Reviews

Certain clinical features of posttraumatic stress disorder (PTSD) appear in other psychiatric diagnoses and therefore can confound accurate diagnosis and treatment. PTSD is frequently comorbid with other classes of psychiatric disorders, including mood, personality, substance use, and psychotic disorders, which can further complicate diagnostic clarity. Comorbidity in PTSD is important to recognize because it has been associated with worse treatment outcomes.¹

In DSM-5, the updated criteria for PTSD included Criterion D: “Negative alterations in cognitions and mood associated with the traumatic event(s) ….”² In addition to inability to remember an important aspect of the traumatic event, this criterion may be met by developing persistent and exaggerated negative beliefs or expectations about oneself, blaming oneself or others for the event, and developing a persistent negative emotional state and decreased interest.² These characteristics overlap with DSM-5 criteria for major depressive disorder (MDD), including low self-worth, guilt, depression, and anhedonia. It is easy to imagine how one could diagnose MDD based on these features if a full history has not been obtained. Similarly, many of the elements in Criterion D overlap with the criteria for anxiety disorders, including irritable behavior, problems with concentration, and sleep disturbance. Re-experiencing symptoms can exist on a continuum with primary psychotic symptoms, and comorbid substance use disorders can add additional diagnostic complexity.

We created the mnemonic FIGHT to help remember the updated DSM-5 criteria for PTSD when considering the differential diagnosis.

Flight. Avoidant symptoms, including efforts to avoid distressing memories, thoughts, or feelings about the traumatic event, as well as avoidance of external reminders.

Intrusive symptoms, such as distressing dreams, intrusive memories, and physiological distress when exposed to cues.

Gloomy cognitions. Negative cognitions and mood associated with the traumatic event.

Hypervigilance. Alterations in arousal, such as irritability, angry outbursts, reckless behavior, and exaggerated startle response.

Trauma. Exposure to actual or threatened death, serious injury, or sexual violence.

A diagnosis of PTSD requires ≥1 month of symptoms that cause significant distress or impairment and are not attributable to the physiological effects of a substance or medical condition. Specifiers in DSM-5 include with depersonalization or derealization, as well as delayed expression.²

Vigilance in the assessment and treatment of PTSD will aid the clinician and patient in producing better care outcomes.

Certain clinical features of posttraumatic stress disorder (PTSD) appear in other psychiatric diagnoses and therefore can confound accurate diagnosis and treatment. PTSD is frequently comorbid with other classes of psychiatric disorders, including mood, personality, substance use, and psychotic disorders, which can further complicate diagnostic clarity. Comorbidity in PTSD is important to recognize because it has been associated with worse treatment outcomes.¹

In DSM-5, the updated criteria for PTSD included Criterion D: “Negative alterations in cognitions and mood associated with the traumatic event(s) ….”² In addition to inability to remember an important aspect of the traumatic event, this criterion may be met by developing persistent and exaggerated negative beliefs or expectations about oneself, blaming oneself or others for the event, and developing a persistent negative emotional state and decreased interest.² These characteristics overlap with DSM-5 criteria for major depressive disorder (MDD), including low self-worth, guilt, depression, and anhedonia. It is easy to imagine how one could diagnose MDD based on these features if a full history has not been obtained. Similarly, many of the elements in Criterion D overlap with the criteria for anxiety disorders, including irritable behavior, problems with concentration, and sleep disturbance. Re-experiencing symptoms can exist on a continuum with primary psychotic symptoms, and comorbid substance use disorders can add additional diagnostic complexity.

We created the mnemonic FIGHT to help remember the updated DSM-5 criteria for PTSD when considering the differential diagnosis.

Flight. Avoidant symptoms, including efforts to avoid distressing memories, thoughts, or feelings about the traumatic event, as well as avoidance of external reminders.

Intrusive symptoms, such as distressing dreams, intrusive memories, and physiological distress when exposed to cues.

Gloomy cognitions. Negative cognitions and mood associated with the traumatic event.

Hypervigilance. Alterations in arousal, such as irritability, angry outbursts, reckless behavior, and exaggerated startle response.

Trauma. Exposure to actual or threatened death, serious injury, or sexual violence.

A diagnosis of PTSD requires ≥1 month of symptoms that cause significant distress or impairment and are not attributable to the physiological effects of a substance or medical condition. Specifiers in DSM-5 include with depersonalization or derealization, as well as delayed expression.²

Vigilance in the assessment and treatment of PTSD will aid the clinician and patient in producing better care outcomes.

Certain clinical features of posttraumatic stress disorder (PTSD) appear in other psychiatric diagnoses and therefore can confound accurate diagnosis and treatment. PTSD is frequently comorbid with other classes of psychiatric disorders, including mood, personality, substance use, and psychotic disorders, which can further complicate diagnostic clarity. Comorbidity in PTSD is important to recognize because it has been associated with worse treatment outcomes.¹

In DSM-5, the updated criteria for PTSD included Criterion D: “Negative alterations in cognitions and mood associated with the traumatic event(s) ….”² In addition to inability to remember an important aspect of the traumatic event, this criterion may be met by developing persistent and exaggerated negative beliefs or expectations about oneself, blaming oneself or others for the event, and developing a persistent negative emotional state and decreased interest.² These characteristics overlap with DSM-5 criteria for major depressive disorder (MDD), including low self-worth, guilt, depression, and anhedonia. It is easy to imagine how one could diagnose MDD based on these features if a full history has not been obtained. Similarly, many of the elements in Criterion D overlap with the criteria for anxiety disorders, including irritable behavior, problems with concentration, and sleep disturbance. Re-experiencing symptoms can exist on a continuum with primary psychotic symptoms, and comorbid substance use disorders can add additional diagnostic complexity.

We created the mnemonic FIGHT to help remember the updated DSM-5 criteria for PTSD when considering the differential diagnosis.

Flight. Avoidant symptoms, including efforts to avoid distressing memories, thoughts, or feelings about the traumatic event, as well as avoidance of external reminders.

Intrusive symptoms, such as distressing dreams, intrusive memories, and physiological distress when exposed to cues.

Gloomy cognitions. Negative cognitions and mood associated with the traumatic event.

Hypervigilance. Alterations in arousal, such as irritability, angry outbursts, reckless behavior, and exaggerated startle response.

Trauma. Exposure to actual or threatened death, serious injury, or sexual violence.

A diagnosis of PTSD requires ≥1 month of symptoms that cause significant distress or impairment and are not attributable to the physiological effects of a substance or medical condition. Specifiers in DSM-5 include with depersonalization or derealization, as well as delayed expression.²

Vigilance in the assessment and treatment of PTSD will aid the clinician and patient in producing better care outcomes.

As psychiatrists, we all come across patients who press our buttons and engender negative feelings, such as anger, frustration, and inadequacy.¹ These patients have been referred to as “hateful” or “difficult” because they disrupt the treatment alliance.^1,2 We are quick to point our fingers at such patients for making our jobs harder, being noncompliant, resisting the therapeutic alliance, and in general, being “problem patients.”³ However, the physician–patient relationship is a 2-way street. Although our patients knowingly or unknowingly play a role in this dynamic, we could be overlooking our role in adversely affecting this relationship. The following factors influence the physician–patient bond.^1,2

Countertransference. We may have negative feelings toward a patient based on our personalities and/or if the patient reminds us of someone we may not like, which could lead us to overprescribe or under­prescribe medications, conduct unnecessary medical workups, distance ourselves from the patient, etc. Accepting our disdain for certain patients and understanding why we have these emotions will allow us to better understand them, ensure that we are not impeding the delivery of appropriate clinical care, and improve rapport.

Listening. It may seem obvious that not listening to our patients negatively impacts rapport. However, in today’s technological world, we may not be really listening to our patients even when we think we are. Answering a text message or reading the patient’s electronic medical record while they are talking to us may increase productivity, but doing so also can interfere with our ability to form a therapeutic alliance. Although we may hear what our patients are saying, such distractions can create a hurdle in listening to what they are telling us.

Empathy often is confused for sympathy. Sympathy entails expressing concern and compassion for one’s distress, whereas empathy includes recognizing and sharing the patient’s emotions. Identifying with and understanding our patients’ situations, drives, and feelings allows us to understand what they are experiencing, see why they are reacting in a negative manner, and protect them from unnecessary emotional distress. Empathy can lead us to know what needs to be said and what should be said. It also can demystify a patient’s suffering. Not providing empathy or substituting sympathy can disrupt the therapeutic alliance.

Projective identification. Patients can project intolerable and negative feelings onto us and coerce us into identifying with what has been projected, allowing them to indirectly take control of our emotions. Our subsequent reactions can unsettle the physician–patient relationship. We need to be attuned to this process and recognize what the patient is provoking within us. Once we understand the process, we can realize that this is how they deal with others under similarly stressful conditions, and then react in a more supportive and healthy manner, rather than reviling our patients and negatively impacting the therapeutic relationship.

As psychiatrists, we all come across patients who press our buttons and engender negative feelings, such as anger, frustration, and inadequacy.¹ These patients have been referred to as “hateful” or “difficult” because they disrupt the treatment alliance.^1,2 We are quick to point our fingers at such patients for making our jobs harder, being noncompliant, resisting the therapeutic alliance, and in general, being “problem patients.”³ However, the physician–patient relationship is a 2-way street. Although our patients knowingly or unknowingly play a role in this dynamic, we could be overlooking our role in adversely affecting this relationship. The following factors influence the physician–patient bond.^1,2

Countertransference. We may have negative feelings toward a patient based on our personalities and/or if the patient reminds us of someone we may not like, which could lead us to overprescribe or under­prescribe medications, conduct unnecessary medical workups, distance ourselves from the patient, etc. Accepting our disdain for certain patients and understanding why we have these emotions will allow us to better understand them, ensure that we are not impeding the delivery of appropriate clinical care, and improve rapport.

Listening. It may seem obvious that not listening to our patients negatively impacts rapport. However, in today’s technological world, we may not be really listening to our patients even when we think we are. Answering a text message or reading the patient’s electronic medical record while they are talking to us may increase productivity, but doing so also can interfere with our ability to form a therapeutic alliance. Although we may hear what our patients are saying, such distractions can create a hurdle in listening to what they are telling us.

Empathy often is confused for sympathy. Sympathy entails expressing concern and compassion for one’s distress, whereas empathy includes recognizing and sharing the patient’s emotions. Identifying with and understanding our patients’ situations, drives, and feelings allows us to understand what they are experiencing, see why they are reacting in a negative manner, and protect them from unnecessary emotional distress. Empathy can lead us to know what needs to be said and what should be said. It also can demystify a patient’s suffering. Not providing empathy or substituting sympathy can disrupt the therapeutic alliance.

Projective identification. Patients can project intolerable and negative feelings onto us and coerce us into identifying with what has been projected, allowing them to indirectly take control of our emotions. Our subsequent reactions can unsettle the physician–patient relationship. We need to be attuned to this process and recognize what the patient is provoking within us. Once we understand the process, we can realize that this is how they deal with others under similarly stressful conditions, and then react in a more supportive and healthy manner, rather than reviling our patients and negatively impacting the therapeutic relationship.

As psychiatrists, we all come across patients who press our buttons and engender negative feelings, such as anger, frustration, and inadequacy.¹ These patients have been referred to as “hateful” or “difficult” because they disrupt the treatment alliance.^1,2 We are quick to point our fingers at such patients for making our jobs harder, being noncompliant, resisting the therapeutic alliance, and in general, being “problem patients.”³ However, the physician–patient relationship is a 2-way street. Although our patients knowingly or unknowingly play a role in this dynamic, we could be overlooking our role in adversely affecting this relationship. The following factors influence the physician–patient bond.^1,2

Countertransference. We may have negative feelings toward a patient based on our personalities and/or if the patient reminds us of someone we may not like, which could lead us to overprescribe or under­prescribe medications, conduct unnecessary medical workups, distance ourselves from the patient, etc. Accepting our disdain for certain patients and understanding why we have these emotions will allow us to better understand them, ensure that we are not impeding the delivery of appropriate clinical care, and improve rapport.

Listening. It may seem obvious that not listening to our patients negatively impacts rapport. However, in today’s technological world, we may not be really listening to our patients even when we think we are. Answering a text message or reading the patient’s electronic medical record while they are talking to us may increase productivity, but doing so also can interfere with our ability to form a therapeutic alliance. Although we may hear what our patients are saying, such distractions can create a hurdle in listening to what they are telling us.

Empathy often is confused for sympathy. Sympathy entails expressing concern and compassion for one’s distress, whereas empathy includes recognizing and sharing the patient’s emotions. Identifying with and understanding our patients’ situations, drives, and feelings allows us to understand what they are experiencing, see why they are reacting in a negative manner, and protect them from unnecessary emotional distress. Empathy can lead us to know what needs to be said and what should be said. It also can demystify a patient’s suffering. Not providing empathy or substituting sympathy can disrupt the therapeutic alliance.

Projective identification. Patients can project intolerable and negative feelings onto us and coerce us into identifying with what has been projected, allowing them to indirectly take control of our emotions. Our subsequent reactions can unsettle the physician–patient relationship. We need to be attuned to this process and recognize what the patient is provoking within us. Once we understand the process, we can realize that this is how they deal with others under similarly stressful conditions, and then react in a more supportive and healthy manner, rather than reviling our patients and negatively impacting the therapeutic relationship.

In response to widely publicized reports highlighting the challenges of suboptimal quality of healthcare, improving patient safety has been a leading healthcare initiative for more than 10 years.^1-4 Numerous strategies to improve patient safety have been proposed,^5-9 but improvements have been limited, which raises questions about whether the right approaches are being employed.^10,11

Checklists have served as a foundation for the standardization and safety of aviation and nuclear power^12,13 and are advocated as simple and effective instruments for ensuring safe care.^7,14,15 Systematic reviews of observational studies suggest that checklists can reduce medical errors and adverse events,^15-19 but these reviews are at risk of bias due to the limitations of observational methods. Furthermore, discordant results of recent high-profile evaluations of the World Health Organization (WHO) Surgical Safety Checklist highlight the need for checklist evaluations using rigorous study designs.^20-22 Therefore, we sought to conduct a systematic review of RCTs (randomized controlled trials) to determine whether checklists, as a type of decision-support tool, are effective at improving patient safety outcomes in hospitalized patients.

The study protocol was registered with the PROSPERO Register of Systematic Reviews (registration number: CRD42016037441) and developed according to the Preferred Reporting Items in Systematic Reviews and Meta-analyses (PRISMA) statement.²³

Search Strategy

On December 8, 2016, we systematically searched Ovid MEDLINE, Ovid EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials. The search was performed using no language or publication date restrictions and included 2 groups of terms (key words with similar characteristics): ‘checklists’ and ‘patient outcomes assessment’. We restricted our search to patient outcomes because these are more patient-oriented than the proximal processes of care that may not translate into outcomes. The search was restricted to RCTs using the Cochrane Highly Sensitive Search Strategy for Identifying Randomized Trials from the Cochrane Collaborative.²⁴ The MEDLINE search strategy is depicted in Appendix I (Supplementary File 1). Reference lists of included articles were manually searched for additional publications. The search strategy was designed with the help of an information scientist (DL). EndNote X7 (Thomas Reuters, Philadelphia, PA, USA) was the reference software used for the management of citations.

Eligibility Criteria

We selected all studies reporting patient safety outcomes of a checklist intervention, using the following inclusion criteria: 1) acute care hospital inpatient population, 2) checklist intervention, 3) contain a control group (ie, no checklist), 4) report one or more patient safety outcome, as defined by the authors (eg, medical errors, adverse events, mortality), and 5) RCT design. We restricted our focus to inpatient populations given the heterogeneity of illness and patient care between acute and community settings. We defined a checklist as a tool that details the essential steps of a task, requiring the target provider to indicate whether an item was completed or not.^1,7 Tools that included only 1 item (eg, electronic prompts) or did not require acknowledgement of the items (eg, guidelines) were excluded. We defined patient safety outcomes as the authors’ definition of patient safety (eg, medical error, adverse event, provider compliance with safety regulations).

Study Selection

Two reviewers (JMB, GW) independently, and in duplicate, reviewed the titles and abstracts of the retrieved citations against the eligibility criteria. The same 2 reviewers subsequently reviewed the full text of relevant articles for inclusion. Eligibility disagreements were resolved by consensus. A Kappa statistic was calculated for reviewer agreement of full-text screening.²⁵ Reviewers were not blinded to author or journal names.²⁶

Data Extraction

The structured data extraction form was calibrated using the first 2 articles. The 2 reviewers (JMB, GW) independently, and in duplicate, extracted data from included studies on the study characteristics, setting, study population, sample size, intervention used, outcomes examined, analytic method, and study quality. The data extraction form is depicted in Appendix II (Supplementary File 2). Coding discrepancies were resolved by consensus.

