depression is more acute than inattention and might drive it.

He is also elevated on a scale measuring social skills and involvement (T score = 65). Here too, it is reasonable to assume that depression is driving social isolation and difficulty relating to peers, especially since while living in Haiti, he was reportedly quite social with peers.

Diagnostic impressions, treatment guidance, prognosis

This youth’s history, presentation on interview, and results of emotional–behavioral forms suggest some difficulty with depression, likely contributing to social isolation. As he has no prior reported history of depression, this is most likely a reaction to missing his former home and difficulty adjusting to his new school and peers.

Treatments should include individual counseling with an evidence-based approach such as Cognitive-Behavioral Therapy (CBT). His counselor should consider emotional processing and social skills building as well.

Prognosis is favorable, with anticipated benefit apparent within 12 sessions of CBT.

How to write a case conceptualization: An outline

The following outline is necessarily general. It can be modified as needed, with points excluded or added, depending on the case.

• Client’s gender, age, level of education, vocational status, marital status
• Referred by whom, why, and for what type of service (e.g., testing, counseling, coaching)
• In the spirit of strengths-based assessment, consider listing the client’s strengths first, before any limitations.
• Consider the full range of positive factors supporting the client.
• Physical health
• Family support
• Financial resources
• Capacity to work
• Resilience or other positive personality traits
• Emotional stability
• Cognitive strengths, per history and testing
• The client’s limitations or relative weaknesses should be described in a way that highlights those most needing attention or treatment.
• Medical conditions affecting daily functioning
• Lack of family or other social support
• Limited financial resources
• Inability to find or hold suitable employment
• Substance abuse or dependence
• Proneness to interpersonal conflict
• Emotional–behavioral problems, including anxious or depressive symptoms
• Cognitive deficits, per history and testing
• Diagnoses that are warranted can be given in either DSM-5 or ICD-10 terms.
• There can be more than one diagnosis given. If that’s the case, consider describing these in terms of primary diagnosis, secondary diagnosis, etc.
• The primary diagnosis should best encompass the client’s key symptoms or traits, best explain their behavior, or most need treatment.
• Take care to avoid over-assigning multiple and potentially overlapping diagnoses.

When writing a case conceptualization, always keep in mind the timeline of significant events or factors in the examinee’s life.

• Decide which events or factors are significant enough to include in a case conceptualization.
• When these points are placed in a timeline, they help you understand how the person has evolved to become who they are now.
• A good timeline can also help you understand which factors in a person’s life might be causative for others. For example, if a person has suffered a frontal head injury in the past year, this might help explain their changeable moods, presence of depressive disorder, etc.

Sample #1: Conceptualization for CBT case

This is a 35-year-old Caucasian man referred by his physician for treatment of generalized anxiety.

Strengths/supports in his case include willingness to engage in treatment, high average intelligence per recent cognitive testing, supportive family, and regular physical exercise (running).

Limiting factors include relatively low stress coping skills, frequent migraines (likely stress related), and relative social isolation (partly due to some anxiety about social skills).

The client’s presentation on interview and review of medical/psychiatric records show a history of chronic worry, including frequent worries about his wife’s health and his finances. He meets criteria for DSM-5 generalized anxiety disorder. He has also described occasional panic-type episodes, which do not currently meet full criteria for panic disorder but could develop into such without preventive therapy.

Treatments should include CBT for generalized anxiety, including keeping a worry journal; regular assessment of anxiety levels with Penn State Worry Questionnaire and/or Beck Anxiety Inventory; cognitive restructuring around negative beliefs that reinforce anxiety; and practice of relaxation techniques, such as progressive muscle relaxation and diaphragmatic breathing .

Prognosis is good, given the evidence for efficacy of CBT for anxiety disorders generally (Hofmann, Asnaani, Vonk, Sawyer, & Fang, 2012).

Sample #2: Conceptualization for DBT case

This 51-year-old Haitian–American woman is self-referred for depressive symptoms, including reported moods of “rage,” “sadness,” and “emptiness.” She says that many of her difficulties involve family, friends, and coworkers who regularly “disrespect” her and “plot against her behind her back.”

Her current psychiatrist has diagnosed her with personality disorder with borderline features, but she doubts the accuracy of this diagnosis.

Strengths/supports include a willingness to engage in treatment, highly developed and marketable computer programming skills, and engagement in leisure activities such as playing backgammon with friends.

Limiting factors include low stress coping skills, mild difficulties with attention and recent memory (likely due in part to depressive affect), and a tendency to self-medicate with alcohol when feeling depressed.

The client’s presentation on interview, review of medical/psychiatric records, and results of MMPI-2 personality inventory corroborate her psychiatrist’s diagnosis of borderline personality disorder.

The diagnosis is supported by a longstanding history of unstable identity, volatile personal relationships with fear of being abandoned, feelings of emptiness, reactive depressive disorder with suicidal gestures, and lack of insight into interpersonal difficulties that have resulted in her often stressed and depressive state.

Treatments should emphasize a DBT group that her psychiatrist has encouraged her to attend but to which she has not yet gone. There should also be regular individual counseling emphasizing DBT skills including mindfulness or present moment focus, building interpersonal skills, emotional regulation, and distress tolerance. There should be a counseling element for limiting alcohol use. Cognitive exercises are also recommended.

Of note, DBT is the only evidence-based treatment for borderline personality disorder (May, Richardi, & Barth, 2016). Prognosis is guardedly optimistic, provided she engages in both group and individual DBT treatments on a weekly basis, and these treatments continue without interruption for at least three months, with refresher sessions as needed.

Sample #3: Conceptualization in a family therapy case

This 45-year-old African-American woman was initially referred for individual therapy for “rapid mood swings” and a tendency to become embroiled in family conflicts. Several sessions of family therapy also appear indicated, and her psychiatrist concurs.

The client’s husband (50 years old) and son (25 years old, living with parents) were interviewed separately and together. When interviewed separately, her husband and son each indicated the client’s alcohol intake was “out of control,” and that she was consuming about six alcoholic beverages throughout the day, sometimes more.

Her husband and son each said the client was often too tired for household duties by the evening and often had rapid shifts in mood from happy to angry to “crying in her room.”

On individual interview, the client stated that her husband and son were each drinking about as much as she, that neither ever offered to help her with household duties, and that her son appeared unable to keep a job, which left him home most of the day, making demands on her for meals, etc.

On interview with the three family members, each acknowledged that the instances above were occurring at home, although father and son tended to blame most of the problems, including son’s difficulty maintaining employment, on the client and her drinking.

Strengths/supports in the family include a willingness of each member to engage in family sessions, awareness of supportive resources such as assistance for son’s job search, and a willingness by all to examine and reduce alcohol use by all family members as needed.

Limiting factors in this case include apparent tendency of all household members to drink to some excess, lack of insight by one or more family members as to how alcohol consumption is contributing to communication and other problems in the household, and a tendency by husband and son to make this client the family scapegoat.

The family dynamic can be conceptualized in this case through a DBT lens.

From this perspective, problems develop within the family when the environment is experienced by one or more members as invalidating and unsupportive. DBT skills with a nonjudgmental focus, active listening to others, reflecting each other’s feelings, and tolerance of distress in the moment should help to develop an environment that supports all family members and facilitates effective communication.

It appears that all family members in this case would benefit from engaging in the above DBT skills, to support and communicate with one another.

Prognosis is guardedly optimistic if family will engage in therapy with DBT elements for at least six sessions (with refresher sessions as needed).

Introduction to case conceptualization – Thomas Field

The following worksheets can be used for case conceptualization and planning.

• Case Conceptualization Worksheet: Individual Counseling helps counselors develop a case conceptualization for individual clients.
• Case Conceptualization Worksheet: Couples Counseling helps counselors develop a case conceptualization for couples.
• Case Conceptualization Worksheet: Family Counseling helps counselors develop a case conceptualization for families.
• Case Conceptualization and Action Plan: Individual Counseling helps clients facilitate conceptualization of their own case, at approximately six weeks into counseling and thereafter at appropriate intervals.
• Case Conceptualization and Action Plan: Couples Counseling helps couples facilitate conceptualization of their own case, at approximately six weeks into counseling and thereafter at appropriate intervals.
• Case Conceptualization and Action Plan: Family Counseling helps families facilitate conceptualization of their own case, at approximately six weeks into counseling and thereafter at appropriate intervals.

17 Science-Based Ways To Apply Positive CBT

These 17 Positive CBT & Cognitive Therapy Exercises [PDF] include our top-rated, ready-made templates for helping others develop more helpful thoughts and behaviors in response to challenges, while broadening the scope of traditional CBT.

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The following resources can be found in the Positive Psychology Toolkit© , and their full versions can be accessed by a subscription.

Analyzing Strengths Use in Different Life Domains can help clients understand their notable strengths and which strengths can be used to more advantage in new contexts.

Family Strength Spotting is another relevant resource. Each family member fills out a worksheet detailing notable strengths of other family members. In reviewing all worksheets, each family member can gain a greater appreciation for other members’ strengths, note common or unique strengths, and determine how best to use these combined strengths to achieve family goals.

Four Front Assessment is another resource designed to help counselors conceptualize a case based on a client’s personal and environmental strengths and weaknesses. The idea behind this tool is that environmental factors in the broad sense, such as a supportive/unsupportive family, are too often overlooked in conceptualizing a case.

If you’re looking for more science-based ways to help others through CBT, check out this collection of 17 validated positive CBT tools for practitioners. Use them to help others overcome unhelpful thoughts and feelings and develop more positive behaviors.

In helping professions, success in working with clients depends first and foremost on how well you understand them.

This understanding is crystallized in a case conceptualization.

Case conceptualization helps answer key questions. Who is this client? How did they become who they are? What supports do they need to reach their goals?

The conceptualization itself depends on gathering all pertinent data on a given case, through record review, interview, behavioral observation, questionnaires completed by the client, etc.

Once the data is assembled, the counselor, coach, or other involved professional can focus on enumerating the client’s strengths, weaknesses, and limitations.

It is also often helpful to put the client’s strengths and limitations in a timeline so you can see how they have evolved and which factors might have contributed to the emergence of others.

Based on this in-depth understanding of the client, you can then tailor specific recommendations for enhancing their strengths, overcoming their weaknesses, and reaching their particular goals.

We hope you have enjoyed this discussion of how to conceptualize cases in the helping professions and that you will find some tools for doing so useful.

We hope you enjoyed reading this article. For more information, don’t forget to download our three Positive CBT Exercises for free .

• Hofmann, S. G., Asnaani, A., Vonk, I. J., Sawyer, A. T., & Fang, A. (2012). The efficacy of cognitive behavioral therapy: A review of meta-analyses. Cognitive Therapy and Research , 36 (5), 427–440.
• May, J. M., Richardi, T. M., & Barth, K. S. (2016). Dialectical behavior therapy as treatment for borderline personality disorder. The Mental Health Clinician , 6 (2), 62–67.
• Sperry, L., & Sperry, J. (2020).  Case conceptualization: Mastering this competency with ease and confidence . Routledge.

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What Is a Case Study?

Weighing the pros and cons of this method of research

Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

Cara Lustik is a fact-checker and copywriter.

Verywell / Colleen Tighe

• Pros and Cons

What Types of Case Studies Are Out There?

Where do you find data for a case study, how do i write a psychology case study.

A case study is an in-depth study of one person, group, or event. In a case study, nearly every aspect of the subject's life and history is analyzed to seek patterns and causes of behavior. Case studies can be used in many different fields, including psychology, medicine, education, anthropology, political science, and social work.

The point of a case study is to learn as much as possible about an individual or group so that the information can be generalized to many others. Unfortunately, case studies tend to be highly subjective, and it is sometimes difficult to generalize results to a larger population.

While case studies focus on a single individual or group, they follow a format similar to other types of psychology writing. If you are writing a case study, we got you—here are some rules of APA format to reference.  

At a Glance

A case study, or an in-depth study of a person, group, or event, can be a useful research tool when used wisely. In many cases, case studies are best used in situations where it would be difficult or impossible for you to conduct an experiment. They are helpful for looking at unique situations and allow researchers to gather a lot of˜ information about a specific individual or group of people. However, it's important to be cautious of any bias we draw from them as they are highly subjective.

What Are the Benefits and Limitations of Case Studies?

A case study can have its strengths and weaknesses. Researchers must consider these pros and cons before deciding if this type of study is appropriate for their needs.

One of the greatest advantages of a case study is that it allows researchers to investigate things that are often difficult or impossible to replicate in a lab. Some other benefits of a case study:

• Allows researchers to capture information on the 'how,' 'what,' and 'why,' of something that's implemented
• Gives researchers the chance to collect information on why one strategy might be chosen over another
• Permits researchers to develop hypotheses that can be explored in experimental research

On the other hand, a case study can have some drawbacks:

• It cannot necessarily be generalized to the larger population
• Cannot demonstrate cause and effect
• It may not be scientifically rigorous
• It can lead to bias

Researchers may choose to perform a case study if they want to explore a unique or recently discovered phenomenon. Through their insights, researchers develop additional ideas and study questions that might be explored in future studies.

It's important to remember that the insights from case studies cannot be used to determine cause-and-effect relationships between variables. However, case studies may be used to develop hypotheses that can then be addressed in experimental research.

Case Study Examples

There have been a number of notable case studies in the history of psychology. Much of  Freud's work and theories were developed through individual case studies. Some great examples of case studies in psychology include:

• Anna O : Anna O. was a pseudonym of a woman named Bertha Pappenheim, a patient of a physician named Josef Breuer. While she was never a patient of Freud's, Freud and Breuer discussed her case extensively. The woman was experiencing symptoms of a condition that was then known as hysteria and found that talking about her problems helped relieve her symptoms. Her case played an important part in the development of talk therapy as an approach to mental health treatment.
• Phineas Gage : Phineas Gage was a railroad employee who experienced a terrible accident in which an explosion sent a metal rod through his skull, damaging important portions of his brain. Gage recovered from his accident but was left with serious changes in both personality and behavior.
• Genie : Genie was a young girl subjected to horrific abuse and isolation. The case study of Genie allowed researchers to study whether language learning was possible, even after missing critical periods for language development. Her case also served as an example of how scientific research may interfere with treatment and lead to further abuse of vulnerable individuals.

Such cases demonstrate how case research can be used to study things that researchers could not replicate in experimental settings. In Genie's case, her horrific abuse denied her the opportunity to learn a language at critical points in her development.

This is clearly not something researchers could ethically replicate, but conducting a case study on Genie allowed researchers to study phenomena that are otherwise impossible to reproduce.