Quality Assessment

The 2 reviewers (JMB, GW) extracted data on study quality independently and in duplicate using 2 approaches. First, reviewers assessed study quality using a component method derived from the Cochrane Collaboration criteria.²⁴ For each included study, the reviewers documented if the authors had adequately described inclusion/exclusion criteria, randomization, allocation concealment, blinding of participants/outcome assessors, attrition, cross over, baseline characteristics, and power calculation. Second, the reviewers calculated and reported the Jadad score for each included study, a validated assessment scale that assigns points (1 to 5) based on randomization, blinding, and attrition.²⁷

Analysis

Owing to the heterogeneity of the data and the small number of studies that satisfied the inclusion criteria, the data were analyzed using guidelines for the narrative synthesis of a systematic review.²⁸ Descriptive statistical findings from each included study were reported. The DerSimonian and Laird method for random-effects models was used to calculate a pooled estimate of 30-day all-cause mortality from the raw data available from a subset of studies (number of events, study population).²⁹ Stata SE version 13.1 (Stata Corp, LP, College Station, TX) was used to perform the statistical analyses.

The literature search identified 11,225 unique citations from which 83 abstracts were eligible for full-text review. We identified 9 full-text articles for inclusion in the review (Figure 1 [Supplementary File 3]). The main reasons for citation exclusion during the full-text review were that the study design was not an RCT (39%) or there was no checklist intervention (34%). Inter-rater agreement for full-text inclusion was fair (K=0.660, 95% confidence interval[CI],0.414-0.828).

Study Characteristics

Characteristics of the included studies are summarized in Tables 1 and 2. Six of the studies were conducted in at least 1teaching hospital.^30-35 The studies varied in target populations for both the checklist user and patients. The outcomes reported varied; 3 studies examined 30-day mortality,^21,30,36 4 studies examined hospital length of stay,^21,30,33,36 and 2 studies reported user compliance with the checklist.^21,31 Five of the studies reported patient outcomes,^{21,30,33,35,36} and 5 studies reported provider-level outcomes related to patient safety (eg, compliance with checklist items such as communication of medications, isolation precautions, etc.).^31-34,37

Description of Checklists

Supplementary File 4 (Table 3) provides a detailed breakdown of the checklists’ purpose and components. Six of the checklists were designed to directly reduce patient safety events,^{21,30,33,35-37} whereas 3 of the checklists were designed to indirectly reduce patient safety events by increasing compliance with processes of care.^31,32,34 Six checklists were constructed and pilot tested by the research team conducting the RCT^30-35 and the 3 remaining studies used modified versions of previously validated checklists.^21,36,37 The number of items included in the checklist ranged from 2 to 54.

Impact of the Checklist

Table 4 summarizes the adverse events, medical errors, resource utilization and/or compliance reported for each checklist. Chaudhary et al. reported significant decreases in Grade III (requiring intervention)³⁸ and IV (life-threatening)³⁸ postoperative complications (23% v. 33%, P = 0.04) and 30-day mortality (5.7% vs 10.0%, P = 0.04) for patients assigned to the Modified WHO Surgical Safety Checklist compared to controls.²¹ Conversely, Haugen et al. reported a nonsignificant reduction in 30-day mortality between the WHO Surgical Safety Checklist group and controls (1.0% vs 1.6%, P = 0.151).³⁶ Bassor et al. reported no significant difference in 30-day hospital readmission for decompensated heart failure for the heart failure discharge checklist group when compared to controls (6% vs. 4%, P = NS); however, an exploratory analysis that excluded patients who died during the follow-up period found a significant difference in 30-day readmission rates (2% vs. 20%, P = 0.02).³⁰ Gentili et al. reported a higher proportion of patients with pain control in the checklist group compared to the controls (67.6% vs. 54.8%), as well as fewer incidents of analgesic therapy–related uncontrolled adverse events (25.9% vs. 49.9%); however, the statistical significance of these differences were not reported.³⁵ The Writing Group for CHECKLIST-ICU reported no significant difference for in-hospital mortality between the checklist and control groups (adjusted odds ratio [AOR] 1.02, 95% CI, 0.82-1.26, P = 0.88), nor for the secondary clinical outcomes examined (Table 4).³³ However, there was a significant difference between the checklist group and control group for 3 of the 7 outcomes related to processes of patient care, including a reduction in the use of both urinary catheters (adjusted rate ratio [ARR] 0.86, 95% CI, 0.80-0.93, P < 0.001) and central venous catheters (ARR 0.90, 95% CI 0.83-0.98, P = 0.02). Masson et al. reported that when using the FASTHUG-MAIDENS checklist, more drug-related problems were identified by pharmacy residents (in relation to the number identified by the ICU pharmacist) both per patient encounter (P = 0.008) and overall (P < 0.001).³⁷ Ong et al. reported higher rates of compliance with isolation precautions for infectious diseases in the checklist group (71% vs. 38%, P < 0.01); however, compliance with the checklist was low (40%) and qualitative analyses found participants were dissatisfied with the checklist.³¹ Salzwedel et al. reported the number of items handed over by anesthesia residents postoperatively to be higher in the checklist group than the control group (48.7% vs. 32.4%, P < 0.001).³² In a more recent study, Salzwedel et al. reported that proportion of items deemed by the attending anesthesiologist as “must be handed over” were more often actually handed over by the anesthesia residents assigned to the checklist group when compared to controls (87.1% vs. 75.0%, P = 0.005).³⁴

30-day Mortality

A random-effects model pooling data from the 3 studies that reported data for 30-day all cause mortality suggested a significant reduction with use of a checklist (OR 0.60, 95% CI, 0.41-0.89; P = 0.01, I² = 0.0%, P = 0.573).

Study Quality

Supplementary File 5 (Table 5) summarizes the quality assessment of the 9 studies. The clarity of description for each intervention varied. All studies reported inclusion/exclusion criteria and randomization procedures. Three studies indicated that outcome assessors were blinded to intervention allocation;^32,34,36 while this was unclear in 2 studies.^21,30 Three studies reported baseline characteristics.^21,30,36 Two studies reported power calculations;^33,37 however, one study had a sample size that was less than that required to achieve the target power.³⁷ The Jadad scores ranged from 1to 5.

This systematic review identified 9 RCTs that examined the impact of a checklist on patient safety outcomes in hospitalized patients. The studies employed checklists with different purposes and elements and measured different patient safety outcomes. The methodological quality of the included studies was moderate. In aggregate, the results suggest that checklists may be effective at improving patient safety outcomes, but the small number of moderate quality studies and the heterogeneity of interventions and outcome measures suggests that there is an urgent need for further evaluation.

The most important observation from our systematic review is the paucity of high quality evidence evaluating checklists’ impact on patient safety outcomes in acute inpatient care. The implementation of checklists is increasingly common as they are relatively low cost to develop and implement, and intuitively make sense. This is particularly true in an era of increasing efforts to standardize care as a means for improving quality and minimizing cost (ie, previous systematic reviews cite 38 unique studies).³⁹ However, implementation of an inadequately tested checklist risks unintended consequences (eg, inefficient resource utilization).¹⁸ The small number of RCTs identified might be owing to quality improvement efforts traditionally focusing on ‘real life’ applicability over rigorous research methodology.⁴⁰ The translation of evidence into clinical practice is known to be slow;⁴¹ however, these more rigorous methodologies reduce the risk of biases and generate high-quality evidence, which help to fulfill the necessity to identify best practices while avoiding these unintended consequences.

The studies varied both in the approaches used to develop checklists and in the number of items included (ranging from 2 to 54). What is the optimal method for developing a checklist and how does this impact their effectiveness?⁴² The answers to these questions are not known. However, this review highlights some important issues to consider when developing a checklist. As the number of items or complexity of a task increases, our ability to efficiently perform the task without aid decreases.^43-45 As such, a well-designed checklist should detail explicit instructions on the what, where, when, and how of a given task in a fashion that ensures a consistent accuracy for completing the work.⁵ It is recommended that construction of a checklist follow the principles of human factors engineering: engage stakeholders and human factors experts in the design; are developed based on user needs and realities; list items in order of importance; are concise and subgroup sections of checklists by task or chronological order; ensure usability and evaluate potential negative consequences (eg time to complete); are pilot tested and validated before implementation; are updated as needed based the on generation of new findings or changes in operational procedures.⁴⁶ These general principles of human factors engineering⁴⁶ provide a practical approach for the development and evaluation of a checklist. In addition, standardization of operational definitions (ie, process, outcome, compliance) is important for study replication and robust meta-analyses.

Checklists used in aviation are perhaps best known¹² and the evidence of their effectiveness is derived from the attribution of aviation errors to incomplete checklists.¹² Although more recently implemented in medicine, checklists have the potential to guide the successful completion of complex tasks in healthcare.⁷ Systematic reviews of observational studies have been conducted for specific checklists (eg, WHO Surgical Safety Checklist) and for select patient populations (eg, surgical patients), and the number of included studies ranges from 7-27 (n = 38 unique studies).^15,16,18,19 For example, Gillespie et al. in a systematic review and meta-analysis reported the implementation of Surgical Safety Checklists to be associated with a reduction in postoperative complications (relative risk [RR] 0.63, 95% CI, 0.58-0.72, P = < 0.001), but not mortality (RR 1.03, 95% CI, 0.73-1.4, P = 0.857).¹⁹ Similarly, Treadwell et al. reported in a systematic review of Surgical Safety Checklists that while data are promising, more evaluation of their impact on clinical outcomes is needed.¹⁸ These recommendations are nicely illustrated by Urbach et al.’s²⁰ and O’Leary et al.’s⁴⁷ evaluations of the mandatory adoption of Surgical Safety Checklists across all hospitals in Ontario, Canada, which respectively demonstrated no significant reductions in 30-day perioperatively conplications for both adult (OR 0.97, 95% CI, 0.90-1.03, P = 0.29) and pediatric (AOR 1.01, 95% CI, 0.90-1.14, P = 0.9) patients. These data not only highlight the need for further evaluation of checklists but are also a reminder that checklists and their associated implementation strategies are complex interventions for which there may be important differences between the efficacy reported in clinical trials and the effectiveness reported in implementation studies.⁴⁸ This all suggests that if checklists are to be effective in improving patient safety, process evaluations of implementation⁴⁹ and realist reviews of published studies⁵⁰ may be important to determine optimal approaches for implementation. We believe that, based on the limited currently available evidence, there is urgency for further robust evaluations of checklists before their widespread implementation. If effective, they should be widely implemented. If ineffective, they should be abandoned to minimize unintended consequences and inefficient use of resources.

There are 4 primary limitations to this review that should be considered when interpreting the findings. First, the RCT design is not the study design employed by most quality improvement initiatives.⁴⁰ While some quality improvement experts may argue that an RCT design is insufficiently flexible for applied settings, it does minimize the risk of biased assessments of intervention effectiveness. Second, our search strategy included an RCT filter. The filter helped restrict the number of citations to be reviewed (n = 11,225) but could have resulted in improperly indexed studies being excluded. To guard against this risk, we used the validated Cochrane Highly Sensitive Search Strategy for Identifying Randomized Trials,²⁴ reviewed reference lists of citations included in the review, and solicited suggestions for missing studies from quality improvement experts. Third, our review was restricted to hospitalized patients. Although the studies evaluated commonly reported safety outcomes across patients with diverse clinical conditions, care settings, and providers that broadly reflect hospital-based care, evaluations of checklists in additional patient and provider groups are needed (eg, hospitalists). Furthermore, the effectiveness of checklists for improving patient safety outcomes in outpatients is important; however, the organizational and patient characteristics of these 2 settings (hospitalized vs outpatient) are sufficiently different to warrant separate systematic reviews. Finally, owing to the heterogeneity of the checklists used and outcomes measured, we were unable to perform a robust meta-analysis. Heterogeneity, combined with the small number of studies identified in our search, prevented us from applying statistical methods to assess for publication bias. This limitation of our systematic review highlights an important gap in the literature and emphasizes the importance of additional primary research to evaluate checklists.

In summary, we identified few RCTs that examined checklists designed to improve patient safety outcomes. The small number of existing studies suggests that checklists may improve patient safety outcomes; however, these observations were not reported for all outcomes examined and the studies were heterogeneous and of limited methodological quality. There is an urgent need for high-quality evaluations of the effectiveness of patient safety checklists in inpatient healthcare settings to substantiate their perceived benefits.

Acknowledgments

We would like to thank Diane Lorenzetti for her help with the development of the search strategy.

Disclosure: The authors have no known conflicts of interest to declare.

Jamie Boyd was supported by a W21C – Alberta Innovates-Health Solutions (AIHS) Collaborative Research and Innovation Opportunities (CRIO) Health Services Research graduate studentship. Guosong Wu was supported by a Western Regional Training Centre (WRTC) for Health Services Research graduate studentship. Dr. Stelfox was supported by a Population Health Investigator Award from Alberta Innovates Health Solutions.

Authors’ Contributions

HTS was responsible for the study’s conception. All 3 authors contributed to the study’s design and interpretation. JB and GW were responsible for searching the literature, reviewing abstracts, selecting full-text articles and critically appraising them. All 3 authors performed the analyses. JB drafted the manuscript and all 3 authors assisted in the successive revisions of the final manuscript. All authors have read and approved the final manuscript.

In response to widely publicized reports highlighting the challenges of suboptimal quality of healthcare, improving patient safety has been a leading healthcare initiative for more than 10 years.^1-4 Numerous strategies to improve patient safety have been proposed,^5-9 but improvements have been limited, which raises questions about whether the right approaches are being employed.^10,11

Checklists have served as a foundation for the standardization and safety of aviation and nuclear power^12,13 and are advocated as simple and effective instruments for ensuring safe care.^7,14,15 Systematic reviews of observational studies suggest that checklists can reduce medical errors and adverse events,^15-19 but these reviews are at risk of bias due to the limitations of observational methods. Furthermore, discordant results of recent high-profile evaluations of the World Health Organization (WHO) Surgical Safety Checklist highlight the need for checklist evaluations using rigorous study designs.^20-22 Therefore, we sought to conduct a systematic review of RCTs (randomized controlled trials) to determine whether checklists, as a type of decision-support tool, are effective at improving patient safety outcomes in hospitalized patients.

The study protocol was registered with the PROSPERO Register of Systematic Reviews (registration number: CRD42016037441) and developed according to the Preferred Reporting Items in Systematic Reviews and Meta-analyses (PRISMA) statement.²³

Search Strategy

On December 8, 2016, we systematically searched Ovid MEDLINE, Ovid EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials. The search was performed using no language or publication date restrictions and included 2 groups of terms (key words with similar characteristics): ‘checklists’ and ‘patient outcomes assessment’. We restricted our search to patient outcomes because these are more patient-oriented than the proximal processes of care that may not translate into outcomes. The search was restricted to RCTs using the Cochrane Highly Sensitive Search Strategy for Identifying Randomized Trials from the Cochrane Collaborative.²⁴ The MEDLINE search strategy is depicted in Appendix I (Supplementary File 1). Reference lists of included articles were manually searched for additional publications. The search strategy was designed with the help of an information scientist (DL). EndNote X7 (Thomas Reuters, Philadelphia, PA, USA) was the reference software used for the management of citations.

Eligibility Criteria

We selected all studies reporting patient safety outcomes of a checklist intervention, using the following inclusion criteria: 1) acute care hospital inpatient population, 2) checklist intervention, 3) contain a control group (ie, no checklist), 4) report one or more patient safety outcome, as defined by the authors (eg, medical errors, adverse events, mortality), and 5) RCT design. We restricted our focus to inpatient populations given the heterogeneity of illness and patient care between acute and community settings. We defined a checklist as a tool that details the essential steps of a task, requiring the target provider to indicate whether an item was completed or not.^1,7 Tools that included only 1 item (eg, electronic prompts) or did not require acknowledgement of the items (eg, guidelines) were excluded. We defined patient safety outcomes as the authors’ definition of patient safety (eg, medical error, adverse event, provider compliance with safety regulations).

Study Selection

Two reviewers (JMB, GW) independently, and in duplicate, reviewed the titles and abstracts of the retrieved citations against the eligibility criteria. The same 2 reviewers subsequently reviewed the full text of relevant articles for inclusion. Eligibility disagreements were resolved by consensus. A Kappa statistic was calculated for reviewer agreement of full-text screening.²⁵ Reviewers were not blinded to author or journal names.²⁶

Data Extraction

The structured data extraction form was calibrated using the first 2 articles. The 2 reviewers (JMB, GW) independently, and in duplicate, extracted data from included studies on the study characteristics, setting, study population, sample size, intervention used, outcomes examined, analytic method, and study quality. The data extraction form is depicted in Appendix II (Supplementary File 2). Coding discrepancies were resolved by consensus.

Quality Assessment

The 2 reviewers (JMB, GW) extracted data on study quality independently and in duplicate using 2 approaches. First, reviewers assessed study quality using a component method derived from the Cochrane Collaboration criteria.²⁴ For each included study, the reviewers documented if the authors had adequately described inclusion/exclusion criteria, randomization, allocation concealment, blinding of participants/outcome assessors, attrition, cross over, baseline characteristics, and power calculation. Second, the reviewers calculated and reported the Jadad score for each included study, a validated assessment scale that assigns points (1 to 5) based on randomization, blinding, and attrition.²⁷

Analysis

Owing to the heterogeneity of the data and the small number of studies that satisfied the inclusion criteria, the data were analyzed using guidelines for the narrative synthesis of a systematic review.²⁸ Descriptive statistical findings from each included study were reported. The DerSimonian and Laird method for random-effects models was used to calculate a pooled estimate of 30-day all-cause mortality from the raw data available from a subset of studies (number of events, study population).²⁹ Stata SE version 13.1 (Stata Corp, LP, College Station, TX) was used to perform the statistical analyses.

The literature search identified 11,225 unique citations from which 83 abstracts were eligible for full-text review. We identified 9 full-text articles for inclusion in the review (Figure 1 [Supplementary File 3]). The main reasons for citation exclusion during the full-text review were that the study design was not an RCT (39%) or there was no checklist intervention (34%). Inter-rater agreement for full-text inclusion was fair (K=0.660, 95% confidence interval[CI],0.414-0.828).

Study Characteristics

Characteristics of the included studies are summarized in Tables 1 and 2. Six of the studies were conducted in at least 1teaching hospital.^30-35 The studies varied in target populations for both the checklist user and patients. The outcomes reported varied; 3 studies examined 30-day mortality,^21,30,36 4 studies examined hospital length of stay,^21,30,33,36 and 2 studies reported user compliance with the checklist.^21,31 Five of the studies reported patient outcomes,^{21,30,33,35,36} and 5 studies reported provider-level outcomes related to patient safety (eg, compliance with checklist items such as communication of medications, isolation precautions, etc.).^31-34,37

Description of Checklists

Supplementary File 4 (Table 3) provides a detailed breakdown of the checklists’ purpose and components. Six of the checklists were designed to directly reduce patient safety events,^{21,30,33,35-37} whereas 3 of the checklists were designed to indirectly reduce patient safety events by increasing compliance with processes of care.^31,32,34 Six checklists were constructed and pilot tested by the research team conducting the RCT^30-35 and the 3 remaining studies used modified versions of previously validated checklists.^21,36,37 The number of items included in the checklist ranged from 2 to 54.

Impact of the Checklist

Table 4 summarizes the adverse events, medical errors, resource utilization and/or compliance reported for each checklist. Chaudhary et al. reported significant decreases in Grade III (requiring intervention)³⁸ and IV (life-threatening)³⁸ postoperative complications (23% v. 33%, P = 0.04) and 30-day mortality (5.7% vs 10.0%, P = 0.04) for patients assigned to the Modified WHO Surgical Safety Checklist compared to controls.²¹ Conversely, Haugen et al. reported a nonsignificant reduction in 30-day mortality between the WHO Surgical Safety Checklist group and controls (1.0% vs 1.6%, P = 0.151).³⁶ Bassor et al. reported no significant difference in 30-day hospital readmission for decompensated heart failure for the heart failure discharge checklist group when compared to controls (6% vs. 4%, P = NS); however, an exploratory analysis that excluded patients who died during the follow-up period found a significant difference in 30-day readmission rates (2% vs. 20%, P = 0.02).³⁰ Gentili et al. reported a higher proportion of patients with pain control in the checklist group compared to the controls (67.6% vs. 54.8%), as well as fewer incidents of analgesic therapy–related uncontrolled adverse events (25.9% vs. 49.9%); however, the statistical significance of these differences were not reported.³⁵ The Writing Group for CHECKLIST-ICU reported no significant difference for in-hospital mortality between the checklist and control groups (adjusted odds ratio [AOR] 1.02, 95% CI, 0.82-1.26, P = 0.88), nor for the secondary clinical outcomes examined (Table 4).³³ However, there was a significant difference between the checklist group and control group for 3 of the 7 outcomes related to processes of patient care, including a reduction in the use of both urinary catheters (adjusted rate ratio [ARR] 0.86, 95% CI, 0.80-0.93, P < 0.001) and central venous catheters (ARR 0.90, 95% CI 0.83-0.98, P = 0.02). Masson et al. reported that when using the FASTHUG-MAIDENS checklist, more drug-related problems were identified by pharmacy residents (in relation to the number identified by the ICU pharmacist) both per patient encounter (P = 0.008) and overall (P < 0.001).³⁷ Ong et al. reported higher rates of compliance with isolation precautions for infectious diseases in the checklist group (71% vs. 38%, P < 0.01); however, compliance with the checklist was low (40%) and qualitative analyses found participants were dissatisfied with the checklist.³¹ Salzwedel et al. reported the number of items handed over by anesthesia residents postoperatively to be higher in the checklist group than the control group (48.7% vs. 32.4%, P < 0.001).³² In a more recent study, Salzwedel et al. reported that proportion of items deemed by the attending anesthesiologist as “must be handed over” were more often actually handed over by the anesthesia residents assigned to the checklist group when compared to controls (87.1% vs. 75.0%, P = 0.005).³⁴

30-day Mortality

A random-effects model pooling data from the 3 studies that reported data for 30-day all cause mortality suggested a significant reduction with use of a checklist (OR 0.60, 95% CI, 0.41-0.89; P = 0.01, I² = 0.0%, P = 0.573).

Study Quality

Supplementary File 5 (Table 5) summarizes the quality assessment of the 9 studies. The clarity of description for each intervention varied. All studies reported inclusion/exclusion criteria and randomization procedures. Three studies indicated that outcome assessors were blinded to intervention allocation;^32,34,36 while this was unclear in 2 studies.^21,30 Three studies reported baseline characteristics.^21,30,36 Two studies reported power calculations;^33,37 however, one study had a sample size that was less than that required to achieve the target power.³⁷ The Jadad scores ranged from 1to 5.

This systematic review identified 9 RCTs that examined the impact of a checklist on patient safety outcomes in hospitalized patients. The studies employed checklists with different purposes and elements and measured different patient safety outcomes. The methodological quality of the included studies was moderate. In aggregate, the results suggest that checklists may be effective at improving patient safety outcomes, but the small number of moderate quality studies and the heterogeneity of interventions and outcome measures suggests that there is an urgent need for further evaluation.

The most important observation from our systematic review is the paucity of high quality evidence evaluating checklists’ impact on patient safety outcomes in acute inpatient care. The implementation of checklists is increasingly common as they are relatively low cost to develop and implement, and intuitively make sense. This is particularly true in an era of increasing efforts to standardize care as a means for improving quality and minimizing cost (ie, previous systematic reviews cite 38 unique studies).³⁹ However, implementation of an inadequately tested checklist risks unintended consequences (eg, inefficient resource utilization).¹⁸ The small number of RCTs identified might be owing to quality improvement efforts traditionally focusing on ‘real life’ applicability over rigorous research methodology.⁴⁰ The translation of evidence into clinical practice is known to be slow;⁴¹ however, these more rigorous methodologies reduce the risk of biases and generate high-quality evidence, which help to fulfill the necessity to identify best practices while avoiding these unintended consequences.

The studies varied both in the approaches used to develop checklists and in the number of items included (ranging from 2 to 54). What is the optimal method for developing a checklist and how does this impact their effectiveness?⁴² The answers to these questions are not known. However, this review highlights some important issues to consider when developing a checklist. As the number of items or complexity of a task increases, our ability to efficiently perform the task without aid decreases.^43-45 As such, a well-designed checklist should detail explicit instructions on the what, where, when, and how of a given task in a fashion that ensures a consistent accuracy for completing the work.⁵ It is recommended that construction of a checklist follow the principles of human factors engineering: engage stakeholders and human factors experts in the design; are developed based on user needs and realities; list items in order of importance; are concise and subgroup sections of checklists by task or chronological order; ensure usability and evaluate potential negative consequences (eg time to complete); are pilot tested and validated before implementation; are updated as needed based the on generation of new findings or changes in operational procedures.⁴⁶ These general principles of human factors engineering⁴⁶ provide a practical approach for the development and evaluation of a checklist. In addition, standardization of operational definitions (ie, process, outcome, compliance) is important for study replication and robust meta-analyses.

Checklists used in aviation are perhaps best known¹² and the evidence of their effectiveness is derived from the attribution of aviation errors to incomplete checklists.¹² Although more recently implemented in medicine, checklists have the potential to guide the successful completion of complex tasks in healthcare.⁷ Systematic reviews of observational studies have been conducted for specific checklists (eg, WHO Surgical Safety Checklist) and for select patient populations (eg, surgical patients), and the number of included studies ranges from 7-27 (n = 38 unique studies).^15,16,18,19 For example, Gillespie et al. in a systematic review and meta-analysis reported the implementation of Surgical Safety Checklists to be associated with a reduction in postoperative complications (relative risk [RR] 0.63, 95% CI, 0.58-0.72, P = < 0.001), but not mortality (RR 1.03, 95% CI, 0.73-1.4, P = 0.857).¹⁹ Similarly, Treadwell et al. reported in a systematic review of Surgical Safety Checklists that while data are promising, more evaluation of their impact on clinical outcomes is needed.¹⁸ These recommendations are nicely illustrated by Urbach et al.’s²⁰ and O’Leary et al.’s⁴⁷ evaluations of the mandatory adoption of Surgical Safety Checklists across all hospitals in Ontario, Canada, which respectively demonstrated no significant reductions in 30-day perioperatively conplications for both adult (OR 0.97, 95% CI, 0.90-1.03, P = 0.29) and pediatric (AOR 1.01, 95% CI, 0.90-1.14, P = 0.9) patients. These data not only highlight the need for further evaluation of checklists but are also a reminder that checklists and their associated implementation strategies are complex interventions for which there may be important differences between the efficacy reported in clinical trials and the effectiveness reported in implementation studies.⁴⁸ This all suggests that if checklists are to be effective in improving patient safety, process evaluations of implementation⁴⁹ and realist reviews of published studies⁵⁰ may be important to determine optimal approaches for implementation. We believe that, based on the limited currently available evidence, there is urgency for further robust evaluations of checklists before their widespread implementation. If effective, they should be widely implemented. If ineffective, they should be abandoned to minimize unintended consequences and inefficient use of resources.

There are 4 primary limitations to this review that should be considered when interpreting the findings. First, the RCT design is not the study design employed by most quality improvement initiatives.⁴⁰ While some quality improvement experts may argue that an RCT design is insufficiently flexible for applied settings, it does minimize the risk of biased assessments of intervention effectiveness. Second, our search strategy included an RCT filter. The filter helped restrict the number of citations to be reviewed (n = 11,225) but could have resulted in improperly indexed studies being excluded. To guard against this risk, we used the validated Cochrane Highly Sensitive Search Strategy for Identifying Randomized Trials,²⁴ reviewed reference lists of citations included in the review, and solicited suggestions for missing studies from quality improvement experts. Third, our review was restricted to hospitalized patients. Although the studies evaluated commonly reported safety outcomes across patients with diverse clinical conditions, care settings, and providers that broadly reflect hospital-based care, evaluations of checklists in additional patient and provider groups are needed (eg, hospitalists). Furthermore, the effectiveness of checklists for improving patient safety outcomes in outpatients is important; however, the organizational and patient characteristics of these 2 settings (hospitalized vs outpatient) are sufficiently different to warrant separate systematic reviews. Finally, owing to the heterogeneity of the checklists used and outcomes measured, we were unable to perform a robust meta-analysis. Heterogeneity, combined with the small number of studies identified in our search, prevented us from applying statistical methods to assess for publication bias. This limitation of our systematic review highlights an important gap in the literature and emphasizes the importance of additional primary research to evaluate checklists.

In summary, we identified few RCTs that examined checklists designed to improve patient safety outcomes. The small number of existing studies suggests that checklists may improve patient safety outcomes; however, these observations were not reported for all outcomes examined and the studies were heterogeneous and of limited methodological quality. There is an urgent need for high-quality evaluations of the effectiveness of patient safety checklists in inpatient healthcare settings to substantiate their perceived benefits.

Acknowledgments

We would like to thank Diane Lorenzetti for her help with the development of the search strategy.

Disclosure: The authors have no known conflicts of interest to declare.

Jamie Boyd was supported by a W21C – Alberta Innovates-Health Solutions (AIHS) Collaborative Research and Innovation Opportunities (CRIO) Health Services Research graduate studentship. Guosong Wu was supported by a Western Regional Training Centre (WRTC) for Health Services Research graduate studentship. Dr. Stelfox was supported by a Population Health Investigator Award from Alberta Innovates Health Solutions.

Authors’ Contributions

HTS was responsible for the study’s conception. All 3 authors contributed to the study’s design and interpretation. JB and GW were responsible for searching the literature, reviewing abstracts, selecting full-text articles and critically appraising them. All 3 authors performed the analyses. JB drafted the manuscript and all 3 authors assisted in the successive revisions of the final manuscript. All authors have read and approved the final manuscript.

In response to widely publicized reports highlighting the challenges of suboptimal quality of healthcare, improving patient safety has been a leading healthcare initiative for more than 10 years.^1-4 Numerous strategies to improve patient safety have been proposed,^5-9 but improvements have been limited, which raises questions about whether the right approaches are being employed.^10,11

Checklists have served as a foundation for the standardization and safety of aviation and nuclear power^12,13 and are advocated as simple and effective instruments for ensuring safe care.^7,14,15 Systematic reviews of observational studies suggest that checklists can reduce medical errors and adverse events,^15-19 but these reviews are at risk of bias due to the limitations of observational methods. Furthermore, discordant results of recent high-profile evaluations of the World Health Organization (WHO) Surgical Safety Checklist highlight the need for checklist evaluations using rigorous study designs.^20-22 Therefore, we sought to conduct a systematic review of RCTs (randomized controlled trials) to determine whether checklists, as a type of decision-support tool, are effective at improving patient safety outcomes in hospitalized patients.

The study protocol was registered with the PROSPERO Register of Systematic Reviews (registration number: CRD42016037441) and developed according to the Preferred Reporting Items in Systematic Reviews and Meta-analyses (PRISMA) statement.²³

Search Strategy

On December 8, 2016, we systematically searched Ovid MEDLINE, Ovid EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials. The search was performed using no language or publication date restrictions and included 2 groups of terms (key words with similar characteristics): ‘checklists’ and ‘patient outcomes assessment’. We restricted our search to patient outcomes because these are more patient-oriented than the proximal processes of care that may not translate into outcomes. The search was restricted to RCTs using the Cochrane Highly Sensitive Search Strategy for Identifying Randomized Trials from the Cochrane Collaborative.²⁴ The MEDLINE search strategy is depicted in Appendix I (Supplementary File 1). Reference lists of included articles were manually searched for additional publications. The search strategy was designed with the help of an information scientist (DL). EndNote X7 (Thomas Reuters, Philadelphia, PA, USA) was the reference software used for the management of citations.

Eligibility Criteria

We selected all studies reporting patient safety outcomes of a checklist intervention, using the following inclusion criteria: 1) acute care hospital inpatient population, 2) checklist intervention, 3) contain a control group (ie, no checklist), 4) report one or more patient safety outcome, as defined by the authors (eg, medical errors, adverse events, mortality), and 5) RCT design. We restricted our focus to inpatient populations given the heterogeneity of illness and patient care between acute and community settings. We defined a checklist as a tool that details the essential steps of a task, requiring the target provider to indicate whether an item was completed or not.^1,7 Tools that included only 1 item (eg, electronic prompts) or did not require acknowledgement of the items (eg, guidelines) were excluded. We defined patient safety outcomes as the authors’ definition of patient safety (eg, medical error, adverse event, provider compliance with safety regulations).

Study Selection

Two reviewers (JMB, GW) independently, and in duplicate, reviewed the titles and abstracts of the retrieved citations against the eligibility criteria. The same 2 reviewers subsequently reviewed the full text of relevant articles for inclusion. Eligibility disagreements were resolved by consensus. A Kappa statistic was calculated for reviewer agreement of full-text screening.²⁵ Reviewers were not blinded to author or journal names.²⁶

Data Extraction

The structured data extraction form was calibrated using the first 2 articles. The 2 reviewers (JMB, GW) independently, and in duplicate, extracted data from included studies on the study characteristics, setting, study population, sample size, intervention used, outcomes examined, analytic method, and study quality. The data extraction form is depicted in Appendix II (Supplementary File 2). Coding discrepancies were resolved by consensus.

Quality Assessment

The 2 reviewers (JMB, GW) extracted data on study quality independently and in duplicate using 2 approaches. First, reviewers assessed study quality using a component method derived from the Cochrane Collaboration criteria.²⁴ For each included study, the reviewers documented if the authors had adequately described inclusion/exclusion criteria, randomization, allocation concealment, blinding of participants/outcome assessors, attrition, cross over, baseline characteristics, and power calculation. Second, the reviewers calculated and reported the Jadad score for each included study, a validated assessment scale that assigns points (1 to 5) based on randomization, blinding, and attrition.²⁷

Analysis

Owing to the heterogeneity of the data and the small number of studies that satisfied the inclusion criteria, the data were analyzed using guidelines for the narrative synthesis of a systematic review.²⁸ Descriptive statistical findings from each included study were reported. The DerSimonian and Laird method for random-effects models was used to calculate a pooled estimate of 30-day all-cause mortality from the raw data available from a subset of studies (number of events, study population).²⁹ Stata SE version 13.1 (Stata Corp, LP, College Station, TX) was used to perform the statistical analyses.

The literature search identified 11,225 unique citations from which 83 abstracts were eligible for full-text review. We identified 9 full-text articles for inclusion in the review (Figure 1 [Supplementary File 3]). The main reasons for citation exclusion during the full-text review were that the study design was not an RCT (39%) or there was no checklist intervention (34%). Inter-rater agreement for full-text inclusion was fair (K=0.660, 95% confidence interval[CI],0.414-0.828).