There are a few different types of case studies that psychologists and other researchers might use:

• Collective case studies : These involve studying a group of individuals. Researchers might study a group of people in a certain setting or look at an entire community. For example, psychologists might explore how access to resources in a community has affected the collective mental well-being of those who live there.
• Descriptive case studies : These involve starting with a descriptive theory. The subjects are then observed, and the information gathered is compared to the pre-existing theory.
• Explanatory case studies : These   are often used to do causal investigations. In other words, researchers are interested in looking at factors that may have caused certain things to occur.
• Exploratory case studies : These are sometimes used as a prelude to further, more in-depth research. This allows researchers to gather more information before developing their research questions and hypotheses .
• Instrumental case studies : These occur when the individual or group allows researchers to understand more than what is initially obvious to observers.
• Intrinsic case studies : This type of case study is when the researcher has a personal interest in the case. Jean Piaget's observations of his own children are good examples of how an intrinsic case study can contribute to the development of a psychological theory.

The three main case study types often used are intrinsic, instrumental, and collective. Intrinsic case studies are useful for learning about unique cases. Instrumental case studies help look at an individual to learn more about a broader issue. A collective case study can be useful for looking at several cases simultaneously.

The type of case study that psychology researchers use depends on the unique characteristics of the situation and the case itself.

There are a number of different sources and methods that researchers can use to gather information about an individual or group. Six major sources that have been identified by researchers are:

• Archival records : Census records, survey records, and name lists are examples of archival records.
• Direct observation : This strategy involves observing the subject, often in a natural setting . While an individual observer is sometimes used, it is more common to utilize a group of observers.
• Documents : Letters, newspaper articles, administrative records, etc., are the types of documents often used as sources.
• Interviews : Interviews are one of the most important methods for gathering information in case studies. An interview can involve structured survey questions or more open-ended questions.
• Participant observation : When the researcher serves as a participant in events and observes the actions and outcomes, it is called participant observation.
• Physical artifacts : Tools, objects, instruments, and other artifacts are often observed during a direct observation of the subject.

If you have been directed to write a case study for a psychology course, be sure to check with your instructor for any specific guidelines you need to follow. If you are writing your case study for a professional publication, check with the publisher for their specific guidelines for submitting a case study.

Here is a general outline of what should be included in a case study.

Section 1: A Case History

This section will have the following structure and content:

Background information : The first section of your paper will present your client's background. Include factors such as age, gender, work, health status, family mental health history, family and social relationships, drug and alcohol history, life difficulties, goals, and coping skills and weaknesses.

Description of the presenting problem : In the next section of your case study, you will describe the problem or symptoms that the client presented with.

Describe any physical, emotional, or sensory symptoms reported by the client. Thoughts, feelings, and perceptions related to the symptoms should also be noted. Any screening or diagnostic assessments that are used should also be described in detail and all scores reported.

Your diagnosis : Provide your diagnosis and give the appropriate Diagnostic and Statistical Manual code. Explain how you reached your diagnosis, how the client's symptoms fit the diagnostic criteria for the disorder(s), or any possible difficulties in reaching a diagnosis.

Section 2: Treatment Plan

This portion of the paper will address the chosen treatment for the condition. This might also include the theoretical basis for the chosen treatment or any other evidence that might exist to support why this approach was chosen.

• Cognitive behavioral approach : Explain how a cognitive behavioral therapist would approach treatment. Offer background information on cognitive behavioral therapy and describe the treatment sessions, client response, and outcome of this type of treatment. Make note of any difficulties or successes encountered by your client during treatment.
• Humanistic approach : Describe a humanistic approach that could be used to treat your client, such as client-centered therapy . Provide information on the type of treatment you chose, the client's reaction to the treatment, and the end result of this approach. Explain why the treatment was successful or unsuccessful.
• Psychoanalytic approach : Describe how a psychoanalytic therapist would view the client's problem. Provide some background on the psychoanalytic approach and cite relevant references. Explain how psychoanalytic therapy would be used to treat the client, how the client would respond to therapy, and the effectiveness of this treatment approach.
• Pharmacological approach : If treatment primarily involves the use of medications, explain which medications were used and why. Provide background on the effectiveness of these medications and how monotherapy may compare with an approach that combines medications with therapy or other treatments.

This section of a case study should also include information about the treatment goals, process, and outcomes.

When you are writing a case study, you should also include a section where you discuss the case study itself, including the strengths and limitiations of the study. You should note how the findings of your case study might support previous research. 

In your discussion section, you should also describe some of the implications of your case study. What ideas or findings might require further exploration? How might researchers go about exploring some of these questions in additional studies?

Need More Tips?

Here are a few additional pointers to keep in mind when formatting your case study:

• Never refer to the subject of your case study as "the client." Instead, use their name or a pseudonym.
• Read examples of case studies to gain an idea about the style and format.
• Remember to use APA format when citing references .

Crowe S, Cresswell K, Robertson A, Huby G, Avery A, Sheikh A. The case study approach .  BMC Med Res Methodol . 2011;11:100.

Crowe S, Cresswell K, Robertson A, Huby G, Avery A, Sheikh A. The case study approach . BMC Med Res Methodol . 2011 Jun 27;11:100. doi:10.1186/1471-2288-11-100

Gagnon, Yves-Chantal.  The Case Study as Research Method: A Practical Handbook . Canada, Chicago Review Press Incorporated DBA Independent Pub Group, 2010.

Yin, Robert K. Case Study Research and Applications: Design and Methods . United States, SAGE Publications, 2017.

By Kendra Cherry, MSEd Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

Person-Centered Therapy Case Study: Examples and Analysis

Introduction

Welcome to The Knowledge Nest's in-depth exploration of person-centered therapy case study examples and analysis. We aim to provide you with comprehensive insights into the therapeutic approach, techniques, and outcomes associated with person-centered counseling. Through real-life case scenarios, we demonstrate the effectiveness of this humanistic and client-centered approach in fostering personal growth and facilitating positive change.

Understanding Person-Centered Therapy

Person-centered therapy, also known as client-centered therapy or Rogerian therapy, is a compassionate and empathetic therapeutic approach developed by the influential psychologist Carl Rogers. This person-centered approach recognizes the profound significance of the therapeutic relationship, placing the individual at the center of the therapeutic process.

Unlike traditional approaches that impose solutions or interpretations on clients, person-centered therapy emphasizes the innate human capacity to move towards growth and self-actualization. By providing a supportive and non-judgmental environment, therapists aim to enhance clients' self-awareness, self-acceptance, and self-discovery. This holistic approach has proven to be particularly effective in addressing a wide range of mental health concerns, empowering individuals to overcome challenges and achieve personal well-being.

Case Study Examples

Case study 1: overcoming social anxiety.

In this case study, we explore how person-centered therapy helped Sarah, a young woman struggling with severe social anxiety, regain her confidence and navigate social interactions. Through the establishment of a strong therapeutic alliance, her therapist cultivated a safe space for Sarah to explore her fears, challenge negative self-perceptions, and develop effective coping strategies. Through the person-centered approach, Sarah experienced significant improvements, enabling her to participate more actively in social situations and regain a sense of belonging.

Case Study 2: Healing from Trauma

John, a military veteran suffering from PTSD, found solace and healing through person-centered therapy. This case study delves into the profound transformation John experienced as he worked collaboratively with his therapist to process unresolved trauma. By providing unconditional positive regard, empathetic listening, and genuine empathy, the therapist created an environment where John felt safe to explore his traumatic experiences. With time, he was able to develop healthier coping mechanisms, embrace self-compassion, and rebuild a sense of purpose.

Case Study 3: Enhancing Self-Esteem

In this case study, we examine Lisa's journey towards building self-esteem and self-worth. Through person-centered therapy, her therapist empowered Lisa to identify and challenge deeply ingrained negative self-beliefs that inhibited her personal growth. By offering non-directive support, active listening, and reflective feedback, the therapist enabled Lisa to develop a more positive self-concept, fostering increased self-esteem, and self-empowerment.

Analysis of Person-Centered Therapy

The therapeutic relationship.

Person-centered therapy places profound importance on the therapeutic relationship as the foundation for positive change. The therapist cultivates an atmosphere of trust, respect, and authenticity, enabling the individual to feel heard and valued. By providing unconditional positive regard, therapists create a non-judgmental space where clients can freely explore their thoughts, emotions, and experiences.

Client-Centered Approach

The client-centered approach encourages individuals to take an active role in their therapeutic journey. The therapist acts as a facilitator, guiding clients towards self-discovery and personal growth. By allowing clients to set the agenda and directing the focus of sessions, the person-centered approach acknowledges the unique needs and perspectives of each individual.

Empowering Self-Awareness and Growth

Person-centered therapy seeks to unlock individuals' innate capacity for self-awareness and personal growth. Through empathic understanding, therapists support clients in gaining insight into their emotions, thoughts, and needs. This heightened self-awareness helps individuals develop healthier coping mechanisms, make meaningful choices, and move towards a more fulfilling life.

Person-centered therapy, as exemplified through the case studies presented, offers a powerful and transformative path towards holistic well-being and personal growth. The Knowledge Nest is committed to providing a platform for sharing knowledge, experiences, and resources related to person-centered counseling. Together, we strive to facilitate positive change, empower individuals, and create a more compassionate and understanding society.

Explore more case studies and resources on person-centered therapy at The Knowledge Nest to discover the profound impact of this therapeutic approach.

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Therapy Session Case Study: Dealing with Anxiety, Stress and Poor Self-Confidence

Therapist and counsellor dr. dawn ferrara gives her perspective on a uptv client session.

We’ve got something a little different for you this time. As you know, often I like to describe therapeutic approaches in depth.

This piece describes one therapy session in detail, but it’s a little different because it’s not written by me but by an “outside pair of eyes.”

Dr. Dawn Ferrara is a Licensed Professional Counsellor and Licensed Marriage & Family Therapist specializing in Anxiety/Stress disorders.

Dawn looks at the session from the perspective of her understanding and experience. It’s so valuable to get a perspective other than your own so we asked Dawn, a skilled psychologist to write a case study for us.

What you have here is an overview of one session with Alice* an  Uncommon Practitioners TV client who came for help with anxiety, stress and low self confidence. Please let me know in the comments section if you find this useful and whether you’d like more professional summations of these therapy sessions.

Here’s to improving psychological knowledge and emotional health,

Identifying information

Alice (age unspecified) is a female client who works in the Information Technology (IT) industry. She has been in the IT field for 25 years and has run her own business successfully for the last 10 years. She is married and she and her spouse work together.

Presenting problem

Alice is seeking help for anxiety, stress and poor self-confidence.

Social history

Alice is married with one daughter. She reports a good personal and professional relationship with her spouse.

Alice’s parents divorced when she was young. She describes feeling “cheated” by that situation. Her father died in 1994 from cancer and never met her daughter. Alice expresses some regret that her father didn’t live to see her succeed as an adult or to meet his granddaughter. Alice’s mother is alive but Alice describes the relationship as strained.

Alice owns her own technology company. She reports that she learned her IT skills as an early adopter of emerging technology and built a career on those skills. She did not receive formal training.

Alice describes her job as quite stressful. She reports that she sometimes has difficulty dealing with demanding clients, especially when she is unable to help them in the ways they expect her to.

These situations evoke bothersome feelings of disappointment and anxiety, and worries about being criticized or judged. She states she becomes annoyed and that these feelings affect her wellbeing.

Mental health history

Alice reports that she has a history of anxiety and depression , for which she has received treatment. Past treatments have included antidepressant medication (unspecified) and diazepam for panic attacks. She is not currently taking medication.

Alice says that following her father’s death, her symptoms worsened.

Alice reports that she has previously used hypnosis for smoking cessation . It appears to have been only partially successful, as she continues to use an e-cigarette.

Session summary

This video is a single therapy session. The first part of the session consists of information gathering and a number of suggestions and reframes to encourage relaxation and assist Alice in gaining insight into some of her issues. The latter part of the session is direct hypnosis. Throughout the session, Mark uses a relaxed, conversational approach .

Mark engages Alice in conversation to clarify and discuss her concerns. As she becomes more comfortable, Alice offers more information and insight into her issues.

She admits to having bursts of intense anxiety but has had a reduction in panic episodes. She attributes that to making better choices about managing situations that she finds provoke anxiety. She identifies criticism and self-doubt as particularly problematic triggers.

Because of her history, Mark asks Alice a series of questions to assess the risk of post-traumatic stress disorder (PTSD). It does not appear that PTSD is a diagnostic consideration at this time.

Mark then reframes anxiety symptoms as an “exercise response”. This is done in order to normalize the anxiety response and reduce the tendency to pathologize its symptoms.

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A metaphor for stress and anxiety

To create a visual representation of anxiety, Mark makes an analogy between unchecked anxiety and a mental bucket of water. Anxiety (water) pours into the bucket and, if left unchecked, eventually fills the bucket and overflows (panic). He equates regular relaxation to emptying the mental bucket so that it doesn’t overflow (anxiety/panic).

Throughout the session, Mark references water creating a sense of calm and flow: filling the bucket, anxiety response as a whirlpool, the surface of water calm and reflective, feelings of calm streaming over.

During this discussion, Alice is attentive and calm with a relaxed posture. She makes good eye contact and responds with ease.

Depressive thinking styles

Now Mark describes the biases of globalizing , internalizing negatives and externalizing positives using a number of examples and analogies. Alice is able to recognize some of those biases in herself. Mark frames Alice’s insight into her biases as “seeing through” them.

As Alice becomes more aware of her biases, she becomes less affected by them because she can recognize them for what they are: inaccurate. The purpose of this reframing is to help Alice to separate herself from her biases, and accept that they do not define who she is.

Because Alice is particularly sensitive to perceived criticism, Mark makes a similar distinction between complaint and criticism, framing them as separate and not reflective of who she is as a person.

Tools for reducing anxiety

Following a discussion of Alice’s physical anxiety symptoms, Mark explains the dynamics of tactical breathing and invites Alice to try the technique. She readily responds and is able to practise the technique successfully and feel the sensation of relaxing.

Using conversational strategies, Mark encourages Alice to visualize scenarios and notice her reactions, first recalling her feelings in the bothersome scenario then visualizing it from afar and noticing differences while breathing and remaining in the moment.

This therapeutic presupposition allows Alice to see that she can react differently to difficult situations and allows her to move towards the hypnotic state.

Guided relaxation

The hypnotic induction begins with Mark describing hypnosis. He references Alice’s enjoyment of mandala painting on stones as an anchor, a way to help her connect with the state of mind-body relaxation and its link to unconscious thought.

The focus of the induction is relaxation training and helping Alice learn to manage her anxiety response. Using a series of embedded commands and visualizations, Alice is able to recognize her anxiety without panic or heightened responses and gently reduce it or brush it aside. She is able to experience remaining in control of her physical and thought responses.

Mark then gives several suggestions for actions going forward. These actions empower Alice to continue to recognize and manage her anxiety response by remaining calm and in control.