Study Characteristics

Characteristics of the included studies are summarized in Tables 1 and 2. Six of the studies were conducted in at least 1teaching hospital.^30-35 The studies varied in target populations for both the checklist user and patients. The outcomes reported varied; 3 studies examined 30-day mortality,^21,30,36 4 studies examined hospital length of stay,^21,30,33,36 and 2 studies reported user compliance with the checklist.^21,31 Five of the studies reported patient outcomes,^{21,30,33,35,36} and 5 studies reported provider-level outcomes related to patient safety (eg, compliance with checklist items such as communication of medications, isolation precautions, etc.).^31-34,37

Description of Checklists

Supplementary File 4 (Table 3) provides a detailed breakdown of the checklists’ purpose and components. Six of the checklists were designed to directly reduce patient safety events,^{21,30,33,35-37} whereas 3 of the checklists were designed to indirectly reduce patient safety events by increasing compliance with processes of care.^31,32,34 Six checklists were constructed and pilot tested by the research team conducting the RCT^30-35 and the 3 remaining studies used modified versions of previously validated checklists.^21,36,37 The number of items included in the checklist ranged from 2 to 54.

Impact of the Checklist

Table 4 summarizes the adverse events, medical errors, resource utilization and/or compliance reported for each checklist. Chaudhary et al. reported significant decreases in Grade III (requiring intervention)³⁸ and IV (life-threatening)³⁸ postoperative complications (23% v. 33%, P = 0.04) and 30-day mortality (5.7% vs 10.0%, P = 0.04) for patients assigned to the Modified WHO Surgical Safety Checklist compared to controls.²¹ Conversely, Haugen et al. reported a nonsignificant reduction in 30-day mortality between the WHO Surgical Safety Checklist group and controls (1.0% vs 1.6%, P = 0.151).³⁶ Bassor et al. reported no significant difference in 30-day hospital readmission for decompensated heart failure for the heart failure discharge checklist group when compared to controls (6% vs. 4%, P = NS); however, an exploratory analysis that excluded patients who died during the follow-up period found a significant difference in 30-day readmission rates (2% vs. 20%, P = 0.02).³⁰ Gentili et al. reported a higher proportion of patients with pain control in the checklist group compared to the controls (67.6% vs. 54.8%), as well as fewer incidents of analgesic therapy–related uncontrolled adverse events (25.9% vs. 49.9%); however, the statistical significance of these differences were not reported.³⁵ The Writing Group for CHECKLIST-ICU reported no significant difference for in-hospital mortality between the checklist and control groups (adjusted odds ratio [AOR] 1.02, 95% CI, 0.82-1.26, P = 0.88), nor for the secondary clinical outcomes examined (Table 4).³³ However, there was a significant difference between the checklist group and control group for 3 of the 7 outcomes related to processes of patient care, including a reduction in the use of both urinary catheters (adjusted rate ratio [ARR] 0.86, 95% CI, 0.80-0.93, P < 0.001) and central venous catheters (ARR 0.90, 95% CI 0.83-0.98, P = 0.02). Masson et al. reported that when using the FASTHUG-MAIDENS checklist, more drug-related problems were identified by pharmacy residents (in relation to the number identified by the ICU pharmacist) both per patient encounter (P = 0.008) and overall (P < 0.001).³⁷ Ong et al. reported higher rates of compliance with isolation precautions for infectious diseases in the checklist group (71% vs. 38%, P < 0.01); however, compliance with the checklist was low (40%) and qualitative analyses found participants were dissatisfied with the checklist.³¹ Salzwedel et al. reported the number of items handed over by anesthesia residents postoperatively to be higher in the checklist group than the control group (48.7% vs. 32.4%, P < 0.001).³² In a more recent study, Salzwedel et al. reported that proportion of items deemed by the attending anesthesiologist as “must be handed over” were more often actually handed over by the anesthesia residents assigned to the checklist group when compared to controls (87.1% vs. 75.0%, P = 0.005).³⁴

30-day Mortality

A random-effects model pooling data from the 3 studies that reported data for 30-day all cause mortality suggested a significant reduction with use of a checklist (OR 0.60, 95% CI, 0.41-0.89; P = 0.01, I² = 0.0%, P = 0.573).

Study Quality

Supplementary File 5 (Table 5) summarizes the quality assessment of the 9 studies. The clarity of description for each intervention varied. All studies reported inclusion/exclusion criteria and randomization procedures. Three studies indicated that outcome assessors were blinded to intervention allocation;^32,34,36 while this was unclear in 2 studies.^21,30 Three studies reported baseline characteristics.^21,30,36 Two studies reported power calculations;^33,37 however, one study had a sample size that was less than that required to achieve the target power.³⁷ The Jadad scores ranged from 1to 5.

This systematic review identified 9 RCTs that examined the impact of a checklist on patient safety outcomes in hospitalized patients. The studies employed checklists with different purposes and elements and measured different patient safety outcomes. The methodological quality of the included studies was moderate. In aggregate, the results suggest that checklists may be effective at improving patient safety outcomes, but the small number of moderate quality studies and the heterogeneity of interventions and outcome measures suggests that there is an urgent need for further evaluation.

The most important observation from our systematic review is the paucity of high quality evidence evaluating checklists’ impact on patient safety outcomes in acute inpatient care. The implementation of checklists is increasingly common as they are relatively low cost to develop and implement, and intuitively make sense. This is particularly true in an era of increasing efforts to standardize care as a means for improving quality and minimizing cost (ie, previous systematic reviews cite 38 unique studies).³⁹ However, implementation of an inadequately tested checklist risks unintended consequences (eg, inefficient resource utilization).¹⁸ The small number of RCTs identified might be owing to quality improvement efforts traditionally focusing on ‘real life’ applicability over rigorous research methodology.⁴⁰ The translation of evidence into clinical practice is known to be slow;⁴¹ however, these more rigorous methodologies reduce the risk of biases and generate high-quality evidence, which help to fulfill the necessity to identify best practices while avoiding these unintended consequences.

The studies varied both in the approaches used to develop checklists and in the number of items included (ranging from 2 to 54). What is the optimal method for developing a checklist and how does this impact their effectiveness?⁴² The answers to these questions are not known. However, this review highlights some important issues to consider when developing a checklist. As the number of items or complexity of a task increases, our ability to efficiently perform the task without aid decreases.^43-45 As such, a well-designed checklist should detail explicit instructions on the what, where, when, and how of a given task in a fashion that ensures a consistent accuracy for completing the work.⁵ It is recommended that construction of a checklist follow the principles of human factors engineering: engage stakeholders and human factors experts in the design; are developed based on user needs and realities; list items in order of importance; are concise and subgroup sections of checklists by task or chronological order; ensure usability and evaluate potential negative consequences (eg time to complete); are pilot tested and validated before implementation; are updated as needed based the on generation of new findings or changes in operational procedures.⁴⁶ These general principles of human factors engineering⁴⁶ provide a practical approach for the development and evaluation of a checklist. In addition, standardization of operational definitions (ie, process, outcome, compliance) is important for study replication and robust meta-analyses.

Checklists used in aviation are perhaps best known¹² and the evidence of their effectiveness is derived from the attribution of aviation errors to incomplete checklists.¹² Although more recently implemented in medicine, checklists have the potential to guide the successful completion of complex tasks in healthcare.⁷ Systematic reviews of observational studies have been conducted for specific checklists (eg, WHO Surgical Safety Checklist) and for select patient populations (eg, surgical patients), and the number of included studies ranges from 7-27 (n = 38 unique studies).^15,16,18,19 For example, Gillespie et al. in a systematic review and meta-analysis reported the implementation of Surgical Safety Checklists to be associated with a reduction in postoperative complications (relative risk [RR] 0.63, 95% CI, 0.58-0.72, P = < 0.001), but not mortality (RR 1.03, 95% CI, 0.73-1.4, P = 0.857).¹⁹ Similarly, Treadwell et al. reported in a systematic review of Surgical Safety Checklists that while data are promising, more evaluation of their impact on clinical outcomes is needed.¹⁸ These recommendations are nicely illustrated by Urbach et al.’s²⁰ and O’Leary et al.’s⁴⁷ evaluations of the mandatory adoption of Surgical Safety Checklists across all hospitals in Ontario, Canada, which respectively demonstrated no significant reductions in 30-day perioperatively conplications for both adult (OR 0.97, 95% CI, 0.90-1.03, P = 0.29) and pediatric (AOR 1.01, 95% CI, 0.90-1.14, P = 0.9) patients. These data not only highlight the need for further evaluation of checklists but are also a reminder that checklists and their associated implementation strategies are complex interventions for which there may be important differences between the efficacy reported in clinical trials and the effectiveness reported in implementation studies.⁴⁸ This all suggests that if checklists are to be effective in improving patient safety, process evaluations of implementation⁴⁹ and realist reviews of published studies⁵⁰ may be important to determine optimal approaches for implementation. We believe that, based on the limited currently available evidence, there is urgency for further robust evaluations of checklists before their widespread implementation. If effective, they should be widely implemented. If ineffective, they should be abandoned to minimize unintended consequences and inefficient use of resources.

There are 4 primary limitations to this review that should be considered when interpreting the findings. First, the RCT design is not the study design employed by most quality improvement initiatives.⁴⁰ While some quality improvement experts may argue that an RCT design is insufficiently flexible for applied settings, it does minimize the risk of biased assessments of intervention effectiveness. Second, our search strategy included an RCT filter. The filter helped restrict the number of citations to be reviewed (n = 11,225) but could have resulted in improperly indexed studies being excluded. To guard against this risk, we used the validated Cochrane Highly Sensitive Search Strategy for Identifying Randomized Trials,²⁴ reviewed reference lists of citations included in the review, and solicited suggestions for missing studies from quality improvement experts. Third, our review was restricted to hospitalized patients. Although the studies evaluated commonly reported safety outcomes across patients with diverse clinical conditions, care settings, and providers that broadly reflect hospital-based care, evaluations of checklists in additional patient and provider groups are needed (eg, hospitalists). Furthermore, the effectiveness of checklists for improving patient safety outcomes in outpatients is important; however, the organizational and patient characteristics of these 2 settings (hospitalized vs outpatient) are sufficiently different to warrant separate systematic reviews. Finally, owing to the heterogeneity of the checklists used and outcomes measured, we were unable to perform a robust meta-analysis. Heterogeneity, combined with the small number of studies identified in our search, prevented us from applying statistical methods to assess for publication bias. This limitation of our systematic review highlights an important gap in the literature and emphasizes the importance of additional primary research to evaluate checklists.

In summary, we identified few RCTs that examined checklists designed to improve patient safety outcomes. The small number of existing studies suggests that checklists may improve patient safety outcomes; however, these observations were not reported for all outcomes examined and the studies were heterogeneous and of limited methodological quality. There is an urgent need for high-quality evaluations of the effectiveness of patient safety checklists in inpatient healthcare settings to substantiate their perceived benefits.

Acknowledgments

We would like to thank Diane Lorenzetti for her help with the development of the search strategy.

Disclosure: The authors have no known conflicts of interest to declare.

Jamie Boyd was supported by a W21C – Alberta Innovates-Health Solutions (AIHS) Collaborative Research and Innovation Opportunities (CRIO) Health Services Research graduate studentship. Guosong Wu was supported by a Western Regional Training Centre (WRTC) for Health Services Research graduate studentship. Dr. Stelfox was supported by a Population Health Investigator Award from Alberta Innovates Health Solutions.

Authors’ Contributions

HTS was responsible for the study’s conception. All 3 authors contributed to the study’s design and interpretation. JB and GW were responsible for searching the literature, reviewing abstracts, selecting full-text articles and critically appraising them. All 3 authors performed the analyses. JB drafted the manuscript and all 3 authors assisted in the successive revisions of the final manuscript. All authors have read and approved the final manuscript.

ObGyns are mindfully choosing their practice environments. The trend, as reported by the American College of Obstetricians and Gynecologists (ACOG),¹ shows movement from private practice to employment: an increasing number of ObGyns have joined large practices and are employed. Overall, fewer than half of US physicians owned their medical practice in 2016, reported the American Medical Association (AMA).² This is the first time that the majority of physicians are not practice owners.

Although employed ObGyns earn 9% less than self-employed ObGyns, ($276,000 vs $300,000, respectively), trading a higher salary for less time spent on administrative tasks seems to be worth the pay cut, reports Medscape. Employed ObGyns reported receiving additional benefits that might not have been available to self-employed ObGyns: professional liability coverage, employer-subsidized health and dental insurance, paid time off, and a retirement plan with employer match.³

What matters to ObGyns when choosing a practice setting?

Several decisions about practice setting need to be made at the beginning and throughout a career, among them the type of practice, desired salary, work-life balance, (the latter 2 may be influenced by practice type), and location.

Type of practice

“Patients benefit when physicians practice in settings they find professionally and personally rewarding,” said AMA President Andrew W. Gurman, MD. “The AMA is committed to helping physicians navigate their practice options and offers innovative strategies and resources to ensure physicians in all practice sizes and setting can thrive in the changing health environment.”²

More and more, that environment is a practice wholly owned by physicians. The AMA reports that in 2016, 55.8% of physicians worked in such a practice (including physicians who have an ownership stake in the practice, those who are employed by the practice, and those who are independent contractors).² An approximate 13.8% of physicians worked at practices with more than 50 physicians in 2016. The majority (57.8%), however, practiced in groups with 10 or fewer physicians. The most common practice type was the single-specialty group (42.8%), followed by the multispecialty group practice (24.6%).²

Paying physicians a salary instead of compensating them based on volume may improve physician satisfaction—it removes the need to deal with complex fee-for-service systems, say Ian Larkin, PhD, and George Loewenstein, PhD. In fee-for-service payment arrangements, physicians may be encouraged to order more tests and procedures because doing so may increase income. A better strategy, say Larkin and Loewenstein, is to switch to a straight salary system. Known for their quality of care and comparatively low costs, the Mayo Clinic, Cleveland Clinic, and Kaiser Permanente have successfully implemented this payment system.⁴

Related article:
ObGyn salaries jumped in the last year

Desired salary

The mean income for ObGyns rose by 3% in 2016 over 2015 ($286,000 compared with $277,000), according to Medscape.⁵ This jump follows a gradual increase over the last few years ($249,000 in 2014; $243,000 in 2013; $242,000 in 2012; $220,000 in 2011).^1,5,6

The highest earnings among all physicians were orthopedists ($489,000), plastic surgeons ($440,000), and cardiologists ($410,000). Pediatricians were the lowest paid physicians at $202,000.³

Fair compensation. Fewer than half (48%) of ObGyns who completed the Medscape survey felt they were fairly compensated in 2016, and 41% of those who were dissatisfied with their compensation believed they deserved to be earning between 11% and 25% more. When asked if they would still choose medicine, 72% of ObGyns answered affirmatively. Of those who would choose medicine again, 76% would choose obstetrics and gynecology once more.³

Gender differences. As in years past, full-time male ObGyns reported higher earnings (13%) than female ObGyns ($306,000 vs $270,000, respectively; (FIGURE 1).^3,5,7,8

Among ObGyns who responded to the 2017 Medscape survey, 14% of women and 10% of men indicated that they work part-time.³ Last year, 13% of female ObGyns reported part-time employment versus 16% of male ObGyns.⁶

Among the ObGyns who answered the 2017 survey, there was a gender gap in participation related to race. Although more men than women responded to the survey, more women than men ObGyns among black/African American (women, 78%), Asian (women, 69%), and white/Caucasian (women, 53%) groups responded. Men outweighed women only among Hispanic/Latino ObGyns (60%) who answered the survey.³

Read about work-life balance, job satisfaction, and burnout

Work-life balance

ACOG predicts that mid-career and younger ObGyns will focus on work-life balance issues. Practice sites (ambulatory, hospital, or a combination) that offer part-time schedules or extra time for nonprofessional matters are becoming the most desirable to these practitioners.¹

What satisfies and dissatisfies ObGyns? ObGyns reported to Medscape that their relationships with patients (41% of respondents) was the most rewarding part of their job (FIGURE 2).³

There are many job aspects that dissatisfy ObGyns, including^1,3,9:

• too many bureaucratic tasks
• the short time allotted for each patient office visit
• electronic health records (EHR) and increased computerization
• not feeling appreciated or properly compensated
• spending too many hours at work
• the impact of regulatory changes on clinical practice.

Bureaucratic tasks remain a primary cause for burnout among all physicians.¹⁰ This year, 56% of all physicians reported spending 10 hours or more per week on paperwork and administrative tasks, up from 35% in the 2014 report. More than half (54%) of ObGyns reported spending 10 hours or more on paperwork.³ For every hour of face-to-face patient time, physicians spent nearly 2 additional hours on their EHR and administration tasks.⁹

Time with patients. Medscape reported that 38% of ObGyns spent more than 45 hours per week with patients (FIGURE 3).

ACOG notes that ObGyns are increasingly referring patients to subspecialists, which frustrates patients and increases their costs.¹

ObGyns rank high in burnout rates. Burnout rates for physicians are twice that of other working adults.¹ ObGyns rank second (56%) in burn out (Emergency Medicine, 59%).¹⁰ When Medscape survey respondents were asked to grade their burnout level from 1 to 7 (1 = “It does not interfere with my life;” 7 = “It is so severe that I am thinking of leaving medicine altogether”), ObGyns ranked their burnout level at 4.3.¹⁰ Female physicians reported a higher percentage of burnout than their male colleagues (55% vs 45%, respectively).¹⁰ An estimated 40% to 75% of ObGyns experienced some level of burnout.¹

According to ACOG, the specialty is included among the “noncontrollable” lifestyle specialties, especially for those aged 50 years or younger. Many Millennials (born 1980 to 2000) do not view their work and professional achievement as central to their lives; ObGyns aged younger than 35 years want to work fewer hours per week compared with their older colleagues, says ACOG. However, when this option is unavailable, an increasing number of Millennials report lowered job satisfaction.¹

Related article:
What can administrators and ObGyns do together to reduce physician burnout?
 