“What I’d like you to do is just to notice in the coming weeks and months what you notice about yourself, maybe after the event… telling yourself perhaps that: “at one point this would have been a problem for me but I just didn’t feel anything. I just put it in perspective.”

“You can just notice those times in coming weeks and months and forever.”

Further strengthening the link between conscious and unconscious thought, the induction is completed with a final suggestion that her unconscious mind and body will continue to be accessible when needed.

Did you find this case study useful? Let us know in the comments below if you’d like to see more professional summations of therapy sessions from Uncommon Practitioners TV, and if there’s anything we can add to them to make them more useful to you.

And if you haven’t joined yet, you can read about Uncommon Practitioners TV here and sign up to be notified when it’s open for new members.

About Mark Tyrrell

Psychology is my passion. I've been a psychotherapist trainer since 1998, specializing in brief, solution focused approaches. I now teach practitioners all over the world via our online courses .

You can get my book FREE when you subscribe to my therapy techniques newsletter. Click here to subscribe free now.

You can also get my articles on YouTube , find me on Instagram , Amazon , Twitter , and Facebook .

*Not her real name

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Alberto, age 55, was brought to the emergency department of a regional medical center by his brother-in-law. Alberto is pacing, demanding, agitated, and speaking vociferously. “I did not wish to come here! My brother-in-law is simply jealous and he is trying to make me appear like I am suffering from some sort of insanity!” Alberto’s treatment is financially subsidized by his brother in law. Alberto will undergo a maximum of 8 sessions at 2 hours each session. The session will start on June 25, 2014.

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Introduction 3

Initial interview 4 Assessment formulation methods utilized 4 Assessment of John presenting problems and goals 5 Analysis and critique of MMT approach 6 Agreed goals 6 Treatment plan 6 CBT interventions 7 Intervention for cognitions-thoughts records 7 Benefits of the approach 7 Interventions for behavior- activity scheduling/diversion techniques 8 Benefits of the approach/ interaction 8 Interventions for imagery/interpersonal- imagery based exposure 8 Benefit of approach 9 Intervention for sensation- relaxation/ visualization 10 Conclusion 11

APPENDIX 1 13

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• Case report
• Open access
• Published: 06 April 2024

Patients' perspectives on buprenorphine subcutaneous implant: a case series

• Claudio Pierlorenzi 1 ,
• Marco Nunzi 1 ,
• Sabino Cirulli 1 ,
• Giovanni Francesco Maria Direnzo 2 ,
• Lucia Curatella 1 ,
• Sandra Liberatori 2 ,
• Annalisa Pascucci 2 ,
• Edoardo Petrone 3 ,
• Generoso Ventre 2 ,
• Concettina Varango 4 ,
• Maria Luisa Pulito 4 ,
• Antonella Varango 4 ,
• Cosimo Dandolo 4 ,
• Brunella Occupati 5 ,
• Roberta Marenzi 6 &
• Claudio Leonardi 7  

Journal of Medical Case Reports volume  18 , Article number:  202 ( 2024 ) Cite this article

1 Altmetric

Metrics details

Considering the enormous burden represented by the opioid use disorder (OUD), it is important to always consider, when implementing opioid agonist therapy (OAT), the potential impact on patient’s adherence, quality of life, and detoxification. Thus, the purpose of the study is to evaluate how the introduction of a novel OAT approach influences these key factors in the management of OUD.

Case presentation

This article marks the pioneering use of OAT through buprenorphine implant in Europe and delves into the experience of six patients diagnosed with OUD at a relatively young age. The patients, comprising both males and a female, are of Caucasian Italian and African Italian ancestry (case 4) and exhibit an age range from 23 to 63, with an average drug abuse history of 19 ± 12 years. All patients were on stable traditional OAT before transitioning to buprenorphine implants. Despite the heterogeneity in social and educational backgrounds, health status, and drug abuse initiation histories, the case series reveals consistent positive treatment outcomes such as detoxification, absence of withdrawal symptoms and of side effects. Notably, all patients reported experiencing a newfound sense of freedom and improved quality of life.

Conclusions

These results emphasise the promising impact of OAT via buprenorphine implants in enhancing the well-being and quality of life in the context of OUD.

Peer Review reports

Introduction

Opioid use disorder (OUD) is a chronic, relapsing condition accounting for over 16 million people worldwide [ 1 , 2 ]. International guidelines recommend opioid agonist therapy (OAT) with sublingual buprenorphine or methadone as first-line treatments of opioid dependence [ 3 ]. However, the rates of oral OAT misuse, abuse, and diversion are of public concern due to their social, sanitary, and economic repercussions [ 4 , 5 ]. Additionally, patient adherence to oral OAT remains a challenge nowadays.

Little research has been carried out about strategies to support long-term remission from opioid dependence [ 6 , 7 ]. An implantable formulation of buprenorphine has been developed to address problems with adherence, diversion, and non-medical use [ 6 ]. The rod-shaped implant consists of a mixture of a polymeric ethylene vinyl acetate matrix and buprenorphine that, following an initial pulse release, delivers a constant and stable medication level over 6 months after a single procedure [ 8 ].

Buprenorphine implant has shown its effectiveness in placebo-controlled studies [ 6 , 8 , 9 ] displaying a significant reduction of the opioid abuse (percentage of opioid-negative urine samples: 36% in implant group vs. 14.4% in placebo) and percentage of participants who completed the study [ 8 ]. As compared with standard sublingual buprenorphine or buprenorphine/naloxone tablets, the implant showed comparable efficacy and adverse event rate [ 6 , 8 ]. A systematic benefit-risk assessment, based on a semiquantitative analysis of the available data, found a favourable profile for buprenorphine implant in comparison to sublingual buprenorphine [ 10 ]. The main benefits identified for buprenorphine implant included: improved compliance and convenience, reduced risk of illicit opioid abuse, quality of life, and risk of misuse/diversion. On the other hand, risks were mostly associated with the insertion and removal procedure. The benefits mentioned so far outweighed the risks [ 10 ]and long-acting buprenorphine implants appears to sustain the long-term remission of patients suffering from OUD [ 10 ].

This article describes a series of patients with OUD who received OAT through buprenorphine implant, marking the pioneering cases at the European level. Each case report provides a comprehensive narrative, encompassing the patients' history and clinical progression, starting from the initiation of drug abuse to the subsequent outcomes (in terms of detoxification, absence of withdrawal symptoms, side effects and improved quality of life) achieved with buprenorphine implant.

Case report 1

Clinical case description.

The patient is a 54-year-old male of Caucasian Italian ancestry with lower secondary education. The patient, the youngest child of 5, experienced the tragic loss of a brother at the age of 17 due to an accident, and the father passed away 38 years ago from gastric haemorrhage. The mother, who is still alive and in fair health, works from home as a seamstress. The patient lives with his mother, but often sleeps away from home because of work. He engaged in a romantic relationship, including cohabitation, which lasted for a few years. Ultimately, at the conclusion of this period, he returned to live with his mother and stated: “ I was not in the right state of mind… Who wants to be with me? I'm never at home… and then I'm fine like this ”. He worked as a welder for a brief period. At the age of 18, he started working as a courier and then as a truck driver for third parties, constantly moving around Italy. Currently, he continues to work as a truck driver, but on his own account.

Medical history

The patient reports having contracted common childhood exanthems and undergoing a splenectomy due to a car accident in his 20s, followed by hemotransfusions. In 1986, he was diagnosed with chronic HCV hepatitis (it is unclear whether it was related to drug addiction), classified as G4, F2-related, and was treated with glecaprevir/pibrentasvir.

Toxicological history

At the age of 23, the patient began his journey with drugs by abusing intravenous heroin, cocaine, and alcohol (in the latter case, moderately). He was referred in April 1991, based on Article 75, to the Addiction Service of Lodi by the Prefecture of Piacenza. Two months later, the patient started OAT with a daily dose of 50 mg of methadone. From the age of 23 to 27, the patient exhibited very oppositional behaviour: he was lying, provocative, sometimes aggressive and threatening. During that period, the patient began and interrupted several therapeutic programmes.

Traditional opioid agonist therapy

In July 2004, the first contact with our Addiction Service occurred. The patient began therapy with sublingual buprenorphine at 8 mg/day in increments, but he never completed the scaling. In this regard, in 2013, we read in the clinical diary: “He is not able to disengage from buprenorphine despite remaining abstinent from drugs for some months” . The patient continued with sublingual buprenorphine 2 mg/day until May 2018, at which point he transitioned to a dosage of 2 mg every other day. The patient maintained this regimen until June 2022.

• Buprenorphine implant

In May 2022 we proposed the subcutaneous buprenorphine implant treatment to the patient, as he appeared to align with the characteristics of the ideal patient. He showed immediate interest and accepted. The selection was based on his consistent use of 2 mg sublingual buprenorphine every other day over the years, prolonged negative drug tests, frequent business-related travel as a lorry driver, and the logistical challenge of attending the Addiction Service every weekend (which also involved transfers to various Services). Furthermore, the patient expressed a desire to avoid encounters with other users at the Addiction Service with whom he no longer wished to share experiences.

In August 2022, the implant surgery was conducted for the patient.

Follow up visits

Throughout the six months of treatment, the patient underwent several visits, including monthly and sometimes fortnightly follow-ups. A urine toxicology check was performed every two weeks, consistently yielding negative results. The patient did not encounter any issues with the implanted arm site, finding it easy to use. He reported a notable absence of the fluctuations ("spikes") experienced with tablet intake, a diminished taste for cigarettes, and a complete lack of cravings for drugs. He expressed satisfaction with his choice but recommended the buprenorphine implant primarily for individuals aiming to cease the use of drugs of abuse. In his perspective, the implant may seem "a bit light" and more suitable for those seeking complete abstinence rather than those intending to remain on agonist therapy. The patient did not have interviews with the psychologist due to work-related commitments.

The organisation and management of the patient’s surgery proceeded smoothly. The patient was consistently monitored through visits, urine tests, and phone calls, especially during his business travels. The psychophysical condition of the patient has always been good, and the patient also observed a stabilisation in his nightly rest. In February 2023, the patient removed the device after the 6-month period, expressing great satisfaction with the experience. Subsequently, the patient did not encounter any issues and did not require buprenorphine/naloxone. In fact, the patient conveyed the intention to abstain from a second implant and forgo further OAT because he felt well. During the months with the implant, he successfully distanced himself from addiction after many years.

Case report 2

The patient is a 63-year-old man of Caucasian Italian ancestry who underwent treatment at the Medical Toxicology Department in Florence. He is a former addict, having maintained abstinence for over 30 years from heroin and methadone. After an extended period of traditional OAT with sublingual buprenorphine, he consistently expressed his desire to discontinue this treatment. Subsequently, the patient was presented with the option of a buprenorphine implant, which he accepted with the goal of achieving detoxification as the dosage in the subcutaneous implant is depleted by the end of the 6th month.

The patient's family history includes a hypertensive mother who died in 2010at the age of 86, a father who died at the age of 89, and an older sister in apparent good health. Throughout his life, the patient has experienced chronic hypoxia, maintained a low body mass index (BMI), and displayed regular diuresis and bowel function. Employed as an office worker, he grapples with insomnia and smokes approximately 15 cigarettes daily. Since the 1990s, the patient has tested positive for Hepatitis C (HCV). In 2008, he was diagnosed with renal heteroplasia on the right side, necessitating surgical exeresis. In 2010, a fracture of the right distal condyle of the femur occurred, prompting surgical intervention. From 2017 onward, the patient has been under the surveillance of the Systemic Manifestations of Hepatitis Virus Centre (MASVE), where he was diagnosed with cryoglobulinemia. Successful HCV eradication measures were undertaken.

The patient began illicit drug abuse in 1978 at the age of 19, with heroin being the primary substance of abuse. Of note, around the age of 30, the patient underwent a period of community day care. Concomitantly, he has consistently used and continues to use cannabinoids. Currently, the patient has been abstinent from heroin use for about 30 years.

From 1982 to 2007, the patient received treatment at the Medical Toxicology Department of the regional reference centre with methadone for heroin use disorder. Subsequently, he underwent OAT with sublingual buprenorphine until October 2022 (Table  1 ), at which point he transitioned to buprenorphine implant therapy.

Psychological aspects prior to buprenorphine implant

The patient exhibits compensated histrionic traits without psychosocial relapse. He is also characterised by an anxious temperament but maintains an on-axis mood [ 8 ]. The acceptance of this treatment stems from the desire for increased freedom, as it eliminates the need for frequent visits to the facility for sublingual buprenorphine, with the ultimate goal of achieving definitive detoxification.

At the time of implantation, the patient was on 8 mg sublingual buprenorphine agonist therapy. The patient underwent subcutaneous implant surgery in October 2022. The implantation was performed at the Vascular Access Centre Unit, Department of Anaesthesia and Resuscitation AOUC (for a comprehensive outline of the procedure, please refer to Additional file 1 : Appendix SI). Except for the initial days when the patient experienced mild withdrawal symptoms and a minor infection at the implant site, promptly addressed with antibiotics, the patient expressed overall satisfaction and happiness with the decision made.

Follow-up visits

The patient engaged in numerous follow-up visits, during which evaluations were performed to assess both physical and psychological outcomes. The Clinical Opiate Withdrawal Scale (COWS) score was employed throughout these visits to monitor the patient's withdrawal symptoms and general well-being (Table  2 ). The COWS categorical score ranges are defined as follows: no withdrawal (0–4), mild (5–12), moderate (13–24), moderately severe (25–36), and severe withdrawal (> 36) [ 11 , 12 ].

The removal of the implant, initially planned at the latest after 7 months from insertion, was delayed by a few months at the patient's request. The patient underwent monitoring of buprenorphine blood levels, which showed a slow decline in values, maintaining excellent toxicological compensation. The removal procedure was scheduled for the July 17, 2023, at the Vascular Access Centre Unit of the AOUC, but it was unsuccessful. After 2 h, the removal intervention was interrupted, and the patient was directed to ultrasound and MRI examination, which allowed visualization of the implants in the subfascial space in the brachial biceps muscle of the left arm instead of subcutaneous space. Following a thorough orthopaedic consultation, it was decided to forgo surgical intervention due to the patient's asymptomatic clinical presentation. Instead, the plan is to monitor the progress through semi-annual follow-ups. As of now, no complications have been identified.

The patient consistently reported minimal withdrawal symptoms and no significant cravings throughout the follow-up period with an excellent toxicological compensation. Furthermore, the patient expressed overall satisfaction with the subcutaneous implant, emphasizing its positive impact on mood, anxiety levels, and sleep patterns. Despite the initial challenges in the removal procedure, the patient's clinical presentation remains asymptomatic, contributing to the overall success of the buprenorphine implant treatment.