Mindfulness about quality of life. The relationship of burnout to quality of life issues is gaining in awareness. In a recent OBG Management article, Lucia DiVenere, MA, noted that, “Being mindful of wellness strategies and practice efficiencies can help ObGyns avoid burnout’s deleterious effects—and thrive both personally and professionally.”¹¹

“We need to stop blaming individuals and treat physician burnout as a system issue…If it affects half our physicians, it is indirectly affecting half our patients,” notes Tait Shanafelt, MD, a hematologist and physician-burnout researcher at the Mayo Clinic.⁹ He says that burnout relates to a physician’s “professional spirit of life, and it primarily affects individuals whose work involves an intense interaction with people.”⁹

The Mayo Clinic in Minneapolis, Minnesota, has taken a lead in developing a space for their physicians to “reset” by offering a room where health professionals can retreat if they need a moment to recover from a traumatic event.⁹

Read about what factors attract ObGyns to specific locations

Location, location, location

Specific areas of the country are more attractive for their higher compensation rates. The highest average compensation was reported by ObGyns in the North Central area ($339,000), West ($301,000), and Great Lakes ($297,000) regions, while the lowest compensation rates were found in the Northwest ($260,000), Southwest ($268,000), and South Central ($275,000) areas.³

Key factors, such as healthy patient populations, higher rates of health insurance coverage, and lower stress levels attract physicians (FIGURE 4). Minnesota ranked the #1 best place to practice because it has the 4th healthiest population, 2nd highest rate of employer-sponsored health insurance, the 17th lowest number of malpractice lawsuits, and a medical board that is the 3rd least harsh in the nation.¹² Unfortunate situations such as the highest malpractice rates per capita, least healthy population, 8th lowest rate of employer-sponsored health insurance, and the 9th lowest compensation rate for physicians make Louisiana the worst place to practice in 2017.¹²

Supply and demand creates substantial geographic imbalances in the number of ObGyns in the United States. ACOG pro-jects that the need for ObGyns will increase nationally by 6% in the next 10 years, although demand will vary geographically from a 27% increase in Nevada to an 11% decrease in West Virginia.¹ Especially vulnerable states (Arizona, Washington, Utah, Idaho) currently have an insufficient supply of ObGyns and are projected to see an increased future demand. Florida, Texas, North Carolina, and Nevada will be at risk, according to ACOG, because the adult female population is expected to increase.¹

2017 Medscape survey demographics

The Medscape Compensation Report 2017 is a based on the responses of 19,270 physicians across 27+ specialties, 5% of whom were ObGyns. Data were collected in an online survey conducted from December 20, 2016, to March 7, 2017.³

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

ObGyns are mindfully choosing their practice environments. The trend, as reported by the American College of Obstetricians and Gynecologists (ACOG),¹ shows movement from private practice to employment: an increasing number of ObGyns have joined large practices and are employed. Overall, fewer than half of US physicians owned their medical practice in 2016, reported the American Medical Association (AMA).² This is the first time that the majority of physicians are not practice owners.

Although employed ObGyns earn 9% less than self-employed ObGyns, ($276,000 vs $300,000, respectively), trading a higher salary for less time spent on administrative tasks seems to be worth the pay cut, reports Medscape. Employed ObGyns reported receiving additional benefits that might not have been available to self-employed ObGyns: professional liability coverage, employer-subsidized health and dental insurance, paid time off, and a retirement plan with employer match.³

What matters to ObGyns when choosing a practice setting?

Several decisions about practice setting need to be made at the beginning and throughout a career, among them the type of practice, desired salary, work-life balance, (the latter 2 may be influenced by practice type), and location.

Type of practice

“Patients benefit when physicians practice in settings they find professionally and personally rewarding,” said AMA President Andrew W. Gurman, MD. “The AMA is committed to helping physicians navigate their practice options and offers innovative strategies and resources to ensure physicians in all practice sizes and setting can thrive in the changing health environment.”²

More and more, that environment is a practice wholly owned by physicians. The AMA reports that in 2016, 55.8% of physicians worked in such a practice (including physicians who have an ownership stake in the practice, those who are employed by the practice, and those who are independent contractors).² An approximate 13.8% of physicians worked at practices with more than 50 physicians in 2016. The majority (57.8%), however, practiced in groups with 10 or fewer physicians. The most common practice type was the single-specialty group (42.8%), followed by the multispecialty group practice (24.6%).²

Paying physicians a salary instead of compensating them based on volume may improve physician satisfaction—it removes the need to deal with complex fee-for-service systems, say Ian Larkin, PhD, and George Loewenstein, PhD. In fee-for-service payment arrangements, physicians may be encouraged to order more tests and procedures because doing so may increase income. A better strategy, say Larkin and Loewenstein, is to switch to a straight salary system. Known for their quality of care and comparatively low costs, the Mayo Clinic, Cleveland Clinic, and Kaiser Permanente have successfully implemented this payment system.⁴

Related article:
ObGyn salaries jumped in the last year

Desired salary

The mean income for ObGyns rose by 3% in 2016 over 2015 ($286,000 compared with $277,000), according to Medscape.⁵ This jump follows a gradual increase over the last few years ($249,000 in 2014; $243,000 in 2013; $242,000 in 2012; $220,000 in 2011).^1,5,6

The highest earnings among all physicians were orthopedists ($489,000), plastic surgeons ($440,000), and cardiologists ($410,000). Pediatricians were the lowest paid physicians at $202,000.³

Fair compensation. Fewer than half (48%) of ObGyns who completed the Medscape survey felt they were fairly compensated in 2016, and 41% of those who were dissatisfied with their compensation believed they deserved to be earning between 11% and 25% more. When asked if they would still choose medicine, 72% of ObGyns answered affirmatively. Of those who would choose medicine again, 76% would choose obstetrics and gynecology once more.³

Gender differences. As in years past, full-time male ObGyns reported higher earnings (13%) than female ObGyns ($306,000 vs $270,000, respectively; (FIGURE 1).^3,5,7,8

Among ObGyns who responded to the 2017 Medscape survey, 14% of women and 10% of men indicated that they work part-time.³ Last year, 13% of female ObGyns reported part-time employment versus 16% of male ObGyns.⁶

Among the ObGyns who answered the 2017 survey, there was a gender gap in participation related to race. Although more men than women responded to the survey, more women than men ObGyns among black/African American (women, 78%), Asian (women, 69%), and white/Caucasian (women, 53%) groups responded. Men outweighed women only among Hispanic/Latino ObGyns (60%) who answered the survey.³

Read about work-life balance, job satisfaction, and burnout

Work-life balance

ACOG predicts that mid-career and younger ObGyns will focus on work-life balance issues. Practice sites (ambulatory, hospital, or a combination) that offer part-time schedules or extra time for nonprofessional matters are becoming the most desirable to these practitioners.¹

What satisfies and dissatisfies ObGyns? ObGyns reported to Medscape that their relationships with patients (41% of respondents) was the most rewarding part of their job (FIGURE 2).³

There are many job aspects that dissatisfy ObGyns, including^1,3,9:

• too many bureaucratic tasks
• the short time allotted for each patient office visit
• electronic health records (EHR) and increased computerization
• not feeling appreciated or properly compensated
• spending too many hours at work
• the impact of regulatory changes on clinical practice.

Bureaucratic tasks remain a primary cause for burnout among all physicians.¹⁰ This year, 56% of all physicians reported spending 10 hours or more per week on paperwork and administrative tasks, up from 35% in the 2014 report. More than half (54%) of ObGyns reported spending 10 hours or more on paperwork.³ For every hour of face-to-face patient time, physicians spent nearly 2 additional hours on their EHR and administration tasks.⁹

Time with patients. Medscape reported that 38% of ObGyns spent more than 45 hours per week with patients (FIGURE 3).

ACOG notes that ObGyns are increasingly referring patients to subspecialists, which frustrates patients and increases their costs.¹

ObGyns rank high in burnout rates. Burnout rates for physicians are twice that of other working adults.¹ ObGyns rank second (56%) in burn out (Emergency Medicine, 59%).¹⁰ When Medscape survey respondents were asked to grade their burnout level from 1 to 7 (1 = “It does not interfere with my life;” 7 = “It is so severe that I am thinking of leaving medicine altogether”), ObGyns ranked their burnout level at 4.3.¹⁰ Female physicians reported a higher percentage of burnout than their male colleagues (55% vs 45%, respectively).¹⁰ An estimated 40% to 75% of ObGyns experienced some level of burnout.¹

According to ACOG, the specialty is included among the “noncontrollable” lifestyle specialties, especially for those aged 50 years or younger. Many Millennials (born 1980 to 2000) do not view their work and professional achievement as central to their lives; ObGyns aged younger than 35 years want to work fewer hours per week compared with their older colleagues, says ACOG. However, when this option is unavailable, an increasing number of Millennials report lowered job satisfaction.¹

Related article:
What can administrators and ObGyns do together to reduce physician burnout?
 

Mindfulness about quality of life. The relationship of burnout to quality of life issues is gaining in awareness. In a recent OBG Management article, Lucia DiVenere, MA, noted that, “Being mindful of wellness strategies and practice efficiencies can help ObGyns avoid burnout’s deleterious effects—and thrive both personally and professionally.”¹¹

“We need to stop blaming individuals and treat physician burnout as a system issue…If it affects half our physicians, it is indirectly affecting half our patients,” notes Tait Shanafelt, MD, a hematologist and physician-burnout researcher at the Mayo Clinic.⁹ He says that burnout relates to a physician’s “professional spirit of life, and it primarily affects individuals whose work involves an intense interaction with people.”⁹

The Mayo Clinic in Minneapolis, Minnesota, has taken a lead in developing a space for their physicians to “reset” by offering a room where health professionals can retreat if they need a moment to recover from a traumatic event.⁹

Read about what factors attract ObGyns to specific locations

Location, location, location

Specific areas of the country are more attractive for their higher compensation rates. The highest average compensation was reported by ObGyns in the North Central area ($339,000), West ($301,000), and Great Lakes ($297,000) regions, while the lowest compensation rates were found in the Northwest ($260,000), Southwest ($268,000), and South Central ($275,000) areas.³

Key factors, such as healthy patient populations, higher rates of health insurance coverage, and lower stress levels attract physicians (FIGURE 4). Minnesota ranked the #1 best place to practice because it has the 4th healthiest population, 2nd highest rate of employer-sponsored health insurance, the 17th lowest number of malpractice lawsuits, and a medical board that is the 3rd least harsh in the nation.¹² Unfortunate situations such as the highest malpractice rates per capita, least healthy population, 8th lowest rate of employer-sponsored health insurance, and the 9th lowest compensation rate for physicians make Louisiana the worst place to practice in 2017.¹²

Supply and demand creates substantial geographic imbalances in the number of ObGyns in the United States. ACOG pro-jects that the need for ObGyns will increase nationally by 6% in the next 10 years, although demand will vary geographically from a 27% increase in Nevada to an 11% decrease in West Virginia.¹ Especially vulnerable states (Arizona, Washington, Utah, Idaho) currently have an insufficient supply of ObGyns and are projected to see an increased future demand. Florida, Texas, North Carolina, and Nevada will be at risk, according to ACOG, because the adult female population is expected to increase.¹

2017 Medscape survey demographics

The Medscape Compensation Report 2017 is a based on the responses of 19,270 physicians across 27+ specialties, 5% of whom were ObGyns. Data were collected in an online survey conducted from December 20, 2016, to March 7, 2017.³

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

ObGyns are mindfully choosing their practice environments. The trend, as reported by the American College of Obstetricians and Gynecologists (ACOG),¹ shows movement from private practice to employment: an increasing number of ObGyns have joined large practices and are employed. Overall, fewer than half of US physicians owned their medical practice in 2016, reported the American Medical Association (AMA).² This is the first time that the majority of physicians are not practice owners.

Although employed ObGyns earn 9% less than self-employed ObGyns, ($276,000 vs $300,000, respectively), trading a higher salary for less time spent on administrative tasks seems to be worth the pay cut, reports Medscape. Employed ObGyns reported receiving additional benefits that might not have been available to self-employed ObGyns: professional liability coverage, employer-subsidized health and dental insurance, paid time off, and a retirement plan with employer match.³

What matters to ObGyns when choosing a practice setting?

Several decisions about practice setting need to be made at the beginning and throughout a career, among them the type of practice, desired salary, work-life balance, (the latter 2 may be influenced by practice type), and location.

Type of practice

“Patients benefit when physicians practice in settings they find professionally and personally rewarding,” said AMA President Andrew W. Gurman, MD. “The AMA is committed to helping physicians navigate their practice options and offers innovative strategies and resources to ensure physicians in all practice sizes and setting can thrive in the changing health environment.”²

More and more, that environment is a practice wholly owned by physicians. The AMA reports that in 2016, 55.8% of physicians worked in such a practice (including physicians who have an ownership stake in the practice, those who are employed by the practice, and those who are independent contractors).² An approximate 13.8% of physicians worked at practices with more than 50 physicians in 2016. The majority (57.8%), however, practiced in groups with 10 or fewer physicians. The most common practice type was the single-specialty group (42.8%), followed by the multispecialty group practice (24.6%).²

Paying physicians a salary instead of compensating them based on volume may improve physician satisfaction—it removes the need to deal with complex fee-for-service systems, say Ian Larkin, PhD, and George Loewenstein, PhD. In fee-for-service payment arrangements, physicians may be encouraged to order more tests and procedures because doing so may increase income. A better strategy, say Larkin and Loewenstein, is to switch to a straight salary system. Known for their quality of care and comparatively low costs, the Mayo Clinic, Cleveland Clinic, and Kaiser Permanente have successfully implemented this payment system.⁴

Related article:
ObGyn salaries jumped in the last year

Desired salary

The mean income for ObGyns rose by 3% in 2016 over 2015 ($286,000 compared with $277,000), according to Medscape.⁵ This jump follows a gradual increase over the last few years ($249,000 in 2014; $243,000 in 2013; $242,000 in 2012; $220,000 in 2011).^1,5,6

The highest earnings among all physicians were orthopedists ($489,000), plastic surgeons ($440,000), and cardiologists ($410,000). Pediatricians were the lowest paid physicians at $202,000.³

Fair compensation. Fewer than half (48%) of ObGyns who completed the Medscape survey felt they were fairly compensated in 2016, and 41% of those who were dissatisfied with their compensation believed they deserved to be earning between 11% and 25% more. When asked if they would still choose medicine, 72% of ObGyns answered affirmatively. Of those who would choose medicine again, 76% would choose obstetrics and gynecology once more.³

Gender differences. As in years past, full-time male ObGyns reported higher earnings (13%) than female ObGyns ($306,000 vs $270,000, respectively; (FIGURE 1).^3,5,7,8

Among ObGyns who responded to the 2017 Medscape survey, 14% of women and 10% of men indicated that they work part-time.³ Last year, 13% of female ObGyns reported part-time employment versus 16% of male ObGyns.⁶

Among the ObGyns who answered the 2017 survey, there was a gender gap in participation related to race. Although more men than women responded to the survey, more women than men ObGyns among black/African American (women, 78%), Asian (women, 69%), and white/Caucasian (women, 53%) groups responded. Men outweighed women only among Hispanic/Latino ObGyns (60%) who answered the survey.³

Read about work-life balance, job satisfaction, and burnout

Work-life balance

ACOG predicts that mid-career and younger ObGyns will focus on work-life balance issues. Practice sites (ambulatory, hospital, or a combination) that offer part-time schedules or extra time for nonprofessional matters are becoming the most desirable to these practitioners.¹

What satisfies and dissatisfies ObGyns? ObGyns reported to Medscape that their relationships with patients (41% of respondents) was the most rewarding part of their job (FIGURE 2).³

There are many job aspects that dissatisfy ObGyns, including^1,3,9:

• too many bureaucratic tasks
• the short time allotted for each patient office visit
• electronic health records (EHR) and increased computerization
• not feeling appreciated or properly compensated
• spending too many hours at work
• the impact of regulatory changes on clinical practice.

Bureaucratic tasks remain a primary cause for burnout among all physicians.¹⁰ This year, 56% of all physicians reported spending 10 hours or more per week on paperwork and administrative tasks, up from 35% in the 2014 report. More than half (54%) of ObGyns reported spending 10 hours or more on paperwork.³ For every hour of face-to-face patient time, physicians spent nearly 2 additional hours on their EHR and administration tasks.⁹

Time with patients. Medscape reported that 38% of ObGyns spent more than 45 hours per week with patients (FIGURE 3).