Case report 3

The patient, a 55-year-old woman of Caucasian Italian ancestry, was admitted to a psychiatric clinic in 2012 with a diagnosis of “depressive syndrome in a patient suffering from bipolar disorder, diffuse polyarthralgias and resumption of alcoholism”. She has been consistently under the care of a trusted psychiatrist since then.

Her primary substance of abuse was heroin until the late 1990s, followed by the development of alcohol use disorder. Alcohol consumption persisted over the years with long periods of remission and brief relapses mainly in a binge-like manner. Due to her history, the patient had been actively engaging with the Alcohol Centre and participating in self-help groups. She has been abstinent from alcohol consumption since 2021 and from heroin for over 20 years.

Since 2004, the patient has been undergoing OAT with buprenorphine (Table  3 ), and during this period, she has also been consistently receiving stable and concurrent psychopharmacological therapy. The patient had repeatedly expressed interest in discontinuing OAT, thus at the end of 2022 she was offered the option of using a buprenorphine implant. The proposed plan involved utilizing the implant for a duration of either 6 or 12 months, contingent on the patient's decision to pursue or decline a second implant at the conclusion of the initial period. This approach aimed to facilitate the detoxification process. At the time of the decision, the patient was in good compensation from a psychiatric and toxicological point of view.

The patient underwent subcutaneous implant surgery in February 2023. For the detailed procedure, please refer to Additional file 1 : Appendix SII. The patient did not show any signs of withdrawal or overdose in the days following implantation.

Psychological aspects following the buprenorphine implant

Generally, the patient considers herself satisfied and happy with the choice made. Moreover, the World Health Organization Quality of Life – BREF (WHOQOL-BREF), a self-report questionnaire assessing quality of life [ 13 ], was administered to the patient. Her assessment yielded the following scores: physical health = 21 (scale range: 7–35), psychological health = 23 (scale range: 6–30), social relationships = 10 (scale range: 3–15), and environment = 27 (scale range: 8–40).

During the follow-up visits, the patient’s physical and psychological state were assessed, and the COWS score was employed to evaluate withdrawal symptoms and general well-being (Table  4 ).

Throughout the observation period, the patient displayed overall well-being. However, as the removal procedure approached, she experienced mild anxiety, which was successfully managed with low doses of sublingual buprenorphine. The clinician notes that the patient's overall progress indicates a positive response to the buprenorphine implant treatment, showcasing effective control over withdrawal symptoms and cravings. The patient herself expresses satisfaction with her experience.

Case report 4

The patient, a 53-year-old male of African Italian ancestry, reported that his initial exposure to drugs, particularly THC, occurred around the age of 12. Subsequently, following the dissolution of his marriage, he had encounters with cocaine and later opioids, leading to the development of addiction.

After a period spent abroad, the patient returned to Italy in 2002 and sought treatment from various Addiction Services, where he began treatment with methadone. Approximately four years ago he transitioned to OAT with sublingual buprenorphine. Upon admission to our Service in May 2022, his therapy consisted of sublingual buprenorphine 6 mg + sublingual naloxone 1.5 mg per day.

During the meetings, the patient consistently demonstrated willingness and motivation. While his language was partially fluent, there were occasional interruptions attributed to difficulties in recalling certain phases of his life history. He showed spontaneity and did not need to be triggered to express himself, showing reflexivity and ability to contextualise. Adequate introspection and the absence of emotional blocks related to traumatic experiences were evident. The patient exhibited an internal locus of control and a sense of self-efficacy overall. From the behavioural point of view, within the service and with the clinical staff, we can highlight a good adherence to the indications given and to the scheduled appointments, and a good general compliance.

Due to pharmacological stability for over 5 years and restricted drug use limited to cannabinoids, the patient was deemed eligible for the buprenorphine implant, meeting the psychosocial inclusion criteria. Following the proposal, he exhibited heightened curiosity about the implant, experiencing a sense of "euphoria" in anticipation of this novel experience. His interest increased during the presentation of the implant procedure, which he quickly accepted. The impetus to accept the proposal stemmed from some of the patient's reflections, especially regarding the potential for a lifestyle change and the reclamation of "his time," envisioning more opportunities for hobbies, family, and travel. Moreover, he imagined the recovery and achievement of life goals linked both to everyday life and to the possibility of planning without “personal” constraints of time and organisation. Eventually, some reflections "almost of tiredness" emerged, referencing both to the regular visits to the Addiction Service and to the interactions with other service users. This weariness stemmed from the perceived hindrance of traditional OAT, seen as a substantial impediment to daily freedom due to the commitment required for therapy. Additionally, it extended to the challenges in achieving personal and life goals.

Since this was the first buprenorphine implant carried out at our facility, it was necessary to draw up a procedure, and have it approved by the Health Management. This protocol encompassed the establishment of a dedicated outpatient file and the provision of a specialized room, serving both for the surgical procedure and for consultations with prospective candidates, some of whom were referred from other Addiction Services.

The patient exhibited a comprehensive shift in mood, a heightened inclination toward openness with others, and a rejuvenated approach to life planning. Following the implant procedure, the patient demonstrated improved speech fluency attributed to heightened introspective abilities. He identified the socio-affective dimension as the most significant element in the initiated change, leading to increased stability on the affective level. This translated into a newfound capacity to navigate relationships with more meaningful and secure emotional grounding. Moreover, the initial days following the implant marked a shift in self-perception and how the patient was perceived by others. The awareness of the significant impact of the intervention on his life became apparent, bringing about a rediscovery of energy, an enhanced "esprit de vivre", and a transformation in interpersonal relations with the Addiction Service staff. Overall, a newfound optimism and fortitude was evident.

During the post-implant interviews, the patient was subjected to a patient-reported outcome (PRO) measure using a visual analog scale (VAS) to capture the severity or other aspects of craving. A VAS measure usually requires participants to indicate their response by marking a point on a 100-mm line, with the extremities represented by 0 as "no craving for heroin" and 100 as "absolute craving for heroin" [ 12 , 14 ]. At the follow-up the patient reported a “lack of craving” in terms of intensity and frequency, and he also denied the possibility of starting drug use in the event of experiencing craving. Throughout the course of treatment, the patient underwent weekly visits during the first month, followed by fortnightly visits in the second month, and eventually transitioning to monthly visits. Toxicological tests were conducted during these visits to monitor the patient's progress. No additional sublingual buprenorphine tablets or other drugs were necessary. Out of 11 toxicological tests carried out on urine samples, 2 were negative for all the substances sought. All other tests showed positivity for cannabinoids; this was consistent with the patient’s reported reduced daily use of THC before going to sleep.

From the outset, the patient expressed a reluctance to pursue a second implant, although he did not entirely rule out the possibility. As a result, the decision was made to defer the removal of the implant, allowing for close follow-up to monitor any changes. If needed, oral therapy could be resumed while awaiting a potential second implant to be grafted. In line with the patient's preferences and the agreement with healthcare providers, the implant remained in place beyond the initially planned sixth month. This extension allowed the patient additional time to contemplate the option of a second implant while ongoing urine buprenorphine screening, toxicological monitoring, and regular interviews were conducted. The removal was originally scheduled for the end of the seventh month. However, due to the patient's unavailability, primarily driven by severe personal reasons, the removal was subsequently postponed by two weeks. As of today, the removal procedure has been successfully performed and the patient exhibits a complete absence of craving and no desire to use substances. During the last interview the patient reported: “Every day I feel better!” .

Overall, the patient has experienced significant improvements in mood, interpersonal openness, and life planning. Additionally, there appears to be a reduction in THC use. Remarkably, even after the removal of the implant, the patient has not reported any cravings related to substance use.

Case report 5

The patient, a 40-year-old male of Caucasian Italian ancestry university graduate currently in permanent employment, initiated drug experimentation around the age of 20. In this period, he became fascinated with and started attending rave parties, leading to gradual experimentation (reported as "controlled") with illicit drugs including Afghan opium, eventually resulting in the development of an addiction disorder.

The patient’s toxicological history indicated a pattern of polyaddiction, involving the use of cannabinoids, particularly hashish, since the age of 18. At the age of 21, he began attending rave parties, engaging in simultaneous and occasional consumption of various drugs such as cocaine, MDMA, amphetamines, LSD, and Ketamine. Subsequently, the patient transitioned from regular opium use to heroin after approximately two years.

He continued his substance use until the age of 25, at which point he initiated treatment with sublingual buprenorphine at an Addiction Service. Upon admission, he had a diagnosis of OUD in protracted remission under treatment with partial OAT (buprenorphine in combination with naloxone), and concomitant depression. Throughout the course of treatment, the patient maintained a steady intake of buprenorphine/naloxone sublingual tablets at a fixed dosage of 2 mg/0.5 mg per day. Since his initial admission, he consistently reported challenges in discontinuing OAT. Specifically, he mentioned being able to refrain from the medication for a few days (up to a maximum of 4 days). However, with the onset of anxiety and intensified cravings for buprenorphine, the patient resumed his daily intake of 2 mg. Since initiating OAT, the patient reported abstinence from opium or heroin use. Despite maintaining a stable clinical picture, the presence of recurrent unsuccessful attempts to discontinue OAT prompted consideration for transitioning from sublingual to subcutaneous therapy. In August 2022, during a toxicology interview, the possibility of buprenorphine implant therapy was proposed to the patient.

In conjunction with the pharmacological aspect of the new therapy, the patient concurrently received treatment with specific antidepressants. Additionally, he has actively participated in individual psychotherapy for a duration of two years and is presently engaged in group psychotherapy. The patient promptly made himself available and demonstrated willing adherence to the instructions provided by the medical staff, consistently attending his scheduled appointments. Notably, he exhibited overall good mentalisation and fair self-esteem.

The patient initially exhibited moderate curiosity during the first interview introducing the buprenorphine implant. However, his interest in the proposed treatment escalated swiftly. This interest and curiosity stimulated thoughts about the prospect of embarking on a new lifestyle. Throughout the interviews, he conveyed that he embraced the proposal due to tiredness from the constant mood swings induced by traditional OAT, which required daily visits to the facility. These factors, coupled with other personal considerations, amplified his discomfort with commitment, hindering the overall pursuit of life goals.

After establishing a dedicated room at our facility, the patient was directed to the Addiction Service, where an external doctor from the hospital conducted the implant surgery. Following the surgery, we maintained continuous monitoring through both group psychotherapy and individual therapy sessions.

Throughout the course of treatment, the patient initially underwent weekly visits during the first month, followed by fortnightly visits in the second and third month, and eventually transitioning to monthly visits. During these regular check-ups, the patient underwent toxicological controls, and notably, no additional sublingual buprenorphine tablets were required.

After the implant procedure, the patient experienced mood stabilization, which he described as surprisingly positive. This positive change was openly shared by the patient within the therapy group. He demonstrated introspective ability, albeit stereotyped, aligning with the ideological and social models of his peer group. Following the implant there appeared to be a recognition of subjective aspects that he had not previously explored, potentially serving as a foundation for renewed self-awareness. Moreover, the patient exhibited rich and articulate language, along with good introspective and self-reflective ability, fair insight, and a proficient recall of his life history. Shortly after the implant, he conveyed his sense of liberation in an email, stating: "…I am a free man…" . In a group session, he elaborated on this feeling, expressing that he now perceives himself as "like everyone else," no longer dependent on the daily tablet, and experiencing mood fluctuations akin to any other individual.

The patient has been undergoing treatment for several months and reported only experiencing a headache in the initial days following the implant. Toxicological controls indicate positivity only for THC, as the patient has consistently used cannabinoids by smoking a "joint" in the evening to relax before going to sleep, with no intention of discontinuing this habit.

In post-implant interviews, the patient underwent the VAS test and reported a "lack of craving" both in terms of intensity and frequency. Furthermore, he expressed no inclination to initiate drug use in the event of experiencing cravings.

From the outset, the patient has made it clear that he had no intention of pursuing a second implant. Although he does not rule out the possibility entirely, his hope is to attain complete liberation from OAT and, more broadly, from drugs. This suggests a reasonably sound capacity for judgment on his part. Hence, the decision was made to defer the removal of the initial implant, utilizing the gradual reduction of the drug, and assessing how best to support the patient on his journey towards detoxification.

The patient appears to be progressing well on the detoxification path, as evidenced by his expressed intention to refrain from further OAT after the removal of the implant. The patient's determination is a crucial factor in the success of the detoxification process. The absence of craving after the removal of the implant, along with the noted mood stabilization and positive treatment perception reported by the patient, are significant indicators contributing to the success of the patient's detoxification journey.

Case report 6

Filippo (fictitious name), a 23-year-old male of Caucasian Italian ancestry, reflects on his childhood, describing it as “normal”. His father is portrayed as a diligent worker, while his mother is characterized as a pragmatic and less sentimental woman. As an intelligent child, Filippo sensed the weight of the expectations his mother had placed on him. During the transition to middle school, he experienced a loss in friendships, became apathetic, distracted, and spent most of his time playing video games, rarely venturing outside. However, there was an improvement in his social life and academic performance during high school, which led Filippo to enrol in university, where he also initiated a romantic relationship with a girl.

In the summer of 2018, following his first year of university, Filippo started experiencing anxiety disorders, making it challenging for him to cope with his exams. Simultaneously, he found out that his girlfriend was using heroin and cocaine. In response, he decided to experiment with these substances. Initially, his usage was occasional and seemed "manageable", but Filippo rapidly developed both physical and mental addiction. Furthermore, he began using cocaine to counteract the effects of heroin. His drug abuse progressively escalated from occasional to daily, extending beyond social contexts to solitary moments. Filippo found himself trapped in a vicious cycle, marked by a constant need to soothe himself and promptly reactivate. His academic performance suffered, and financial resources were increasingly diverted towards substance abuse. Recognizing the severity of the situation, Filippo sought help from a psychiatrist-psychotherapist, who advised him to approach an Addiction Service. Although Filippo was not fully convinced, he perceived that seeking help was his only viable option. When he shared his predicament with his family, their initial response was a mix of anger and concern. However, that single conversation remained an isolated instance, and subsequently, they seemed to adopt an approach of denial, choosing not to acknowledge the reality of Filippo's struggles.

Filippo initiated his treatment at the Addiction Service in January 2020 with a dosage of 2 mg of sublingual buprenorphine. This regimen was subsequently increased to 4 mg after a few weeks. Notably, Filippo demonstrated commendable adherence to the treatment regimen, attending interviews regularly and concurrently engaging in private psychotherapy. He ceased his heroin use immediately after commencing OAT, and he also managed to discontinue cocaine, with only a few relapses in October 2020. Subsequently, Filippo experienced improvements in mood, school performance, and social interactions. However, his main concern revolved around the prospect of discontinuing the daily tablet intake.