ACOG notes that ObGyns are increasingly referring patients to subspecialists, which frustrates patients and increases their costs.¹

ObGyns rank high in burnout rates. Burnout rates for physicians are twice that of other working adults.¹ ObGyns rank second (56%) in burn out (Emergency Medicine, 59%).¹⁰ When Medscape survey respondents were asked to grade their burnout level from 1 to 7 (1 = “It does not interfere with my life;” 7 = “It is so severe that I am thinking of leaving medicine altogether”), ObGyns ranked their burnout level at 4.3.¹⁰ Female physicians reported a higher percentage of burnout than their male colleagues (55% vs 45%, respectively).¹⁰ An estimated 40% to 75% of ObGyns experienced some level of burnout.¹

According to ACOG, the specialty is included among the “noncontrollable” lifestyle specialties, especially for those aged 50 years or younger. Many Millennials (born 1980 to 2000) do not view their work and professional achievement as central to their lives; ObGyns aged younger than 35 years want to work fewer hours per week compared with their older colleagues, says ACOG. However, when this option is unavailable, an increasing number of Millennials report lowered job satisfaction.¹

Related article:
What can administrators and ObGyns do together to reduce physician burnout?
 

Mindfulness about quality of life. The relationship of burnout to quality of life issues is gaining in awareness. In a recent OBG Management article, Lucia DiVenere, MA, noted that, “Being mindful of wellness strategies and practice efficiencies can help ObGyns avoid burnout’s deleterious effects—and thrive both personally and professionally.”¹¹

“We need to stop blaming individuals and treat physician burnout as a system issue…If it affects half our physicians, it is indirectly affecting half our patients,” notes Tait Shanafelt, MD, a hematologist and physician-burnout researcher at the Mayo Clinic.⁹ He says that burnout relates to a physician’s “professional spirit of life, and it primarily affects individuals whose work involves an intense interaction with people.”⁹

The Mayo Clinic in Minneapolis, Minnesota, has taken a lead in developing a space for their physicians to “reset” by offering a room where health professionals can retreat if they need a moment to recover from a traumatic event.⁹

Read about what factors attract ObGyns to specific locations

Location, location, location

Specific areas of the country are more attractive for their higher compensation rates. The highest average compensation was reported by ObGyns in the North Central area ($339,000), West ($301,000), and Great Lakes ($297,000) regions, while the lowest compensation rates were found in the Northwest ($260,000), Southwest ($268,000), and South Central ($275,000) areas.³

Key factors, such as healthy patient populations, higher rates of health insurance coverage, and lower stress levels attract physicians (FIGURE 4). Minnesota ranked the #1 best place to practice because it has the 4th healthiest population, 2nd highest rate of employer-sponsored health insurance, the 17th lowest number of malpractice lawsuits, and a medical board that is the 3rd least harsh in the nation.¹² Unfortunate situations such as the highest malpractice rates per capita, least healthy population, 8th lowest rate of employer-sponsored health insurance, and the 9th lowest compensation rate for physicians make Louisiana the worst place to practice in 2017.¹²

Supply and demand creates substantial geographic imbalances in the number of ObGyns in the United States. ACOG pro-jects that the need for ObGyns will increase nationally by 6% in the next 10 years, although demand will vary geographically from a 27% increase in Nevada to an 11% decrease in West Virginia.¹ Especially vulnerable states (Arizona, Washington, Utah, Idaho) currently have an insufficient supply of ObGyns and are projected to see an increased future demand. Florida, Texas, North Carolina, and Nevada will be at risk, according to ACOG, because the adult female population is expected to increase.¹

2017 Medscape survey demographics

The Medscape Compensation Report 2017 is a based on the responses of 19,270 physicians across 27+ specialties, 5% of whom were ObGyns. Data were collected in an online survey conducted from December 20, 2016, to March 7, 2017.³

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

For ObGyns, 2 intensely stressful career milestones are the day you start your practice and the day you decide to put it up for sale.

One of us, Dr. Baum, started a practice in 1976. At that time, many clinicians seemed to work right up until the day they died—in mid-examination or with scalpel in hand! Today, clinicians seriously contemplate leaving an active practice at age 55, 60, or, more traditionally, 65.

ObGyns in group practice, even those with only 1 or 2 partners, presumably have in place a well-thought-out and properly drafted contract with buyout and phase-down provisions. For members of a group practice, it is imperative to critically review and discuss contractual arrangements periodically and decide if they make sense as much now as they did at the start. ObGyns who continually revisit their contracts probably have an exit strategy that is fairly self-executing and effective and that will provide the seller with a seamless transition to retirement.

A solo ObGyn who is selling a practice has 3 basic options: find a successor physician, sell to a hospital or to a larger group, or close the practice.

Related article:
ObGyns’ choice of practice environment is a big deal

Preparing your practice for sale

Regardless of who will take over your practice, you need to prepare for its transition.

The most important aspect of selling your practice is knowing its finances and ensuring that they are in order. Any serious buyer will ask to examine your books, see how you are running the business, and assess its vitality and potential growth. Simply, a buyer will want to know where your revenue comes from and where it goes.

Your practice will be attractive to a buyer if it shows a stable or growing revenue base, an attractive payer mix, reasonable overhead, and personal income that is steady if not increasing. If your earning capacity is low or declining, you will need to explain why.

Timing is key

We strongly recommend beginning the process 3 to 5 years before your intended exit.

By starting early, up to 5 years in advance, you can maximize the likelihood that your practice will retain all or most of its value. Moreover, you can use the long lead time to thoroughly explore all available options and find a committed buyer.

Selling a practice can be a complicated affair, and many ObGyns do not have the requisite skills. So much of the success in selling depends on the specifics of the practice, the physician, and the market (the hospital and physician environment).

Identifying potential buyers

Other ObGyns. Recruiting an ObGyn to take over your practice seems to be the best option but can prove very difficult in today’s environment. Many younger clinicians are either joining large groups or becoming hospital employees.

Other physician groups. While working your way down your list of potential buyers, you should also be quietly, subtly, and tactfully assessing other practices, even your competitors, to see if any are candidates for merging with and/or acquiring yours and all your charts, records, and referring physicians.

Hospitals. In today’s health care environment, in which more than half of clinicians are becoming hospital employees, selling to your associated hospital may be a viable option.

Your practice is probably contributing millions of dollars in income to that hospital each year, and of course the hospital would like to maintain this revenue stream. You should consider talking to the hospital’s CEO or medical director.

Hospitals also know that, if you leave and the market cannot absorb the resulting increase in demand for care, patients may go elsewhere, to a competing hospital or outside the community. Rather than lose your market share, a hospital may consider the obvious solution: recruit a replacement ObGyn for your practice.

Your goal here is to negotiate an agreement in which your hospital will recruit a replacement ObGyn, provide financial support, and transition your practice to that ObGyn over a specified period.

The hospital could acquire your practice and either employ you during the transition or provide recruiting support and an income guarantee to help your practice pay the new physician’s salary. Whether to sell or remain independent is often driven by the needs and desires of the recruit. As the vast majority of clinicians coming out of training are seeking employment, in most cases the agreement will require a sale.

Selling to a hospital a few years before your retirement can be a plus. You might find employment a welcome respite from the daunting responsibility of managing your own practice. Life can become much less stressful as you introduce and transition your patients to the new ObGyn. You will be working less, taking fewer calls, and maintaining or even increasing your income, all without the burden of managing the practice.

Read about determining your practice’s value

Putting a monetary value on your practice

After deciding to sell your practice, you need to determine its value. Buying a practice may be the largest financial transaction a young ObGyn will ever make. For a retiring physician, valuation of a practice may reflect a career’s worth of “sweat equity.”

What is your practice worth?

All ObGyns believe their practice is worth far more than any young ObGyn or hospital is willing to pay for it. After all, you have spent a medical lifetime creating, building, and nurturing your practice. You have cared for several thousand patients, who have been loyal and may want to stay with the practice under its new ObGyn. So, how does a retiring physician put a value on his or her practice and then “cast the net” to the marketplace? How do you find a buyer who will pay the asking price and then help the practice make the transition from seller to buyer and continue to serve their patients?

The buyer’s perspective on value. In a pure sense, the value of any asset is what a potential buyer is willing to pay. From a value standpoint, the price that potential buyers are willing to pay varies by the specifics of the situation, regardless of what a valuation or practice appraisal might indicate.

For example, once your plan to retire becomes known, why would a young ObGyn agree to pay X dollars for all your medical records? After all, the potential buyer knows that your existing patients and your referral base will need to seek care from another ObGyn after you leave, and they will likely stay with the practice if they feel they will be treated well by the new clinician.

A hospital may take a similar tack but more often will be willing to pay fair market value for your practice. Hospitals, however, cannot legally pay more than fair market value as determined by an independent appraiser.

Related article:
Four pillars of a successful practice: 1. Keep your current patients happy

Valuation methods

The valuation of any business generally is approached in terms of market, assets, and income.

The market approach usually is taken only with regard to office real estate. Given the lack of reliable and comparable sales information, this approach is seldom used in the valuation of medical practices. If you own your office real estate, a real estate appraiser will establish its fair market value.

In the assets approach, the individual assets of a medical practice are valued on the basis of their current market values. These assets are either tangible or intangible.

Tangible assets can be seen and touched. Furniture, equipment, and office real estate are examples.

The fair market value of used furniture and equipment is most often determined by replacement cost. The value of these items is limited. Usually it starts at 50% of the cost of buying new furniture or equipment of the same utility. From there, the value is lowered on the basis of the age and condition of the items.

Often, the market value of major ObGyn office equipment, such as a DXA (dual-energy x-ray absorptiometry) scanner, is based on similar items for sale or recently sold in the used secondary equipment market.

Tangible assets may include accounts receivable (A/R). A/R represents uncollected payment for work performed. Most buyers want to avoid paying for A/R and assuming the risk of collections. Generally, you should expect to retain your A/R and pay a small or nominal fee to have the buyer handle the collections after you have retired.

Intangible assets are not physical. Examples include the physician’s name, phone number, reputation, referral base, trained staff, and medical records—in other words, what gets patients to keep coming back. Most physicians value these goodwill or “blue-sky” assets highly. Today, unfortunately, most sellers are unable to reap any financial benefit from their intangible assets.

The income approach is based on the premise that the value of any business is in the income it generates for its owner. In simple terms, value in the income approach is a multiple of the cash the business generates after expenses.

Read important keys to transitioning the practice

Transitioning the practice: Role of the seller and the buyer

First and very important is the contract agreement regarding the overlap period, when both the exiting ObGyn and the new ObGyn are at the practice. We suggest making the overlap a minimum of 6 months and a maximum of 1 year. During this period, the exiting physician can introduce the incoming physician to the patients. A face-to-face introduction can amount to an endorsement, which can ease a patient’s mind and help her decide to take on the new ObGyn and philosophy rather than search elsewhere for obstetric and gynecologic care. The new ObGyn also can use the overlap period to become familiar and comfortable with the staff and learn the process for physician and staff management of case flow, from scheduling and examination to insurance and patient follow-up.

We suggest that the exiting ObGyn send a farewell/welcome letter to patients and referring physicians. The letter should state the exiting ObGyn’s intention to leave (or retire from) the practice and should introduce the ObGyn who will be taking over.

The exiting ObGyn should also take the new ObGyn to meet the physicians who have been providing referrals over the years. We suggest visiting each referring physician’s office to make the introduction. Another good way to introduce a new ObGyn to referring physicians and other professionals—endocrinologists, cardiologists, nurses, pharmaceutical representatives—is to host an open house at your practice. Invite the staff members of the referring physicians as well, since they can be invaluable in making referrals.

We recommend that the exiting ObGyn spend the money to update all the practice’s stationery, brochures, and print materials and ensure they look professional. Note that it is not acceptable to place the new ObGyn’s name under the exiting ObGyn’s name. If the practice has a website, introduce the new physician there and make any necessary updates regarding office hours and accepted insurance plans.

If the exiting ObGyn’s practice lacks a robust Internet and social media presence, the new ObGyn should establish one. We recommend setting up an interactive website that patients can use to make appointments and pay bills. The website should have an email component that can be used to ask questions, raise concerns, and get answers. We also recommend opening Facebook, YouTube, and Twitter accounts for the practice and being active on these social media.

In our experience, smoothly transitioning practices can achieve patient retention rates as high as 90% to 95%. For practices without a plan, however, these rates may be as low as 50%, or worse. Therefore, work out a plan in advance, and include the steps described here, so that on arrival the new ObGyn can hit the ground running.

Acquiring a successful medical practice is doable and offers many advantages, such as autonomy and the ability to make business decisions affecting the practice. Despite all the changes happening in health care, we still think this is the best way to go.

Related article:
Four pillars of a successful practice: 4. Motivate your staff

Bottom line

Selling an ObGyn practice can be a daunting process. However, deciding to sell your practice, performing the valuation, and ensuring a smooth transition are part and parcel of making the transfer a success, equitable for both the buyer and the seller.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

For ObGyns, 2 intensely stressful career milestones are the day you start your practice and the day you decide to put it up for sale.

One of us, Dr. Baum, started a practice in 1976. At that time, many clinicians seemed to work right up until the day they died—in mid-examination or with scalpel in hand! Today, clinicians seriously contemplate leaving an active practice at age 55, 60, or, more traditionally, 65.

ObGyns in group practice, even those with only 1 or 2 partners, presumably have in place a well-thought-out and properly drafted contract with buyout and phase-down provisions. For members of a group practice, it is imperative to critically review and discuss contractual arrangements periodically and decide if they make sense as much now as they did at the start. ObGyns who continually revisit their contracts probably have an exit strategy that is fairly self-executing and effective and that will provide the seller with a seamless transition to retirement.

A solo ObGyn who is selling a practice has 3 basic options: find a successor physician, sell to a hospital or to a larger group, or close the practice.

Related article:
ObGyns’ choice of practice environment is a big deal

Preparing your practice for sale

Regardless of who will take over your practice, you need to prepare for its transition.

The most important aspect of selling your practice is knowing its finances and ensuring that they are in order. Any serious buyer will ask to examine your books, see how you are running the business, and assess its vitality and potential growth. Simply, a buyer will want to know where your revenue comes from and where it goes.

Your practice will be attractive to a buyer if it shows a stable or growing revenue base, an attractive payer mix, reasonable overhead, and personal income that is steady if not increasing. If your earning capacity is low or declining, you will need to explain why.

Timing is key

We strongly recommend beginning the process 3 to 5 years before your intended exit.

By starting early, up to 5 years in advance, you can maximize the likelihood that your practice will retain all or most of its value. Moreover, you can use the long lead time to thoroughly explore all available options and find a committed buyer.

Selling a practice can be a complicated affair, and many ObGyns do not have the requisite skills. So much of the success in selling depends on the specifics of the practice, the physician, and the market (the hospital and physician environment).

Identifying potential buyers

Other ObGyns. Recruiting an ObGyn to take over your practice seems to be the best option but can prove very difficult in today’s environment. Many younger clinicians are either joining large groups or becoming hospital employees.

Other physician groups. While working your way down your list of potential buyers, you should also be quietly, subtly, and tactfully assessing other practices, even your competitors, to see if any are candidates for merging with and/or acquiring yours and all your charts, records, and referring physicians.

Hospitals. In today’s health care environment, in which more than half of clinicians are becoming hospital employees, selling to your associated hospital may be a viable option.

Your practice is probably contributing millions of dollars in income to that hospital each year, and of course the hospital would like to maintain this revenue stream. You should consider talking to the hospital’s CEO or medical director.

Hospitals also know that, if you leave and the market cannot absorb the resulting increase in demand for care, patients may go elsewhere, to a competing hospital or outside the community. Rather than lose your market share, a hospital may consider the obvious solution: recruit a replacement ObGyn for your practice.

Your goal here is to negotiate an agreement in which your hospital will recruit a replacement ObGyn, provide financial support, and transition your practice to that ObGyn over a specified period.

The hospital could acquire your practice and either employ you during the transition or provide recruiting support and an income guarantee to help your practice pay the new physician’s salary. Whether to sell or remain independent is often driven by the needs and desires of the recruit. As the vast majority of clinicians coming out of training are seeking employment, in most cases the agreement will require a sale.

Selling to a hospital a few years before your retirement can be a plus. You might find employment a welcome respite from the daunting responsibility of managing your own practice. Life can become much less stressful as you introduce and transition your patients to the new ObGyn. You will be working less, taking fewer calls, and maintaining or even increasing your income, all without the burden of managing the practice.

Read about determining your practice’s value

Putting a monetary value on your practice

After deciding to sell your practice, you need to determine its value. Buying a practice may be the largest financial transaction a young ObGyn will ever make. For a retiring physician, valuation of a practice may reflect a career’s worth of “sweat equity.”

What is your practice worth?

All ObGyns believe their practice is worth far more than any young ObGyn or hospital is willing to pay for it. After all, you have spent a medical lifetime creating, building, and nurturing your practice. You have cared for several thousand patients, who have been loyal and may want to stay with the practice under its new ObGyn. So, how does a retiring physician put a value on his or her practice and then “cast the net” to the marketplace? How do you find a buyer who will pay the asking price and then help the practice make the transition from seller to buyer and continue to serve their patients?

The buyer’s perspective on value. In a pure sense, the value of any asset is what a potential buyer is willing to pay. From a value standpoint, the price that potential buyers are willing to pay varies by the specifics of the situation, regardless of what a valuation or practice appraisal might indicate.