In January 2022, after Filippo's previous doctor departed from the service, I had a clinical interview with Filippo. During this meeting, I suggested a questionnaire to assess the current state of his therapy and his interest in transitioning to newly available drug formulations. Filippo embraced the idea of transitioning to a subcutaneous buprenorphine implant with enthusiasm. Despite considering the possibility of balancing his personal life with regular visits to the Addiction Service, he expressed a keen interest in the new treatment. At that point, he had been on a 4 mg sublingual buprenorphine tablet regimen for approximately two years, and his toxicological tests consistently showed negative results for illicit drugs.

Filippo's excitement stemmed from several profound considerations: the weariness of identifying himself as an addict, a label that he felt no longer accurately portrayed his current state; the conscious desire to disengage from the daily ritual of medication, which he defined as a "substitute" for his previous heroin use, and thus corresponded to him as if still "getting high" every day; and the wish to regain control over his daily routine without being tethered to the demands of therapy, envisioning a future where he could plan vacations and travel abroad without the constraints of regular visits. Lastly, Filippo held a hopeful anticipation of achieving a definitive conclusion to his therapy, marking a significant milestone in his journey towards recovery. Despite receiving comprehensive information from the data sheet, Filippo's determination to pursue the subcutaneous buprenorphine implant treatment remained unwavering. He maintained a steadfast commitment to this choice, eagerly anticipating further details about the practicality and feasibility of undergoing the implant procedure. The Addiction Service practitioners collaborated closely with the hospital pharmacy and the Palliative Care operating unit to efficiently organize the day of the surgery. On the morning of the surgery, Filippo exhibited no signs of agitation. He adhered to the given directions and refrained from taking the morning sublingual buprenorphine tablet. Without experiencing any withdrawal symptoms, he maintained focus on the day's objective. The surgical procedure proceeded smoothly, lasting approximately an hour, after which Filippo proceeded to attend his university activities.

In the days following the surgery, Filippo reported a sustained, almost heightened sense of well-being, exceptional concentration (especially in his studies), and an energy level he had not experienced before. While there may have been a brief, two-day period resembling a hypomanic phase, Filippo soon returned to a stable and regular state of well-being, seamlessly resuming his daily activities. Despite being aware of the option to supplement the implant with buprenorphine tablets, Filippo never felt the necessity to do so. In agreement with the department director, we limited Filippo's visits to the Ser.D to the bare minimum needed to perform the monitoring required by the implant protocol. These included urine tests at various intervals post-intervention: 1 week, 2 weeks, 1.5 months, 3 months, 4.5 months, 6 months, and 7 months. During these visits, we assessed his overall health, general well-being, reactions at the implantation site, degree of patient satisfaction, and any withdrawal or craving symptoms, along with potential drug abuse.

In our regular phone interviews with Filippo, he would describe positive events that were taking place in his life. Approximately four months post-intervention, during an in-person interview, we delved into the impact of the implant on Filippo's lifestyle. A significant transformation was evident: his self-perception had undergone a complete shift. During the six-month period of the implant, Filippo encountered an emotional reconnection with his mother when he shared his experience with the subcutaneous treatment. Until then, his addiction had only been briefly mentioned within the family context, resulting in a negative outcome. This revelation left his mother surprised, astonished, and moved, but also visibly proud.

On a separate occasion, Filippo attended a party and unexpectedly spent the night away from home. He emphasized that he only realized the next day that such spontaneity would not have been possible without the implant. Without the need for daily tablets, he could participate freely without the fear of experiencing withdrawal symptoms the following morning. He no longer needed the “daily heroin substitute” and he no longer needed heroin. These and other episodes strengthened his conviction to “get rid” of therapy and of the fear of not being able to “walk without that crutch”. His determination grew, accompanied by the belief that the removal of the implant would mark the conclusion of his therapy. Filippo explicitly requested the removal of the implant not at the initially specified deadline but at a later time, and he duly signed a written request expressing this desire.

The implant removal occurred in mid-November 2022, precisely 7 months and 9 days after its initial placement. Despite Filippo was at the time a little tense, the removal proceeded smoothly. The urine test conducted at this time still showed a positive result for buprenorphine. In the subsequent days, Filippo experienced symptoms including chills, tearing, arthralgia, and asthenia. Initially attributing these symptoms to a form of flu without strong conviction, he persevered. After 20 days, despite lingering discomfort, his determination to discontinue oral OAT prevailed. The subsequent urine test confirmed the absence of buprenorphine, marking the achievement of Filippo's goal.

General discussion

The buprenorphine implant represents an innovative formulation for OAT, specifically designed for individuals with OUD who have achieved stabilization through prior oral therapy. Notably, the implant demonstrates equivalent therapeutic effectiveness and similar rates of adverse effects when compared to standard sublingual buprenorphine or buprenorphine/naloxone tablets [ 6 , 8 ]. Nonetheless, a comprehensive risk–benefit evaluation has revealed several advantages associated with the subcutaneous buprenorphine implant in comparison to conventional OAT [ 10 ]. These benefits include enhanced treatment adherence, improved quality of life for patients, decreased likelihood of engaging in illicit opioid abuse, and a reduced risk of misuse or diversion [ 10 ]. These findings have been validated through the experiences of the first six patients in Europe who underwent the buprenorphine implant, as outlined in this case series. The report provides insights into the tangible effects of the buprenorphine implant on patients' quality of life and the achievement of therapeutic objectives, specifically focusing on abstinence from illicit drug abuse and the detoxification process.

Eligible patients were carefully assessed by the medical equipe in terms of clinical, psychological, and pharmacological status. All patients had refrained from using illicit drugs, were receiving low-dose sublingual buprenorphine (≤ 8 mg), demonstrated adherence to OAT and regular visits to the Addiction Service, and exhibited psychological stability. The heterogeneity observed in this group of patients stemmed from variations in sociocultural background, gender, age, duration of substance abuse history, length of the period of drug abstinence, and the specifics of their medical and pharmacological history, including the duration, dosage, and any prior OAT before transitioning to buprenorphine (Table  5 ).

Buprenorphine implant emerges as a viable treatment alternative for diverse patient profiles, contingent upon achieving a certain level of pharmacological stability (≤ 8 mg), psychological well-being, and a documented recent history of drug withdrawal.

The reaction of the patients to the implant proposal ranged from moderate interest in some cases to genuine enthusiasm in others as delineated in Table  6 (Buprenorphine implant proposal). All patients embraced the buprenorphine implant to enhance their quality of life, eliminating the need for regular visits to the Addiction Service for the administration of tablets and moving closer to complete detoxification.

To assess the impact of both traditional OAT and buprenorphine implant, a semi-quantitative narrative analysis was conducted [ 15 , 16 , 17 , 18 ]. Every quote pertaining to patients' experiences with either treatment was considered in the analysis and subsequently categorised into one or more of the following topics: commitment to achieving complete detoxification, disengagement from therapy, smoothness of therapy, emotional impact, and improved quality of life in terms of free-time, finances, work, and interpersonal relationships (Fig.  1 ). Subsequently, the positive or negative valence associated with each statement was recorded. The implant was viewed as a valuable means to achieve abstinence from both drugs and medications, as evidenced by a total of 22 positive statements (Fig.  1 A), compared to 6 for traditional OAT (Fig.  1 B). The regular attendance at the Addiction Service was seen as a “constraint that disrupted daily routines” and “contributed to social stigma”, undermining patients' commitment to therapy and overall quality of life (7 out of 9 negative statements). The desire to break free from the daily tablet intake, perceived as a “substitute for heroin” and a source of mood swings, was a common sentiment. In contrast to the peaks associated with oral intake, the subcutaneous implant offered a stable release of buprenorphine, as evidenced by the 22 positive statements (Fig.  1 A) compared to 7 (Fig.  1 B) associated with traditional oral intake. This consistency helped in mitigating both physical and emotional fluctuations experienced by the patients.

A narrative analysis of patients' reported experiences was conducted for both traditional OAT ( A ) and buprenorphine implant ( B ). The analysis was conducted by categorizing the statements related to each treatment into the five identified topics positioned at the vertices of the pentagon. The number of positive (blue line) and negative (red line) statements per topic were plotted along the direction of the corresponding vertex and connected by a 5-pointed closed line. The distance from the centre indicates the frequency of iterations. Notably, the scale of the pentagon differs between the two graphs

In terms of surgical procedure, the buprenorphine implant insertion was carried out in a specialised facility, by a professional surgeon, and no significant issues were encountered for any of the patients (Table  6 , Surgery outcome). Solely one patient developed a minor infection at the implant site, which was promptly addressed with antibiotics. He also reported a subjective feeling of overdose in the initial days post-insertion, followed by mild withdrawal symptoms, that were stabilised by a 3-day course of 1 mg sublingual buprenorphine. Consistent with findings from a previous study [ 19 ], the buprenorphine implant insertion procedure and the subsequent adaptation to treatment appear to be overall safe and well-tolerated.

During 6 months of follow-up, as outlined in Table  6 (Follow-up visits), the potential onset of withdrawal symptoms was closely monitored through regular assessments for most patients. Psychometric tests were also conducted to evaluate various aspects. Importantly, no patient reported experiencing cravings throughout the course of treatment, and all toxicological tests yielded negative results for the detection of illegal opioid abuse. All the patients expressed satisfaction with the buprenorphine implant treatment, and most of them reported being content with their decision, as indicated in Fig.  1 and Table  6 (End of therapy). On an emotional level, all patients reported a sense of well-being, with 18 positive statements compared to 3 positive statements for traditional OAT (Fig.  1 A, B), and no instances of relapse were noted. Half of the patients experienced increased lucidity, improved introspective ability, and greater stability on the affective level (Table  6 , End of therapy). The majority showed an on-axis mood (4 out of 6), absence of anxiety, hypnic pattern within limits, and restful sleep. Two out of six patients explicitly described a marked improvement in self-perception during the 6-month buprenorphine implant treatment. Overall, buprenorphine implant was perceived as a step closer to complete detoxification with 13 positive statements (Fig.  1 A) vs. 5 positive statements for traditional OAT (Fig.  1 B).

The removal procedure was successful for most of the patients, and none of them opted for a second implant. Solely one patient reintroduced sublingual buprenorphine at low dosages, although this decision was not prompted by any withdrawal symptom. Most importantly, none of the patients experienced craving episodes, indicating the potential for them to continue living without any OAT and ultimately achieve complete detoxification.

In summary, this case series explores the pioneering use of buprenorphine implant as a treatment option for OUD in a small European cohort of eligible patients. The findings suggest positive outcomes, including improved patient satisfaction and quality of life, reduced stigma associated with regular clinic attendance, and perceived advantages in achieving opioid abstinence. However, certain limitations must be acknowledged, including the small sample size, the relatively short follow-up period, and the reliance on self-reported questionnaires to evaluate patients’ perspective and experiences. The relatively small yet heterogenous sample size, while providing valuable insights into how various patient profiles might respond to this treatment approach, could affect the generalizability of the findings to a broader population. Moreover, the variability in the frequency and duration of follow-up visits, while enabling to capture the moderate-to-long term effects of the treatment, limits the ability to assess longer-term outcomes. Furthermore, the study's reliance on self-reported questionnaires while focusing on patients’ perspective, might introduce the possibility of response bias. This could include an inclination to offer responses that align with social expectations or recall biases. Therefore, in future studies the adoption of standardized assessment tools will ensure consistency and facilitate more robust cross-study comparisons. Future research should prioritise larger cohorts, encompassing comparative analyses with traditional OAT, and long-term investigations to assess sustained efficacy and diverse dynamics of patient profiles. Collaborative efforts to standardize assessment protocols across facilities would further strengthen the reproducibility of research findings in this evolving field.

Final conclusions

This case series outlines the therapeutic journey of the first six European patients who underwent buprenorphine implant therapy. The results demonstrate favourable outcomes, including successful opioid abstention, alleviation of withdrawal symptoms, and enhanced quality of life and psychological well-being. Importantly, the treatment exhibited a high level of safety and tolerability, with no significant adverse events reported during the peri-operative period. The smooth insertion procedure and subsequent adaptation highlight the consistent benefits of the implant, with most patients achieving complete abstention, a milestone that might have been challenging with traditional approaches. Overall, the patients' satisfaction with the buprenorphine implant underscores its potential as a viable treatment option for pharmacologically stable individuals seeking to transition from traditional OAT. Nevertheless, further research into patient profiles, craving dynamics, and patient-centred outcomes is essential for optimizing personalized interventions in the field of addiction medicine.

Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

Abbreviations

• Opioid use disorder
• Opioid agonist therapy

Hepatitis C Virus

Centro Manifestazioni Sistemiche Virus Epatitici, Systemic Manifestations of Hepatitis Virus Centre

World Health Organization Quality of Life-BREF

Tetrahydrocannabinol

Visual analog scale

Methylenedioxymethamphetamine

Lysergic acid diethylamide

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CV, MLP, AV, and CD collected, analysed, and interpreted the patient data regarding the Case n.1. BO collected, analysed, and interpreted the patient data regarding Case reports 2 and 3. CL, SB, GFMD, LC, SL, MN, AP, EP, CP, and GV collected, analysed, and interpreted the patient data regarding Case reports 4 and 5. RM collected, analysed, and interpreted the patient data regarding the Case report 6. All authors participated in the writing process, reviewed, and approved the final version of the manuscript.

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Additional file 1: case report 1..

Buprenorphine implant procedure.

Additional file 2: Case report 2.

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Pierlorenzi, C., Nunzi, M., Cirulli, S. et al. Patients' perspectives on buprenorphine subcutaneous implant: a case series. J Med Case Reports 18 , 202 (2024). https://doi.org/10.1186/s13256-024-04483-6

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The plasma kynurenine-to-tryptophan ratio as a biomarker of tuberculosis disease in people living with HIV on antiretroviral therapy: an exploratory nested case–control study

• Sivaporn Gatechompol 1 , 2 , 3 ,
• René Lutter 4 , 5 ,
• Frédéric M. Vaz 6 , 7 ,
• Sasiwimol Ubolyam 1 , 2 ,
• Anchalee Avihingsanon 1 , 2 ,
• Stephen J. Kerr 1 , 8 ,
• Frank van Leth 9 &
• Frank Cobelens 3  

BMC Infectious Diseases volume  24 , Article number:  372 ( 2024 ) Cite this article

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Metrics details

Non-sputum-based tests are needed to predict or diagnose tuberculosis (TB) disease in people living with HIV (PWH). The enzyme indoleamine 2, 3-dioxygenase-1 (IDO1) is expressed in tuberculoid granuloma and catabolizes tryptophan (Trp) to kynurenine (Kyn). IDO1 activity compromises innate and adaptive immune responses, promoting mycobacterial survival. The plasma Kyn-to-Trp (K/T) ratio is a potential TB diagnostic and/or predictive biomarker in PWH on long-term antiretroviral therapy (ART).

We compared plasma K/T ratios in samples from PWH, who were followed up prospectively and developed TB disease after ART initiation. Controls were matched for age and duration of ART. Kyn and Trp were measured at 3 timepoints; at TB diagnosis, 6 months before TB diagnosis and 6 months after TB diagnosis, using ultra performance liquid chromatography combined with mass spectrometry.

The K/T ratios were higher for patients with TB disease at time of diagnosis (median, 0.086; IQR, 0.069–0.123) compared to controls (0.055; IQR 0.045–0.064; p = 0.006), but not before or after TB diagnosis. K/T ratios significantly declined after successful TB treatment, but increased upon treatment failure. The K/T ratios showed a parabolic correlation with CD4 cell counts in participants with TB ( p  = 0.005), but there was no correlation in controls.

Conclusions

The plasma K/T ratio helped identify TB disease and may serve as an adjunctive biomarker for for monitoring TB treatment in PWH. Validation studies to ascertain these findings and evaluate the optimum cut-off for diagnosis of TB disease in PWH should be undertaken in well-designed prospective cohorts.

Trial registration

ClinicalTrials.gov Identifier: NCT00411983.

Peer Review reports

In the past decades a variety of diagnostic tests for tuberculosis (TB) ranging from smear microscopy to nucleic acid amplification test have become available. Despite this, TB morbidity and mortality are still unacceptably high. In 2021, there were an estimated 1.4 million deaths among HIV-negative people and an additional 187,000 deaths among people living with HIV (PWH) [ 1 ]. Among PWH, paucibacillary and extra-pulmonary TB (EPTB) pose diagnostic challenges [ 2 , 3 ]. Diagnosis of EPTB requires a high degree of clinical suspicion and special diagnostic procedures in order to get microbiologically positive specimens, while PWH with TB less often produce sputum [ 4 , 5 ]. Therefore, sensitive and specific non-sputum-based tests are needed to predict the development of clinical TB, so rapid diagnostic and management decisions can be made.

Indoleamine 2, 3-dioxygenase (IDO)1 is an inducible tryptophan-catabolizing enzyme expressed in tuberculoid granuloma [ 6 ]. IDO1 like its isoform IDO2, which is enzymatically less active and rarely expressed, and the constitutively expressed liver enzyme tryptophan dioxygenase (TDO) catabolize tryptophan (Trp) to kynurenine (Kyn) [ 7 ]. The production of kynurenine is the rate-limiting step in the IDO/TDO-kynurenine pathway, thus changes in kynurenine are reflect alterations in the IDO1 activity. IDO1 activity can therefore be estimated using the Kyn-to-Trp ratio in plasma (K/T ratio). IDO-mediated Trp depletion results in T-cell anergy and apoptosis, whereas the accumulation of Kyn suppresses T-cell differentiation and function [ 8 ]. Animal studies have demonstrated that M. tuberculosis infection is associated with high expression of IDO in the granuloma, leading to compromised T cell function which promotes mycobacterial survival and growth [ 9 , 10 ].

IDO activity reflected by the K/T ratio has been proposed as a potential biomarker for the diagnosis of TB, and monitoring treatment outcomes in children [ 11 ], pregnant women [ 12 ], HIV-negative [ 13 , 14 ] and HIV-positive [ 15 ] individuals. This enzyme has also been recognized as an immune response biomarker that plays a pivotal role in HIV immune dysfunction [ 7 ]. A previous longitudinal PWH cohort demonstrated that plasma K/T ratios were elevated 6 months before clinical TB symptoms became apparent, and declined after successful treatment [ 15 ]. A recent study in pregnant women living with HIV demonstrated plasma K/T ratios were elevated in women with TB disease at time of diagnosis [ 12 ]. However, no studies yet have evaluated the performance of the K/T ratio as a TB diagnostic or predictive biomarker among PWH on long-term antiretroviral therapy (ART). In this study, we evaluated whether the plasma K/T ratio could predict the occurrence of TB disease, diagnose TB disease, and monitor treatment response in PWH.

Study participants

This study used biobanked plasma samples from HIV-NAT 006 (HN006), a prospective, clinic-based cohort that has enrolled adults living with HIV aged ≥ 18 years since 1996 (Clinicaltrials.gov NCT00411983, first registered on 15/12/2006). In this cohort, the participants were seen every 6 months at HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok. Care for HIV infection was provided according to the prevailing Thai treatment guidelines at the time participants attended follow-up visits. The following variables were collected at each clinic visit: body temperature, body weight, body mass index (BMI), physical examination findings, full differential blood counts, lipid profile, creatinine, and alanine aminotransferase (ALT). CD4 + and CD8 + lymphocyte counts performed by automated fluorescence-activated flow cytometry as well as HIV RNA were measured every 12 months.

Plasma samples were collected and stored at each visit. Ten mL of whole blood were collected in ethylene diamine tetra acetate (EDTA) tubes and centrifuged (3000 rpm) at 4ºC for 20 min. Plasma samples were aliquoted into volumes of 500 μL and stored at ≤ -70ºC until analysis.

Ethical approval

The study protocol was approved by the medical ethics committee, Faculty of Medicine, Chulalongkorn University, Bangkok (IRB No.161/45) and conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All participants in HN006 cohort provided written informed consent and consented for the use of plasma stored samples in this study.

Definition of case and control participants

During the follow-up visits, participants with symptoms and/or signs of TB disease were assessed by physical examination, chest radiography, sputum smear microscopy and culture for M. tuberculosis and/or GeneXpert MTB/RIF (Xpert; Cepheid, Sunnyvale, CA, which was available from 2012 onward). TB disease was bacteriologically confirmed by smear microscopy, culture or Xpert, or clinically diagnosed based on radiologic evidence of TB without bacteriological confirmation combined with a good clinical response to antituberculosis treatment.

We included participants with TB disease who had samples available at 3 different time points: 1) 6 months before TB diagnosis, 2) around TB diagnosis (the allowable window for sample collection was 2 months before or after initiation of TB treatment), and 3) 6 months after TB diagnosis. We matched controls from HN006 cohort with individual cases (1:1) based on age and ART duration with one year window around the date of the TB diagnosis visit. Then, we further selected only controls that with samples available at all 3 timepoints. If there was more than one control eligible to be matched with individual cases, the control was randomly selected. We did not test for latent TB infection in the controls, since TB preventive therapy was not recommended by Thai National guidelines at that time. According to the clinical records, control participants had no respiratory symptoms or signs and symptoms of active TB at visit 2, (the visit used to match with TB cases. The study flow chart describing participant recruitment is shown in Fig.  1 .

The study flow chart describing participants recruitment

* Six cases had only one match; 7 cases had one or more potential matches. For these cases, the control was randomly selected from available matches

Quantitation of plasma tryptophan, kynurenine and downstream metabolites

Kyn and Trp were separated by ultra-performance liquid chromatography and measured by tandem mass spectrometry (UPLC-MS/MS) system (Waters, Milford, MA, USA). The selected plasma samples were shipped at or below -70 °C to the Amsterdam University Medical Centers for analysis. Upon analyses, samples were thawed rapidly at room temperature and a mixture of stable isotope-labeled internal standards was added to 50 μl of plasma. The samples were deproteinized using acetonitrile, dried under nitrogen, and reconstituted in 100 μl of 0.1% heptafluorobutyric acid. Aliquots (10 μl) of the extracts were injected into the UPLC–MS/MS system comprising of Acquity Xevo TQ-XS system operated in positive ESI mode using multiple reaction monitoring (MRM) for preselected analytes and an overall run time was 6 min. The MRM transition which gave the most intense signal was chosen for quantification. IDO activity was calculated as the ratio of measured kynurenine concentration to measured tryptophan concentration (K/T ratio). In order to capture all metabolites in the Trp and Kyn pathways, we measured other metabolites including anthranilic acid, 3OH-kynurenine, 3OH-anthranilic acid, quinolinic acid, kynurenic acid and xanthurenic acid (Supplementary Fig.  1 ). We also calculated the ratio of the sum of all determined kynurenine metabolites to Trp concentration (Sum/T ratio).

Statistical Analysis

Non-normally distributed data was presented as medians with interquartile ranges (IQR). Cross-sectional comparisons of plasma Trp concentration, Kyn concentration, and the K/T ratio between TB patient and control samples at each visit were tested using the Mann–Whitney U test. Changes of K/T ratio between the visits among TB patients were tested using Wilcoxon signed-rank test. Based on two-way scatterplot appearances, regression models with quadratic terms were used to investigate associations between the K/T ratio at TB diagnosis visit and clinical variables including CD4 count and body mass index (BMI). Pearson’s correlation coefficient was calculated from the predicted regression values.

We calculated a receiver operating characteristic curve (ROC) to evaluate the most optimal cutoff point for K/T ratio that can be used to diagnose TB based on Liu’s index. We assessed the sensitivity, specificity and discriminative ability of the model using the area under the ROC curve (AROC) and 95% CIs around these estimates were obtained by bootstrapping the estimates with 1000 replication.

A P -value for two-sided test less than or equal to 0.05 was considered statistically significant. The statistical analysis was done by using Stata version 17 (StataCorp., College Station, TX, USA) and figures were done by using GraphPad Prism 9 software (GraphPad Software, USA).

Demographic data of the study participants

Among 130 participants who developed active TB after ART initiation (Fig.  1 ), we identified 13 pulmonary TB patients with three consecutive plasma samples available. Ten were bacteriologically confirmed and 3 were clinically diagnosed. At TB diagnosis visit, the clinical characteristics of TB patients included fever (85%), weight loss (62%), cough (46%) and cervical lymphadenopathy (39%). At the time of TB diagnosis, three (23%) TB cases had detectable HIV viral load. The HIV viral loads for these cases were 5.75, 6.29 and 6.41 log10 copies/mL, respectively. All controls had undetectable HIV viral load (< 40 copies/ml).

Ten TB patients were successfully treated with the standard TB 6-month regimen (isoniazid, rifampin, pyrazinamide, and ethambutol). Three patients had poor treatment response due to poor adherence and adverse effects from TB treatment.

The median age of the TB patients at TB diagnosis was 41.6 years (interquartile range (IQR), 36.1–52.1). All of the participants were Thai and 8/13 (62%) were male. The median CD4 cell count at TB diagnosis was 370 (189–577) cells/mm 3 and median duration of ART was 12.2 (4.2–16.8) years. Of the samples taken at the time of TB diagnosis among the TB patients, 9/13 (69.2%) were collected at a median of 1 (0.8–1.7) month before TB treatment initiation while 4/13 (30.8%) were collected at a median of 0.9 (0.8–1) month after TB treatment initiation. The demographic and clinical characteristics of the patients with TB and the controls are summarized in Table 1 .

Plasma kynurenine and tryptophan ratio among PWH with tuberculosis and controls

At the time of TB diagnosis, the K/T ratio was significantly higher among participants with TB (median, 0.086 (0.069–0.123)) compared to the controls at the corresponding visit (0.055 (0.045–0.064); p  = 0.006). There were no significant differences between study groups at the visits 6 months before or after TB diagnosis (Fig.  2 a). The sum of the metabolites to tryptophan ratio was also significantly higher at TB diagnosis (Fig.  2 b). Assessing each metabolite in the pathway separately, we found no significant differences in the concentration of kynurenine, tryptophan and OH-kynurenine between TB participants and controls. However, concentrations of anthranilic acid, kynurenic acid, OH-anthranilic acid, xanthurenic acid and quinolinic acid were significantly lower in the participants with TB compared to the controls (Fig.  3 ), including timepoints 6 months before and 6 months after TB diagnosis.

a  Plasma kynurenine to tryptophan ratio and b  sum of metabolites to tryptophan ratio in TB participants compared to that in controls at each visit. The bars represent the median with error bars indicating 95% confidence interval. The p values were calculated using Mann–Whitney test

Concentrations of tryptophan and kynurenine metabolites in plasma from TB patients and controls at each visit. The bars represent the median with error bars indicating 95% confidence interval. The Y axis scale differs between the metabolites

In addition, we conducted a sensitivity analysis which excluded the 3 TB participants with poor treatment outcomes. This sensitivity analysis gave similar results: at the time of TB diagnosis, the K/T ratio was significantly higher among participants with TB (median, 0.097; IQR, 0.070–0.127) compared to the controls at the corresponding visit (0.055; IQR 0.045–0.064; p  = 0.004) (Fig. S 2 ).

The plasma K/T ratio was associated with clinical response after TB treatment

The majority of participants who were treated successfully had significantly decreased K/T ratios after TB treatment (Fig.  4 a). For these, at the time of TB diagnosis, the median K/T ratio was 0.064 (0.049–0.096) compared to 0.057 ((0.053–0.734), p = 0.017) 6 months post treatment (Fig.  4 c). In contrast, the three participants who experienced treatment failure had higher levels of K/T ratio as well as lower levels of CD4 blood cell counts after TB treatment, compared to at diagnosis (Fig.  4 b).

a  The plasma K/T ratio after TB treatment in participants who were treated successfully. b The plasma K/T ratio and CD4 count of the participants who had treatment failure. Each dot or line represents an individual. c The median of K/T ratio at the time of TB diagnosis compared to 6 months post treatment among TB participants who were treated successfully

Correlation between K/T ratio and clinical variables

We analyzed the correlation of plasma K/T ratios with clinical variables of TB patients and controls. Plasma K/T ratios showed a parabolic correlation with CD4 cell counts in participants with TB ( p  = 0.005), but there was no correlation in controls (Fig.  5 ). There was no correlation between plasma K/T ratio and BMI in either group.

Plasma K/T ratios showed a quadratic association with CD4 cell counts in participants with TB disease, but not in controls. Body mass index showed no correlation with K/T ratio in either group

Diagnostic value of plasma K/T ratio for tuberculosis among PWH

We investigated the performance of plasma K/T ratio to diagnose TB disease in PWH, using both bacteriologically confirmed and clinically diagnosed TB at diagnosis as true-positives. For controls, we used the K/T ratio at the corresponding visit as true-negatives. We found that the K/T ratio achieved an AUC of 0.77 (95%CI 0.60–0.94) for diagnosis of tuberculosis (Fig.  6 ).

Diagnostic performance of plasma K/T ratio for tuberculosis diagnosis in PWH

According to the WHO target product profile (TPP) for a triage test to identify people suspected of having TB, the minimum requirements for sensitivity and specificity are 90% and 70%, respectively [ 16 ]. At a cutoff of 0.054, the K/T ratio provided a sensitivity of 92% and a specificity of 46%. At a cutoff of 0.064, the K/T ratio provided a specificity of 70% and sensitivity of 77%. The minimum WHO TPP requirements for a non-sputum based diagnostic test are 65% for sensitivity and 98% for specificity. At a cutoff of 0.070, the K/T ratio provided a sensitivity of 69% and a specificity of 77%. At a cutoff of 0.098, the K/T ratio provided a specificity of 100% against a sensitivity of 38%.