For example, once your plan to retire becomes known, why would a young ObGyn agree to pay X dollars for all your medical records? After all, the potential buyer knows that your existing patients and your referral base will need to seek care from another ObGyn after you leave, and they will likely stay with the practice if they feel they will be treated well by the new clinician.

A hospital may take a similar tack but more often will be willing to pay fair market value for your practice. Hospitals, however, cannot legally pay more than fair market value as determined by an independent appraiser.

Related article:
Four pillars of a successful practice: 1. Keep your current patients happy

Valuation methods

The valuation of any business generally is approached in terms of market, assets, and income.

The market approach usually is taken only with regard to office real estate. Given the lack of reliable and comparable sales information, this approach is seldom used in the valuation of medical practices. If you own your office real estate, a real estate appraiser will establish its fair market value.

In the assets approach, the individual assets of a medical practice are valued on the basis of their current market values. These assets are either tangible or intangible.

Tangible assets can be seen and touched. Furniture, equipment, and office real estate are examples.

The fair market value of used furniture and equipment is most often determined by replacement cost. The value of these items is limited. Usually it starts at 50% of the cost of buying new furniture or equipment of the same utility. From there, the value is lowered on the basis of the age and condition of the items.

Often, the market value of major ObGyn office equipment, such as a DXA (dual-energy x-ray absorptiometry) scanner, is based on similar items for sale or recently sold in the used secondary equipment market.

Tangible assets may include accounts receivable (A/R). A/R represents uncollected payment for work performed. Most buyers want to avoid paying for A/R and assuming the risk of collections. Generally, you should expect to retain your A/R and pay a small or nominal fee to have the buyer handle the collections after you have retired.

Intangible assets are not physical. Examples include the physician’s name, phone number, reputation, referral base, trained staff, and medical records—in other words, what gets patients to keep coming back. Most physicians value these goodwill or “blue-sky” assets highly. Today, unfortunately, most sellers are unable to reap any financial benefit from their intangible assets.

The income approach is based on the premise that the value of any business is in the income it generates for its owner. In simple terms, value in the income approach is a multiple of the cash the business generates after expenses.

Read important keys to transitioning the practice

Transitioning the practice: Role of the seller and the buyer

First and very important is the contract agreement regarding the overlap period, when both the exiting ObGyn and the new ObGyn are at the practice. We suggest making the overlap a minimum of 6 months and a maximum of 1 year. During this period, the exiting physician can introduce the incoming physician to the patients. A face-to-face introduction can amount to an endorsement, which can ease a patient’s mind and help her decide to take on the new ObGyn and philosophy rather than search elsewhere for obstetric and gynecologic care. The new ObGyn also can use the overlap period to become familiar and comfortable with the staff and learn the process for physician and staff management of case flow, from scheduling and examination to insurance and patient follow-up.

We suggest that the exiting ObGyn send a farewell/welcome letter to patients and referring physicians. The letter should state the exiting ObGyn’s intention to leave (or retire from) the practice and should introduce the ObGyn who will be taking over.

The exiting ObGyn should also take the new ObGyn to meet the physicians who have been providing referrals over the years. We suggest visiting each referring physician’s office to make the introduction. Another good way to introduce a new ObGyn to referring physicians and other professionals—endocrinologists, cardiologists, nurses, pharmaceutical representatives—is to host an open house at your practice. Invite the staff members of the referring physicians as well, since they can be invaluable in making referrals.

We recommend that the exiting ObGyn spend the money to update all the practice’s stationery, brochures, and print materials and ensure they look professional. Note that it is not acceptable to place the new ObGyn’s name under the exiting ObGyn’s name. If the practice has a website, introduce the new physician there and make any necessary updates regarding office hours and accepted insurance plans.

If the exiting ObGyn’s practice lacks a robust Internet and social media presence, the new ObGyn should establish one. We recommend setting up an interactive website that patients can use to make appointments and pay bills. The website should have an email component that can be used to ask questions, raise concerns, and get answers. We also recommend opening Facebook, YouTube, and Twitter accounts for the practice and being active on these social media.

In our experience, smoothly transitioning practices can achieve patient retention rates as high as 90% to 95%. For practices without a plan, however, these rates may be as low as 50%, or worse. Therefore, work out a plan in advance, and include the steps described here, so that on arrival the new ObGyn can hit the ground running.

Acquiring a successful medical practice is doable and offers many advantages, such as autonomy and the ability to make business decisions affecting the practice. Despite all the changes happening in health care, we still think this is the best way to go.

Related article:
Four pillars of a successful practice: 4. Motivate your staff

Bottom line

Selling an ObGyn practice can be a daunting process. However, deciding to sell your practice, performing the valuation, and ensuring a smooth transition are part and parcel of making the transfer a success, equitable for both the buyer and the seller.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

For ObGyns, 2 intensely stressful career milestones are the day you start your practice and the day you decide to put it up for sale.

One of us, Dr. Baum, started a practice in 1976. At that time, many clinicians seemed to work right up until the day they died—in mid-examination or with scalpel in hand! Today, clinicians seriously contemplate leaving an active practice at age 55, 60, or, more traditionally, 65.

ObGyns in group practice, even those with only 1 or 2 partners, presumably have in place a well-thought-out and properly drafted contract with buyout and phase-down provisions. For members of a group practice, it is imperative to critically review and discuss contractual arrangements periodically and decide if they make sense as much now as they did at the start. ObGyns who continually revisit their contracts probably have an exit strategy that is fairly self-executing and effective and that will provide the seller with a seamless transition to retirement.

A solo ObGyn who is selling a practice has 3 basic options: find a successor physician, sell to a hospital or to a larger group, or close the practice.

Related article:
ObGyns’ choice of practice environment is a big deal

Preparing your practice for sale

Regardless of who will take over your practice, you need to prepare for its transition.

The most important aspect of selling your practice is knowing its finances and ensuring that they are in order. Any serious buyer will ask to examine your books, see how you are running the business, and assess its vitality and potential growth. Simply, a buyer will want to know where your revenue comes from and where it goes.

Your practice will be attractive to a buyer if it shows a stable or growing revenue base, an attractive payer mix, reasonable overhead, and personal income that is steady if not increasing. If your earning capacity is low or declining, you will need to explain why.

Timing is key

We strongly recommend beginning the process 3 to 5 years before your intended exit.

By starting early, up to 5 years in advance, you can maximize the likelihood that your practice will retain all or most of its value. Moreover, you can use the long lead time to thoroughly explore all available options and find a committed buyer.

Selling a practice can be a complicated affair, and many ObGyns do not have the requisite skills. So much of the success in selling depends on the specifics of the practice, the physician, and the market (the hospital and physician environment).

Identifying potential buyers

Other ObGyns. Recruiting an ObGyn to take over your practice seems to be the best option but can prove very difficult in today’s environment. Many younger clinicians are either joining large groups or becoming hospital employees.

Other physician groups. While working your way down your list of potential buyers, you should also be quietly, subtly, and tactfully assessing other practices, even your competitors, to see if any are candidates for merging with and/or acquiring yours and all your charts, records, and referring physicians.

Hospitals. In today’s health care environment, in which more than half of clinicians are becoming hospital employees, selling to your associated hospital may be a viable option.

Your practice is probably contributing millions of dollars in income to that hospital each year, and of course the hospital would like to maintain this revenue stream. You should consider talking to the hospital’s CEO or medical director.

Hospitals also know that, if you leave and the market cannot absorb the resulting increase in demand for care, patients may go elsewhere, to a competing hospital or outside the community. Rather than lose your market share, a hospital may consider the obvious solution: recruit a replacement ObGyn for your practice.

Your goal here is to negotiate an agreement in which your hospital will recruit a replacement ObGyn, provide financial support, and transition your practice to that ObGyn over a specified period.

The hospital could acquire your practice and either employ you during the transition or provide recruiting support and an income guarantee to help your practice pay the new physician’s salary. Whether to sell or remain independent is often driven by the needs and desires of the recruit. As the vast majority of clinicians coming out of training are seeking employment, in most cases the agreement will require a sale.

Selling to a hospital a few years before your retirement can be a plus. You might find employment a welcome respite from the daunting responsibility of managing your own practice. Life can become much less stressful as you introduce and transition your patients to the new ObGyn. You will be working less, taking fewer calls, and maintaining or even increasing your income, all without the burden of managing the practice.

Read about determining your practice’s value

Putting a monetary value on your practice

After deciding to sell your practice, you need to determine its value. Buying a practice may be the largest financial transaction a young ObGyn will ever make. For a retiring physician, valuation of a practice may reflect a career’s worth of “sweat equity.”

What is your practice worth?

All ObGyns believe their practice is worth far more than any young ObGyn or hospital is willing to pay for it. After all, you have spent a medical lifetime creating, building, and nurturing your practice. You have cared for several thousand patients, who have been loyal and may want to stay with the practice under its new ObGyn. So, how does a retiring physician put a value on his or her practice and then “cast the net” to the marketplace? How do you find a buyer who will pay the asking price and then help the practice make the transition from seller to buyer and continue to serve their patients?

The buyer’s perspective on value. In a pure sense, the value of any asset is what a potential buyer is willing to pay. From a value standpoint, the price that potential buyers are willing to pay varies by the specifics of the situation, regardless of what a valuation or practice appraisal might indicate.

For example, once your plan to retire becomes known, why would a young ObGyn agree to pay X dollars for all your medical records? After all, the potential buyer knows that your existing patients and your referral base will need to seek care from another ObGyn after you leave, and they will likely stay with the practice if they feel they will be treated well by the new clinician.

A hospital may take a similar tack but more often will be willing to pay fair market value for your practice. Hospitals, however, cannot legally pay more than fair market value as determined by an independent appraiser.

Related article:
Four pillars of a successful practice: 1. Keep your current patients happy

Valuation methods

The valuation of any business generally is approached in terms of market, assets, and income.

The market approach usually is taken only with regard to office real estate. Given the lack of reliable and comparable sales information, this approach is seldom used in the valuation of medical practices. If you own your office real estate, a real estate appraiser will establish its fair market value.

In the assets approach, the individual assets of a medical practice are valued on the basis of their current market values. These assets are either tangible or intangible.

Tangible assets can be seen and touched. Furniture, equipment, and office real estate are examples.

The fair market value of used furniture and equipment is most often determined by replacement cost. The value of these items is limited. Usually it starts at 50% of the cost of buying new furniture or equipment of the same utility. From there, the value is lowered on the basis of the age and condition of the items.

Often, the market value of major ObGyn office equipment, such as a DXA (dual-energy x-ray absorptiometry) scanner, is based on similar items for sale or recently sold in the used secondary equipment market.

Tangible assets may include accounts receivable (A/R). A/R represents uncollected payment for work performed. Most buyers want to avoid paying for A/R and assuming the risk of collections. Generally, you should expect to retain your A/R and pay a small or nominal fee to have the buyer handle the collections after you have retired.

Intangible assets are not physical. Examples include the physician’s name, phone number, reputation, referral base, trained staff, and medical records—in other words, what gets patients to keep coming back. Most physicians value these goodwill or “blue-sky” assets highly. Today, unfortunately, most sellers are unable to reap any financial benefit from their intangible assets.

The income approach is based on the premise that the value of any business is in the income it generates for its owner. In simple terms, value in the income approach is a multiple of the cash the business generates after expenses.

Read important keys to transitioning the practice

Transitioning the practice: Role of the seller and the buyer

First and very important is the contract agreement regarding the overlap period, when both the exiting ObGyn and the new ObGyn are at the practice. We suggest making the overlap a minimum of 6 months and a maximum of 1 year. During this period, the exiting physician can introduce the incoming physician to the patients. A face-to-face introduction can amount to an endorsement, which can ease a patient’s mind and help her decide to take on the new ObGyn and philosophy rather than search elsewhere for obstetric and gynecologic care. The new ObGyn also can use the overlap period to become familiar and comfortable with the staff and learn the process for physician and staff management of case flow, from scheduling and examination to insurance and patient follow-up.

We suggest that the exiting ObGyn send a farewell/welcome letter to patients and referring physicians. The letter should state the exiting ObGyn’s intention to leave (or retire from) the practice and should introduce the ObGyn who will be taking over.

The exiting ObGyn should also take the new ObGyn to meet the physicians who have been providing referrals over the years. We suggest visiting each referring physician’s office to make the introduction. Another good way to introduce a new ObGyn to referring physicians and other professionals—endocrinologists, cardiologists, nurses, pharmaceutical representatives—is to host an open house at your practice. Invite the staff members of the referring physicians as well, since they can be invaluable in making referrals.

We recommend that the exiting ObGyn spend the money to update all the practice’s stationery, brochures, and print materials and ensure they look professional. Note that it is not acceptable to place the new ObGyn’s name under the exiting ObGyn’s name. If the practice has a website, introduce the new physician there and make any necessary updates regarding office hours and accepted insurance plans.

If the exiting ObGyn’s practice lacks a robust Internet and social media presence, the new ObGyn should establish one. We recommend setting up an interactive website that patients can use to make appointments and pay bills. The website should have an email component that can be used to ask questions, raise concerns, and get answers. We also recommend opening Facebook, YouTube, and Twitter accounts for the practice and being active on these social media.

In our experience, smoothly transitioning practices can achieve patient retention rates as high as 90% to 95%. For practices without a plan, however, these rates may be as low as 50%, or worse. Therefore, work out a plan in advance, and include the steps described here, so that on arrival the new ObGyn can hit the ground running.

Acquiring a successful medical practice is doable and offers many advantages, such as autonomy and the ability to make business decisions affecting the practice. Despite all the changes happening in health care, we still think this is the best way to go.

Related article:
Four pillars of a successful practice: 4. Motivate your staff

Bottom line

Selling an ObGyn practice can be a daunting process. However, deciding to sell your practice, performing the valuation, and ensuring a smooth transition are part and parcel of making the transfer a success, equitable for both the buyer and the seller.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Patients with chronic, severe mental illness live much shorter lives than the general population. The 25-year loss in life expectancy for people with chronic mental illness has been attributed to higher rates of cardiovascular disease driven by increased smoking, obesity, poverty, and poor nutrition.¹ These individuals also face the added burden of struggling with a psychiatric condition that often interferes with their ability to make optimal preventative health decisions, including staying up to date on vaccinations.² A recent review from Toronto, Canada, found that the influenza vaccination rates among homeless adults with mental illness—a population at high risk of respiratory illness—was only 6.7% compared with 31.1% for the general population of Ontario.³

Mental health professionals may serve as the only contacts to offer medical care to this vulnerable population, leading some psychiatric leaders to advocate that psychiatrists be considered primary care providers within accountable care organizations. Because most vaccines are easily available, mental health professionals should know about key immunizations to guide their patients accordingly.

In the United States, approximately 45,000 adults die annually from vaccine-preventable diseases, the majority from influenza.⁴ When combined with the most recent Adult Immunization Schedule and general recommendations adapted from the CDC,^5,6 the mnemonic ARM SHOT allows for a quick assessment of risk factors to guide administration and education about most vaccinations (Table 1). ARM SHOT involves assessing the following components of an individual’s health status and living arrangements to determine one’s risk of contracting communicable diseases:

• Age
• Risk of exposure
• Medical conditions (comorbidities)
• Substance use history
• HIV status or other immunocompromised states
• Occupancy, or living arrangements
• Tobacco use.

We recommend keeping a copy of the Adult Immunization Schedule (age ≥19) and/or the immunization schedule for children and adolescents (age ≤18) close for quick reference. Here, we provide a case and then explore how each component of the ARM SHOT mnemonic applies in decision-making.

Case Evaluating risk, assess needs

Ms. W, age 24, has bipolar I disorder, most recently manic with psychotic features. She presents for follow-up in clinic after a 5-day hospitalization for mania and comorbid alcohol use disorder. Her medical comorbidities include asthma and active tobacco use. She is taking lurasidone, 20 mg/d, and lithium, 900 mg/d. Her case manager is working to place Ms. W in a residential substance use disorder treatment program. Ms. W is on a waiting list to establish care with a primary care physician and has a history of poor engagement with medical services in general; prior attempts to place her with a primary care physician failed.

In advance of Ms. W’s transfer to a residential treatment facility, you have been asked to place a Mantoux screening test for tuberculosis (purified protein derivative), which raises the important question about her susceptibility to infectious diseases in general. To protect Ms. W from preventable diseases for which vaccines are available, you review the ARM SHOT mnemonic to broadly assess her candidacy for vaccinations.

Age

Age may be the most important determinant of a patient’s need for vaccination (Table 2). The CDC immunization schedules account for age-specific risks for diseases, complications, and responses to vaccination (Figure 1).⁶

Influenza vaccination. Adults can have an intramuscular or intradermal inactivated influenza vaccination yearly in the fall or winter, unless they have an allergy to a vaccine component such as egg protein. Those with such an allergy can receive a recombinant influenza vaccine. Until the 2016 to 2017 flu season, an intranasal mist of live, attenuated influenza vaccine was available to healthy, non-pregnant women, ages 2 to 49, without high-risk medical conditions. However, the CDC dropped its recommendation for this vaccine because data showed it did not effectively prevent the flu.⁷ Individuals age ≥65 can receive either the standard- or high-dose inactivated influenza vaccination. The latter contains 4 times the amount of antigen with the intention of triggering a stronger immune response in older adults.