Non-sputum-based biomarkers are needed to diagnose and predict the occurrence of TB disease and monitor the effect of TB treatment in order to reduce TB morbidity and mortality in PWH. In this study, we assessed IDO activity by measuring plasma K/T ratios to diagnose and predict TB disease and monitor the response to TB treatment in PWH on ART from a longitudinal HIV cohort. We found that baseline plasma K/T ratios did not predict the occurrence of TB disease over a 6-month period, but were significantly higher among PWH with TB disease compared to PWH without TB at the time of TB diagnosis. In addition, the plasma K/T ratio significantly declined at 6 months relative to the time of TB diagnosis among TB patients who responded to treatment.

These findings are consistent with previous studies from an African TB cohort with HIV co-infection [ 15 ] and a population of HIV-negative persons with pulmonary TB disease from Georgia [ 13 ]. However, unlike the African TB cohort with HIV [ 15 ], we found no significant differences between the two groups from our study at 6 months before TB diagnosis. A possible explanation for this difference is that the plasma K/T ratios in our study were 15.7- fold lower compared to those of the PWH with TB in the African cohort (0.086 vs 1.35). It is possible that this difference is due to the use and duration of ART. Our participants were on long-term ART with a median duration of 12.2 years, whereas only 50% of the participants in the African cohort received ART at the time of TB diagnosis and were followed up to only 4 years. Previous cohort studies among PWH showed significantly decreased K/T ratios after ART initiation [ 17 , 18 , 19 ]. However, these levels remained higher compared to those observed in individuals without HIV infection [ 18 ] and the elevated IDO level did not normalize, even after more than 7 years of ART [ 20 ].

During the course of HIV infection, elevated IDO activity leads to a distortion in the differentiation of CD4 T-cells and directly hampers T-cell immune responses, thus contributing to HIV disease progression [ 21 ]. An in vitro study showed that IDO mRNA expression is elevated in peripheral blood mononuclear cells (PBMCs) from PWH compared with healthy controls, and inhibition of IDO results in increased CD4 + T-cell proliferative responses in PBMCs from PWH [ 22 ]. A cohort study among PWH initiating ART demonstrated that a higher KT ratio predicted poor CD4 + T-cell count recovery and increased mortality [ 17 ]. IDO activity also positively correlates with the size of HIV DNA reservoir in PBMCs of PWH receiving ART [ 23 ]. In addition, the level of IDO activities in the PWH co-infected with TB are higher compared to those with HIV mono-infection, both before and after ART initiation [ 24 ].

The plasma K/T ratios at the time of TB diagnosis in our study were comparable to those in a TB cohort without HIV from Georgia and a multidrug-resistant TB cohort from South Africa of which 75% of participants were HIV positive [ 13 ].

We found a trend toward decreased plasma K/T ratios in successfully treated patients, in line with previous studies [ 12 , 13 , 15 ]. However, we also observed 3/10 successfully treated patients did not have any change in K/T ratio after treatment. It is possible these patients had other inflammatory or infectious conditions, as the kynurenine pathway can be activated by infectious agents, inflammatory mediators and stress [ 25 ]. The participants who experienced treatment failure had increased K/T ratios after treatment, paralleled by a decrease in CD4 counts. Thus, the K/T ratio may have potential as a biomarker for TB treatment monitoring [ 26 ]. Current recommendations for TB treatment monitoring rely on sputum and culture conversion. However, sputum smear has a low sensitivity and cannot identify viable bacilli. Also, M. tuberculosis culture has a long turnaround time and risk for cross-contamination. In addition, a study among HIV-negative pulmonary TB patients in Japan showed that higher IDO activity at the time of TB diagnosis was an independent predictor for mortality [ 14 ].

A remarkable finding from the detailed analyses of various kynurenine metabolites was that patients who developed TB disease had lower baseline values for kynurenic acid, xanthurenic acid and quinolinic acid at all time points (Fig.  2 ). Kynurenine can be metabolized via three pathways by the enzymes kynureninase (KYNU), kynurenine 3-monooxygenase (KMO) and kynurenine aminotransferase (KAT) (Supplementary Fig.  1 ). Kynurenine is predominantly metabolized by KMO [ 27 ]. From these findings, it appears that both the KYNU and KAT activity are reduced in TB patients, and/or the clearance of these metabolites is enhanced in this group. It is important to realize that the systemic levels of these kynurenine metabolites may not reflect local levels, and further research is needed to understand whether these differences contribute to developing TB disease, or were found by chance.

The K/T ratio showed a significant parabolic (U-shaped) correlation with CD4 cell counts in TB participants but not in the controls. In vitro studies reported that the tryptophan catabolites kynurenine and picolinic acid can inhibit T-cell proliferation [ 28 ] and in vitro inhibition of IDO activity in peripheral blood mononuclear cells from PWH resulted in increased CD4 T-cell counts [ 22 ]. A study among PWH in Uganda showed that a higher K/T ratio at 12 months after ART initiation could predict slower CD4 T-cell count recovery, after adjusting for pre-ART CD4 T-cell count, viral load, age, and sex [ 17 ]. This suggests the correlation between high K/T ratio and low CD4 T cell count may be related to the cytotoxic and/or proliferation inhibitory effects of kynurenine. We also found a correlation between high K/T ratio and high CD4 T cells count. Since CD4 T cells are key components of the immune response against M. tuberculosis , high CD4 cell counts can enhance responses to TB leading to more IDO activity. We found no correlation between K/T ratio and BMI in either of our study groups.

Our analysis showed that the plasma K/T ratios achieved acceptable accuracy for diagnosing TB disease (AUC = 0.77). At a cutoff of 0.054, the K/T ratio produced a sensitivity of 92% and a specificity of 46%, which does not meet the current minimum WHO TPP requirements for a triage test. However, triage tests need to be simple low-cost tests, that can be used by low-skilled providers to rule out TB at the point-of care. Therefore, to serve as a triage test, the K/T ratio will require technological development. A recent study evaluating the K/T ratio in plasma from PWH with TB disease compared to those without TB, using enzyme-linked immunosorbent assay (ELISA) based on monoclonal antibodies, showed good agreement against mass spectrometry [ 29 ]. We also showed that K/T ratio may have utility for TB treatment monitoring, although we could not compare its accuracy against agreed requirements as there is currently no WHO TPP for this use.

There were several potential limitations to our study. First, we had a small sample size that limits the precision of our results. Second, we did not include individuals with other lung diseases to compare with the TB patients. However, a previous study among PWH showed that the K/T ratio had discriminatory power to differentiate between TB and pneumonia patients [ 15 ]. Last, we did not determine the contribution of either of the enzymes, TDO, IDO1 and IDO2, that convert tryptophan to kynurenine. The contribution of TDO to systemic kynurenine and downstream metabolites is likely to be low, as TDO also functions in healthy individuals without leading to systemic kynurenine and downstream metabolites. We cannot exclude a role for IDO2, which is less active than IDO1 and its level of expression is not known. Nevertheless, the kynurenine levels and levels of downstream metabolites were discriminatory, independent of which of the IDO isoforms contributed.

In summary, our study demonstrated the plasma K/T ratio, measured by UPLC-MS/MS, had ability to identify TB disease and may serve as an adjunctive biomarker for TB treatment monitoring among PWH. Further studies conducted in well-designed prospective cohorts are necessary to validate our study results, and ascertain the optimal plasma K/T ratio cut-off for diagnosis of TB disease in PWH.

Availability of data and materials

The datasets generated and/or analysed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

Alanine aminotransferase

Antiretroviral therapy

Body mass index

Confidence interval

Extra-pulmonary TB

Ethylene diamine tetra acetate

Indoleamine 2, 3-dioxygenase-1

Interquartile range

Multiple reaction monitoring

Kynureninase

Kynurenine aminotransferase

Kynurenine 3-monooxygenase

Kynurenine/ tryptophan ratio

People living with HIV

Receiver operating characteristic curve

Sum of all determined kynurenine metabolites to tryptophan concentration

• Tuberculosis

Ultra-performance liquid chromatography, a tandem mass spectrometer

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Acknowledgements

The authors would like to thank the HIV-NAT 006 study participants and the study team for their contribution to this cohort.

This work was supported by HIV-NAT, Thai Red Cross AIDS Research Centre,

Bangkok, Thailand; and Center of Excellence in Tuberculosis, Faculty of Medicine,

Chulalongkorn University, Bangkok, Thailand.

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Sivaporn Gatechompol, Sasiwimol Ubolyam, Anchalee Avihingsanon & Stephen J. Kerr

Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Sivaporn Gatechompol, Sasiwimol Ubolyam & Anchalee Avihingsanon

Department of Global Health and Amsterdam Institute for Global Health and Development, Amsterdam University Medical Centers Location University of Amsterdam, Amsterdam, The Netherlands

Sivaporn Gatechompol & Frank Cobelens

Department of Experimental Immunology, Amsterdam UMC and Amsterdam Infection and Immunity Institute, University of Amsterdam, Amsterdam, The Netherlands

René Lutter

Department of Pulmonary Diseases, Amsterdam UMC, University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands

Department of Core Facility Metabolomics, Amsterdam UMC, Amsterdam, The Netherlands

Frédéric M. Vaz

Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

Biostatistics Excellence Centre, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

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SG, RL, SK, FvL and FC involved in conceptualization of the idea. SG performed statistical analysis, interpreted the data, first draft and revised manuscript. FMV performed the laboratory testing. SU collected the stored samples. AA edited the manuscript. RL, SK, FvL and FC supervised and edited the manuscript. All authors read and approved the final manuscript.

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Gatechompol, S., Lutter, R., Vaz, F.M. et al. The plasma kynurenine-to-tryptophan ratio as a biomarker of tuberculosis disease in people living with HIV on antiretroviral therapy: an exploratory nested case–control study. BMC Infect Dis 24 , 372 (2024). https://doi.org/10.1186/s12879-024-09258-4

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Case study: 60-year-old female presenting with shortness of breath.

Deepa Rawat ; Sandeep Sharma .

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Last Update: February 20, 2023 .

• Case Presentation

The patient is a 60-year-old white female presenting to the emergency department with acute onset shortness of breath.  Symptoms began approximately 2 days before and had progressively worsened with no associated, aggravating, or relieving factors noted. She had similar symptoms approximately 1 year ago with an acute, chronic obstructive pulmonary disease (COPD) exacerbation requiring hospitalization. She uses BiPAP ventilatory support at night when sleeping and has requested to use this in the emergency department due to shortness of breath and wanting to sleep.

She denies fever, chills, cough, wheezing, sputum production, chest pain, palpitations, pressure, abdominal pain, abdominal distension, nausea, vomiting, and diarrhea.

She reports difficulty breathing at rest, forgetfulness, mild fatigue, feeling chilled, requiring blankets, increased urinary frequency, incontinence, and swelling in her bilateral lower extremities that are new-onset and worsening. Subsequently, she has not ambulated from bed for several days except to use the restroom due to feeling weak, fatigued, and short of breath.

There are no known ill contacts at home. Her family history includes significant heart disease and prostate malignancy in her father. Social history is positive for smoking tobacco use at 30 pack years. She quit smoking 2 years ago due to increasing shortness of breath. She denies all alcohol and illegal drug use. There are no known foods, drugs, or environmental allergies.

Past medical history is significant for coronary artery disease, myocardial infarction, COPD, hypertension, hyperlipidemia, hypothyroidism, diabetes mellitus, peripheral vascular disease, tobacco usage, and obesity.  Past surgical history is significant for an appendectomy, cardiac catheterization with stent placement, hysterectomy, and nephrectomy.

Her current medications include fluticasone-vilanterol 100-25 mcg inhaled daily, hydralazine 50 mg by mouth, 3 times per day, hydrochlorothiazide 25 mg by mouth daily, albuterol-ipratropium inhaled every 4 hours PRN, levothyroxine 175 mcg by mouth daily, metformin 500 mg by mouth twice per day, nebivolol 5 mg by mouth daily, aspirin 81 mg by mouth daily, vitamin D3 1000 units by mouth daily, clopidogrel 75 mg by mouth daily, isosorbide mononitrate 60 mg by mouth daily, and rosuvastatin 40 mg by mouth daily.

Physical Exam

Initial physical exam reveals temperature 97.3 F, heart rate 74 bpm, respiratory rate 24, BP 104/54, HT 160 cm, WT 100 kg, BMI 39.1, and O2 saturation 90% on room air.

Constitutional:  Extremely obese, acutely ill-appearing female. Well-developed and well-nourished with BiPAP in place. Lying on a hospital stretcher under 3 blankets.

HEENT: 

• Head: Normocephalic and atraumatic
• Mouth: Moist mucous membranes 
• Macroglossia
• Eyes: Conjunctiva and EOM are normal. Pupils are equal, round, and reactive to light. No scleral icterus. Bilateral periorbital edema present.
• Neck: Neck supple. No JVD present. No masses or surgical scarring. 
• Throat: Patent and moist

Cardiovascular:  Normal rate, regular rhythm, and normal heart sound with no murmur. 2+ pitting edema bilateral lower extremities and strong pulses in all four extremities.

Pulmonary/Chest:  No respiratory status distress at this time, tachypnea present, (+) wheezing noted, bilateral rhonchi, decreased air movement bilaterally. The patient was barely able to finish a full sentence due to shortness of breath.

Abdominal:  Soft. Obese. Bowel sounds are normal. No distension and no tenderness

Skin: Skin is very dry

Neurologic: Alert, awake, able to protect her airway. Moving all extremities. No sensation losses

• Initial Evaluation

Initial evaluation to elucidate the source of dyspnea was performed and included CBC to establish if an infectious or anemic source was present, CMP to review electrolyte balance and review renal function, and arterial blood gas to determine the PO2 for hypoxia and any major acid-base derangement, creatinine kinase and troponin I to evaluate the presence of myocardial infarct or rhabdomyolysis, brain natriuretic peptide, ECG, and chest x-ray. Considering that it is winter and influenza is endemic in the community, a rapid influenza assay was obtained as well.

Largely unremarkable and non-contributory to establish a diagnosis.

Showed creatinine elevation above baseline from 1.08 base to 1.81, indicating possible acute injury. EGFR at 28 is consistent with chronic renal disease. Calcium was elevated to 10.2. However, when corrected for albumin, this corrected to 9.8 mg/dL. Mild transaminitis is present as seen in alkaline phosphatase, AST, and ALT measurements which could be due to liver congestion from volume overload.

Initial arterial blood gas with pH 7.491, PCO2 27.6, PO2 53.6, HCO3 20.6, and oxygen saturation 90% on room air, indicating respiratory alkalosis with hypoxic respiratory features.

Creatinine kinase was elevated along with serial elevated troponin I studies. In the setting of her known chronic renal failure and acute injury indicated by the above creatinine value, a differential of rhabdomyolysis is determined.

Influenza A and B: Negative

Normal sinus rhythm with non-specific ST changes in inferior leads. Decreased voltage in leads I, III, aVR, aVL, aVF.

Chest X-ray

Findings: Bibasilar airspace disease that may represent alveolar edema. Cardiomegaly noted. Prominent interstitial markings were noted. Small bilateral pleural effusions

Radiologist Impression: Radiographic changes of congestive failure with bilateral pleural effusions greater on the left compared to the right

• Differential Diagnosis
• Acute on chronic COPD exacerbation
• Acute on chronic renal failure
• Bacterial pneumonia
• Congestive heart failure
• Pericardial effusion
• Hypothyroidism
• Influenza pneumonia
• Pulmonary edema
• Pulmonary embolism
• Confirmatory Evaluation

On the second day of the admission patient’s shortness of breath was not improved, and she was more confused with difficulty arousing on conversation and examination. To further elucidate the etiology of her shortness of breath and confusion, the patient's husband provided further history. He revealed that she is poorly compliant with taking her medications. He reports that she “doesn’t see the need to take so many pills.”

Testing was performed to include TSH, free T4, BNP, repeated arterial blood gas, CT scan of the chest, and echocardiogram. TSH and free T4 evaluate hypothyroidism. BNP evaluates fluid load status and possible congestive heart failure. CT scan of the chest will look for anatomical abnormalities. An echocardiogram is used to evaluate left ventricular ejection fraction, right ventricular function, pulmonary artery pressure, valvular function, pericardial effusion, and any hypokinetic area.

• TSH: 112.717 (H)
• Free T4: 0.56 (L)
• TSH and Free T4 values indicate severe primary hypothyroidism. 

BNP can be falsely low in obese patients due to the increased surface area. Additionally, adipose tissue has BNP receptors which augment the true BNP value. Also, African American patients with more excretion may have falsely low values secondary to greater excretion of BNP. This test is not that helpful in renal failure due to the chronic nature of fluid overload. This allows for desensitization of the cardiac tissues with a subsequent decrease in BNP release.

Repeat arterial blood gas on BiPAP ventilation shows pH 7.397, PCO2 35.3, PO2 72.4, HCO3 21.2, and oxygen saturation 90% on 2 L supplemental oxygen.

CT chest without contrast was primarily obtained to evaluate the left hemithorax, especially the retrocardiac area.

Radiologist Impression: Tiny bilateral pleural effusions. Pericardial effusion. Coronary artery calcification. Some left lung base atelectasis with minimal airspace disease.

Echocardiogram

The left ventricular systolic function is normal. The left ventricular cavity is borderline dilated.

The pericardial fluid is collected primarily posteriorly, laterally but not apically. There appeared to be a subtle, early hemodynamic effect of the pericardial fluid on the right-sided chambers by way of an early diastolic collapse of the RA/RV and delayed RV expansion until late diastole. A dedicated tamponade study was not performed. 

The estimated ejection fraction appears to be in the range of 66% to 70%. The left ventricular cavity is borderline dilated.

The aortic valve is abnormal in structure and exhibits sclerosis.

The mitral valve is abnormal in structure. Mild mitral annular calcification is present. There is bilateral thickening present. Trace mitral valve regurgitation is present.

• Myxedema coma or severe hypothyroidism
• Pericardial effusion secondary to myxedema coma
• COPD exacerbation
• Acute on chronic hypoxic respiratory failure
• Acute respiratory alkalosis
• Bilateral community-acquired pneumonia
• Small bilateral pleural effusions
• Acute mild rhabdomyolysis
• Acute chronic, stage IV, renal failure
• Elevated troponin I levels, likely secondary to Renal failure 
• Diabetes mellitus type 2, non-insulin-dependent
• Extreme obesity
• Hepatic dysfunction

The patient was extremely ill and rapidly decompensating with multisystem organ failure, including respiratory failure, altered mental status, acute on chronic renal failure, and cardiac dysfunction. The primary concerns for the stability of the patient revolved around respiratory failure coupled with altered mental status. In the intensive care unit (ICU), she rapidly began to fail BiPAP therapy. Subsequently, the patient was emergently intubated in the ICU.  A systemic review of therapies and hospital course is as follows:

Considering the primary diagnosis of myxedema coma, early supplementation with thyroid hormone is essential. Healthcare providers followed the American Thyroid Association recommendations, which recommend giving combined T3 and T4 supplementation; however, T4 alone may also be used. T3 therapy is given as a bolus of 5 to 20 micrograms intravenously and continued at 2.5 to 10 micrograms every 8 hours. An intravenous loading dose of 300 to 600 micrograms of T4 is followed by a daily intravenous dose of 50 to 100 micrograms. Repeated monitoring of TSH and T4 should be performed every 1 to 2 days to evaluate the effect and to titrate the dose of medication. The goal is to improve mental function. Until coexistent adrenal insufficiency is ruled out using a random serum cortisol measurement, 50 to 100 mg every 8 hours of hydrocortisone should be administered. In this case, clinicians used hydrocortisone 100 mg IV every 8 hours. Dexamethasone 2 to 4 mg every 12 hours is an alternative therapy.

The patient’s mental status rapidly worsened despite therapy. In the setting of her hypothyroidism history, this may be myxedema coma or due to the involvement of another organ system. The thyroid supplementation medications and hydrocortisone were continued. A CT head without contrast was normal.

Respiratory

For worsening metabolic acidosis and airway protection, the patient was emergently intubated. Her airway was deemed high risk due to having a large tongue, short neck, and extreme obesity. As the patient’s heart was preload dependent secondary to pericardial effusion, a 1-liter normal saline bolus was started. Norepinephrine was started at a low dose for vasopressor support, and ketamine with low dose Propofol was used for sedation. Ketamine is a sympathomimetic medication and usually does not cause hypotension as all other sedatives do. The patient was ventilated with AC mode of ventilation, tidal volume of 6 ml/kg ideal body weight, flow 70, initial fio2 100 %, rate 26 per minute (to compensate for metabolic acidosis), PEEP of 8.

Cardiovascular

She was determined to be hemodynamically stable with a pericardial effusion. This patient’s cardiac dysfunction was diastolic in nature, as suggested by an ejection fraction of 66% to 70%. The finding of posterior pericardial effusion further supported this conclusion. The posterior nature of this effusion was not amenable to pericardiocentesis. As such, this patient was preload dependent and showed signs of hypotension. The need for crystalloid fluid resuscitation was balanced against the impact increased intravascular volume would have on congestive heart failure and fluid overload status. Thyroid hormone replacement as above should improve hypotension. However, vasopressor agents may be used to maintain vital organ perfusion targeting a mean arterial pressure of greater than 65 mm Hg as needed. BP improved after fluid bolus, and eventually, the norepinephrine was stopped. Serial echocardiograms were obtained to ensure that the patient did not develop tamponade physiology. Total CK was elevated, which was likely due to Hypothyroidism compounded with chronic renal disease.

Infectious Disease

Blood cultures, urine analysis, and sputum cultures were obtained. The patient's white blood cell count was normal. This is likely secondary to her being immunocompromised due to hypothyroidism and diabetes. In part, the pulmonary findings of diffuse edema and bilateral pleural effusions can be explained by cardiac dysfunction. Thoracentesis of pleural fluid was attempted, and the fluid was analyzed for cytology and gram staining to rule out infectious or malignant causes as both a therapeutic and diagnostic measure. Until these results return, broad-spectrum antibiotics are indicated and may be discontinued once the infection is ruled out completely.

Gastrointestinal

Nasogastric tube feedings were started on the patient after intubation. She tolerated feedings well. AST and ALT were mildly elevated, which was thought to be due to hypothyroidism, and as the TSH and free T4 improved, her AST and ALT improved. Eventually, these values became normal once her TSH level was close to 50.

Her baseline creatinine was found to be close to 1.08 in prior medical records. She presented with a creatinine of 1.8 in the emergency department. Since hypothyroidism causes fluid retention in part because thyroid hormone encourages excretion of free water and partly due to decreased lymphatic function in returning fluid to vascular circulation.  Aggressive diuresis was attempted. As a result, her creatinine increased initially but improved on repeated evaluation, and the patient had a new baseline creatinine of 1.6. Overall she had a net change in the fluid status of 10 liters negative by her ten days of admission in the ICU.

Mildly anemic otherwise, WBC and platelet counts were normal. Electrolyte balance should be monitored closely, paying attention to sodium, potassium, chloride, and calcium specifically as these are worsened in both renal failure and myxedema. 

Daily sedation vacations were enacted, and the patient's mental status improved and was much better when TSH was around 20. The bilateral pleural effusions improved with aggressive diuresis. Breathing trials were initiated when the patient's fio2 requirements decreased to 60% and a PEEP of 8. She was eventually extubated onto BiPAP and then high-flow nasal cannula while off of BiPAP. Pericardial fluid remained stable, and no cardiac tamponade pathology developed. As a result, it was determined that a pericardial window was unnecessary. Furthermore, she was not a candidate for pericardiocentesis as the pericardial effusion was located posterior to the heart. Her renal failure improved with improved cardiac function, diuretics, and thyroid hormone replacement.

After extubation patient had speech and swallow evaluations and was able to resume an oral diet. The patient was eventually transferred out of the ICU to the general medical floor and eventually to a rehabilitation unit.

Despite the name myxedema coma, most patients will not present in a coma status. This illness is at its core a severe hypothyroidism crisis that leads to systemic multiorgan failure. Thyroid hormones T3, and to a lesser extent, T4 act directly on a cellular level to upregulate all metabolic processes in the body. Therefore, deficiency of this hormone is characterized by systemic decreased metabolism and decreased glucose utilization along with increased production and storage of osmotically active mucopolysaccharide protein complexes into peripheral tissues resulting in diffuse edema and swelling of tissue. [1]

Myxedema coma is an illness that occurs primarily in females at a rate of 4:1 compared to men. It typically impacts the elderly at the age of greater than 60 years old, and approximately 90% of cases occur during the winter months. Myxedema coma is the product of longstanding unidentified or undertreated hypothyroidism of any etiology. Thyroid hormone is necessary throughout the body and acts as a regulatory hormone that affects many organ systems. [2] In cardiac tissues, myxedema coma manifests as decreased contractility with subsequent reduction in stroke volume and overall cardiac output.  Bradycardia and hypotension are typically present also. Pericardial effusions occur due to the accumulation of mucopolysaccharides in the pericardial sac, which leads to worsened cardiac function and congestive heart failure from diastolic dysfunction. Capillary permeability is also increased throughout the body leading to worsened edema. Electrocardiogram findings may include bradycardia and low-voltage, non-specific ST waveform changes with possible inverted T waves.

Neurologic tissues are impacted in myxedema coma leading to the pathognomonic altered mental status resulting from hypoxia and decreased cerebral blood flow secondary to cardiac dysfunction as above. Additionally, hypothyroidism leads to decreased glucose uptake and utilization in neurological tissue, thus worsening cognitive function.

The pulmonary system typically manifests this disease process through hypoventilation secondary to the central nervous system (CNS) depression of the respiratory drive with blunting of the response to hypoxia and hypercapnia. Additionally, metabolic dysfunction in the muscles of respiration leads to respiratory fatigue and failure, macroglossia from mucopolysaccharide driven edema of the tongue leads to mechanical obstruction of the airway, and obesity hypoventilation syndrome with the decreased respiratory drive as most hypothyroid patients suffer from obesity.

Renal manifestations include decreased glomerular filtration rate from the reduced cardiac output and increased systemic vascular resistance coupled with acute rhabdomyolysis lead to acute kidney injury. In the case of our patient above who has a pre-existing renal disease status post-nephrectomy, this is further worsened.  The net effect is worsened fluid overload status compounding the cardiac dysfunction and edema. [3]

The gastrointestinal tract is marked by mucopolysaccharide-driven edema as well leading to malabsorption of nutrients, gastric ileus, and decreased peristalsis. Ascites is common because of increased capillary permeability in the intestines coupled with coexistent congestive heart failure and congestive hepatic failure. Coagulopathies are common to occur as a result of this hepatic dysfunction.

Evaluation: The diagnosis of myxedema coma, as with all other diseases, is heavily reliant on the history and physical exam. A past medical history including hypothyroidism is highly significant whenever decreased mental status or coma is identified. In the absence of identified hypothyroidism, myxedema coma is a diagnosis of exclusion when all other sources of coma have been ruled out. If myxedema coma is suspected, evaluation of thyroid-stimulating hormone (TSH), free thyroxine (T4), and serum cortisol is warranted. T4 will be extremely low. TSH is variable depending on the etiology of hypothyroidism, with a high TSH indicating primary hypothyroidism and a low or normal TSH indicating secondary etiologies. Cortisol may be low indicating adrenal insufficiency because of hypothyroidism.  [4]

Prognosis: Myxedema coma is a medical emergency. With proper and rapid diagnosis and initiation of therapy, the mortality rate is still as high as 25% to 50%. The most common cause of death is due to respiratory failure. The factors which suggest a poorer prognosis include increased age, persistent hypothermia, bradycardia, low score Glasgow Coma Scale, or multi-organ impairment indicated by high APACHE (Acute Physiology and Chronic Health Evaluation) II score. For these reasons, placement in an intensive care unit with a low threshold for intubation and mechanical ventilation can improve mortality outcomes. [3] [5]

• Pearls of Wisdom
• Not every case of shortness of breath is COPD or congestive heart failure (CHF). While less likely, a history of hypothyroidism should raise suspicion of myxedema coma in a patient with any cognitive changes.
• Myxedema is the great imitator illness that impacts all organ systems. It can easily be mistaken for congestive heart failure, COPD exacerbation, pneumonia, renal injury or failure, or neurological insult.
• Initial steps in therapy include aggressive airway management, thyroid hormone replacement, glucocorticoid therapy, and supportive measures.
• These patients should be monitored in an intensive care environment with continuous telemetry. [6]
• Enhancing Healthcare Team Outcomes

This case demonstrates how all interprofessional healthcare team members need to be involved in arriving at a correct diagnosis, particularly in more challenging cases such as this one. Clinicians, specialists, nurses, pharmacists, laboratory technicians all bear responsibility for carrying out the duties pertaining to their particular discipline and sharing any findings with all team members. An incorrect diagnosis will almost inevitably lead to incorrect treatment, so coordinated activity, open communication, and empowerment to voice concerns are all part of the dynamic that needs to drive such cases so patients will attain the best possible outcomes.

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Case Study of 60 year old female presenting with Shortness of Breath Contributed by Sandeep Sharma, MD

Disclosure: Deepa Rawat declares no relevant financial relationships with ineligible companies.

Disclosure: Sandeep Sharma declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Rawat D, Sharma S. Case Study: 60-Year-Old Female Presenting With Shortness of Breath. [Updated 2023 Feb 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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