Human papillomavirus (HPV) immunization. The ACIP recommendation⁹ has been for children to receive routine vaccination for the 4 major strains of HPV—strains 6, 11, 16, and 18—starting at ages 11 to 12 to confer protection from HPV-associated diseases, such as genital warts, oropharyngeal cancer, and anal cancer; cancers of the cervix, vulva, and vagina in women; and penile cancer in men. Ideally, the vaccines are administered prior to HPV exposure from sexual contact. The quadrivalent HPV vaccine is safe and is administered as a 3-dose series, with the second and third doses given 2 and 6 months, respectively, after the initial dose. Adolescent girls also have the option of a bivalent HPV vaccine.

In 2016, the FDA approved a 9-valent HPV vaccine, a simpler 2-dose schedule for children ages 9 to 14 (2 doses at least 6 months apart). Leading cancer centers have endorsed this vaccine based on strong comparative data with the 3-dose regimen.¹⁰ For those not previously vaccinated, the HPV vaccine is available for women ages 13 to 26 and for men ages 13 to 21 (although men ages 22 to 26 can receive the vaccine, and it is recommended for men who have sex with men [MSM]). Women do not require Papanicolaou, serum pregnancy, HPV DNA, or HPV antibody tests prior to vaccination. If a woman becomes pregnant, remaining doses of the vaccine should be postponed until after delivery. Women still need to follow recommendations for cervical cancer screening because the HPV vaccine does not cover all genital strains of the virus. For sexually active individuals who might have HPV or genital warts, immunization has no clinical effect except to prevent other HPV strains.

Measles, mumps, and rubella (MMR) vaccine. All adults should receive, at minimum, 1 dose of MMR vaccination unless serological immunity can be verified or if contraindicated. Two doses of the vaccine are recommended for students attending post-high school institutions, health care personnel, and international travelers because they are at higher risk for exposure and transmission of measles and mumps. Individuals born before 1957 are considered immune to measles and mumps. A measles outbreak from December 2014 to February 2015¹¹ highlighted the importance of maintaining one’s immunity status for MMR.

Case continued

Based on Ms. W’s age, she should be offered vaccinations for influenza and opportunities to receive vaccinations for HPV, Tdap (the primary series, a Tdap or Td booster), and MMR, if appropriate and not completed previously.

Risk of exposure

Certain behaviors will increase the risk of exposure to and transmission of diseases communicable by blood and other bodily fluids (Table 3). These behaviors include needle injections (eg, during use of illicit drugs) and sexual activity with multiple partners, including MSM or promiscuity/impulsivity during a manic episode. A common consequence of risky behaviors is comorbid infection of HIV and viral hepatitis for those with substance use disorder or those who engage in high-risk sexual practices.^12,13

Hepatitis B virus (HBV) immunization. Vaccination is one of the most effective ways to prevent HBV infection, which is why it is offered to all health care workers. HBV immunization is a 3-dose series in which the second and third doses are given 1 and 6 months after the initial doses, respectively. In addition to certain medical risk factors or conditions that indicate HBV vaccination, people should be offered the vaccine if they are in a higher risk occupation, travel, are of Asian or Pacific Islander ethnicity from an endemic area, or have any present or suspected sexually transmitted diseases.

Hepatitis A virus (HAV) vaccination. HAV is transmitted via fecal–oral routes, often from contaminated water or food, or through household or sexual contact with an infected person. Individuals should receive the HAV vaccine if they use illicit drugs by any route of administration, work with primates infected with HAV, travel to countries with unknown or high rates of HAV, or have chronic liver disease (ie, hepatitis, alcohol use disorder, or non-alcoholic fatty liver disease) or clotting deficiencies. The CDC Health Information for International Travel, commonly called the “Yellow Book,” publishes vaccination recommendations for those who plan travel to specific countries.¹⁴

Case continued

Ms. W’s history of mania (if such episodes included increased sexual activity) and substance use would make her a candidate for the HBV and HAV vaccinations and could also strengthen our previous recommendation that she receive the HPV vaccination.

Medical conditions

Patients with certain medical conditions may have difficulty fighting infections or become more susceptible to morbidity and mortality from coinfection with vaccine-preventable illnesses. Secondary effects of psychotropic medications that may carry implications for vaccine recommendations (eg, risk of agranulocytosis and impaired cell-medicated immunity with mirtazapine and clozapine or renal impairment from lithium use) are of particular concern in psychiatric patients.²

To help care for these patients, the CDC has developed a “medical conditions” schedule (Figure 2). This schedule makes vaccination recommendations for those with a weakened immune system, including patients with HIV, chronic obstructive pulmonary disease (COPD), diabetes, hepatitis, asplenia, end-stage renal disease, cardiac disease, and pregnancy.

Case continued

Because of Ms. W’s asthma, the CDC schedule recommends ensuring she is up to date on her influenza, pneumococcal, and Tdap vaccinations.

Substance use

Patients with combined psychiatric and substance use disorders (“dual diagnosis”) have lower rates of receiving preventive care than patients with either condition alone.¹⁵ Substance use can be behaviorally disinhibiting, leading to increased risk of exposures from sexual contact or other risky activities. The use of illicit substances can provide a nidus for infection depending on the route of administration and can result in negative effects on organ systems, compromising one’s ability to ward off infection.

Patients who use any illicit drugs, regardless of the method of delivery, should be recommended for HAV vaccination. For those with alcohol use disorder and/or chronic liver disease, and/or seeking treatment for substance use, hepatitis B screening and vaccination is recommended.

Case continued

From a substance use perspective, discussion of vaccination status for both hepatitis A and B would be important for Ms. W.

HIV or immunocompromised

Persons with severe mental illness have high rates of HIV, with almost 8 times the risk of exposure, compared with the general population due to myriad reasons, including greater rates of substance abuse, higher risk sexual behavior, and lack of awareness of HIV transmission.^12,13 Patients with mental illness are also at risk of leukopenia and agranulocytosis from certain drugs used to treat their conditions, such as clozapine.

Pregnancy is a challenge for women with mental illness because of the pharmacologic risk and immune-system compromise to the mother and baby. A pregnant woman who has HIV with a CD4 count <200, or has a weakened immune system from an organ transplant or a similar condition, is a candidate for certain vaccines based on the Adult Immunization Schedule (Figure 2). However, these patients should avoid live vaccines, such as the intranasal mist of live influenza, MMR, VZV, and varicella, to avoid illness from these inoculations.
 

Case continued

Ms. W should undergo testing for pregnancy and HIV (and preferably other sexually transmitted infections per general preventive health guidelines) before receiving any live vaccinations.

Occupancy

Aside from direct transmission of bodily fluids, infectious diseases also can spread through droplets/secretions from the throat and respiratory tract. Close quarters or lengthy contact enhances communicability by droplets, and therefore people who reside in a communal living space (eg, individuals in substance use treatment facilities or those who reside in a nursing home) are most susceptible.

The bacterial disease Neisseria meningitidis (meningococcus) can spread through droplets and can cause pneumonia, bacteremia, and meningitis. Vaccination is indicated, and in some states is mandated, for college students who live in residence halls and missed routine vaccination by age 16. Meningococcus conjugate vaccine is administered in 2 doses; each dose may be given at least 2 months apart for those with HIV, asplenia, or persistent complement-related disorders. A single dose may be recommended for travelers to areas where meningococcal disease is hyperendemic or epidemic, military recruits, or microbiologists. For those age ≥55 and older, meningococcal polysaccharide vaccine is recommended over meningococcal conjugate vaccine.

Influenza, MMR, diphtheria, pertussis, and pneumococcus also spread through droplet contact.

Case continued

If Ms. W had not previously received the meningococcus vaccine as part of adolescent immunizations, she could benefit from this vaccine because she plans to enter a residential substance use disorder treatment program.

Tobacco use

Patients with psychiatric illness are twice as likely to smoke compared with the general population.¹⁶ Adult smokers, especially those with chronic lung disease, are at higher risk for influenza and pneumococcal-related illness; they should be vaccinated against these illnesses regardless of age (as discussed in the “Age” section).

Case continued

Because she smokes, Ms. W should receive counseling on vaccinations, such as influenza and pneumonia, to lessen her risk of respiratory illnesses and downstream sepsis.

Conclusion

Ms. W’s case represents an unfortunately all-too-common scenario where her multifaceted biopsychosocial circumstances place her at high risk for vaccine-preventable conditions. Her weight is recorded and laboratory work ordered to evaluate her pregnancy status, blood counts, lipids, complete metabolic panel, lithium level, and HIV status. Fortunately, she had received her series of MMR, meningococcal, and Tdap vaccinations when she was younger. Influenza, HPV, HAV, HBV, and pneumococcal vaccinations were all recommended to her, all of which can be given on the same day (HAV and HBV often are available as a combined vaccine). Ms. W receives a renewal of her psychiatric medications and counseling on healthy living habits (eg, diet and exercise, quitting tobacco and alcohol use, and safe sex practices) and the importance of immunizations.

Vaccination is 1 of the 10 great public health achievements of the 20th century when one considers how immunization of vaccine-preventable diseases has reduced morbidity, mortality, and health-associated costs.¹⁷ As mental health professionals, we can help pass on the direct and indirect benefits of immunizations to an often underserved and undertreated population to help improve their health outcomes and quality of life.

Patients with chronic, severe mental illness live much shorter lives than the general population. The 25-year loss in life expectancy for people with chronic mental illness has been attributed to higher rates of cardiovascular disease driven by increased smoking, obesity, poverty, and poor nutrition.¹ These individuals also face the added burden of struggling with a psychiatric condition that often interferes with their ability to make optimal preventative health decisions, including staying up to date on vaccinations.² A recent review from Toronto, Canada, found that the influenza vaccination rates among homeless adults with mental illness—a population at high risk of respiratory illness—was only 6.7% compared with 31.1% for the general population of Ontario.³

Mental health professionals may serve as the only contacts to offer medical care to this vulnerable population, leading some psychiatric leaders to advocate that psychiatrists be considered primary care providers within accountable care organizations. Because most vaccines are easily available, mental health professionals should know about key immunizations to guide their patients accordingly.

In the United States, approximately 45,000 adults die annually from vaccine-preventable diseases, the majority from influenza.⁴ When combined with the most recent Adult Immunization Schedule and general recommendations adapted from the CDC,^5,6 the mnemonic ARM SHOT allows for a quick assessment of risk factors to guide administration and education about most vaccinations (Table 1). ARM SHOT involves assessing the following components of an individual’s health status and living arrangements to determine one’s risk of contracting communicable diseases:

• Age
• Risk of exposure
• Medical conditions (comorbidities)
• Substance use history
• HIV status or other immunocompromised states
• Occupancy, or living arrangements
• Tobacco use.

We recommend keeping a copy of the Adult Immunization Schedule (age ≥19) and/or the immunization schedule for children and adolescents (age ≤18) close for quick reference. Here, we provide a case and then explore how each component of the ARM SHOT mnemonic applies in decision-making.

Case Evaluating risk, assess needs

Ms. W, age 24, has bipolar I disorder, most recently manic with psychotic features. She presents for follow-up in clinic after a 5-day hospitalization for mania and comorbid alcohol use disorder. Her medical comorbidities include asthma and active tobacco use. She is taking lurasidone, 20 mg/d, and lithium, 900 mg/d. Her case manager is working to place Ms. W in a residential substance use disorder treatment program. Ms. W is on a waiting list to establish care with a primary care physician and has a history of poor engagement with medical services in general; prior attempts to place her with a primary care physician failed.

In advance of Ms. W’s transfer to a residential treatment facility, you have been asked to place a Mantoux screening test for tuberculosis (purified protein derivative), which raises the important question about her susceptibility to infectious diseases in general. To protect Ms. W from preventable diseases for which vaccines are available, you review the ARM SHOT mnemonic to broadly assess her candidacy for vaccinations.

Age

Age may be the most important determinant of a patient’s need for vaccination (Table 2). The CDC immunization schedules account for age-specific risks for diseases, complications, and responses to vaccination (Figure 1).⁶

Influenza vaccination. Adults can have an intramuscular or intradermal inactivated influenza vaccination yearly in the fall or winter, unless they have an allergy to a vaccine component such as egg protein. Those with such an allergy can receive a recombinant influenza vaccine. Until the 2016 to 2017 flu season, an intranasal mist of live, attenuated influenza vaccine was available to healthy, non-pregnant women, ages 2 to 49, without high-risk medical conditions. However, the CDC dropped its recommendation for this vaccine because data showed it did not effectively prevent the flu.⁷ Individuals age ≥65 can receive either the standard- or high-dose inactivated influenza vaccination. The latter contains 4 times the amount of antigen with the intention of triggering a stronger immune response in older adults.

Human papillomavirus (HPV) immunization. The ACIP recommendation⁹ has been for children to receive routine vaccination for the 4 major strains of HPV—strains 6, 11, 16, and 18—starting at ages 11 to 12 to confer protection from HPV-associated diseases, such as genital warts, oropharyngeal cancer, and anal cancer; cancers of the cervix, vulva, and vagina in women; and penile cancer in men. Ideally, the vaccines are administered prior to HPV exposure from sexual contact. The quadrivalent HPV vaccine is safe and is administered as a 3-dose series, with the second and third doses given 2 and 6 months, respectively, after the initial dose. Adolescent girls also have the option of a bivalent HPV vaccine.

In 2016, the FDA approved a 9-valent HPV vaccine, a simpler 2-dose schedule for children ages 9 to 14 (2 doses at least 6 months apart). Leading cancer centers have endorsed this vaccine based on strong comparative data with the 3-dose regimen.¹⁰ For those not previously vaccinated, the HPV vaccine is available for women ages 13 to 26 and for men ages 13 to 21 (although men ages 22 to 26 can receive the vaccine, and it is recommended for men who have sex with men [MSM]). Women do not require Papanicolaou, serum pregnancy, HPV DNA, or HPV antibody tests prior to vaccination. If a woman becomes pregnant, remaining doses of the vaccine should be postponed until after delivery. Women still need to follow recommendations for cervical cancer screening because the HPV vaccine does not cover all genital strains of the virus. For sexually active individuals who might have HPV or genital warts, immunization has no clinical effect except to prevent other HPV strains.

Measles, mumps, and rubella (MMR) vaccine. All adults should receive, at minimum, 1 dose of MMR vaccination unless serological immunity can be verified or if contraindicated. Two doses of the vaccine are recommended for students attending post-high school institutions, health care personnel, and international travelers because they are at higher risk for exposure and transmission of measles and mumps. Individuals born before 1957 are considered immune to measles and mumps. A measles outbreak from December 2014 to February 2015¹¹ highlighted the importance of maintaining one’s immunity status for MMR.

Case continued

Based on Ms. W’s age, she should be offered vaccinations for influenza and opportunities to receive vaccinations for HPV, Tdap (the primary series, a Tdap or Td booster), and MMR, if appropriate and not completed previously.

Risk of exposure

Certain behaviors will increase the risk of exposure to and transmission of diseases communicable by blood and other bodily fluids (Table 3). These behaviors include needle injections (eg, during use of illicit drugs) and sexual activity with multiple partners, including MSM or promiscuity/impulsivity during a manic episode. A common consequence of risky behaviors is comorbid infection of HIV and viral hepatitis for those with substance use disorder or those who engage in high-risk sexual practices.^12,13

Hepatitis B virus (HBV) immunization. Vaccination is one of the most effective ways to prevent HBV infection, which is why it is offered to all health care workers. HBV immunization is a 3-dose series in which the second and third doses are given 1 and 6 months after the initial doses, respectively. In addition to certain medical risk factors or conditions that indicate HBV vaccination, people should be offered the vaccine if they are in a higher risk occupation, travel, are of Asian or Pacific Islander ethnicity from an endemic area, or have any present or suspected sexually transmitted diseases.

Hepatitis A virus (HAV) vaccination. HAV is transmitted via fecal–oral routes, often from contaminated water or food, or through household or sexual contact with an infected person. Individuals should receive the HAV vaccine if they use illicit drugs by any route of administration, work with primates infected with HAV, travel to countries with unknown or high rates of HAV, or have chronic liver disease (ie, hepatitis, alcohol use disorder, or non-alcoholic fatty liver disease) or clotting deficiencies. The CDC Health Information for International Travel, commonly called the “Yellow Book,” publishes vaccination recommendations for those who plan travel to specific countries.¹⁴

Case continued

Ms. W’s history of mania (if such episodes included increased sexual activity) and substance use would make her a candidate for the HBV and HAV vaccinations and could also strengthen our previous recommendation that she receive the HPV vaccination.

Medical conditions

Patients with certain medical conditions may have difficulty fighting infections or become more susceptible to morbidity and mortality from coinfection with vaccine-preventable illnesses. Secondary effects of psychotropic medications that may carry implications for vaccine recommendations (eg, risk of agranulocytosis and impaired cell-medicated immunity with mirtazapine and clozapine or renal impairment from lithium use) are of particular concern in psychiatric patients.²

To help care for these patients, the CDC has developed a “medical conditions” schedule (Figure 2). This schedule makes vaccination recommendations for those with a weakened immune system, including patients with HIV, chronic obstructive pulmonary disease (COPD), diabetes, hepatitis, asplenia, end-stage renal disease, cardiac disease, and pregnancy.

Case continued

Because of Ms. W’s asthma, the CDC schedule recommends ensuring she is up to date on her influenza, pneumococcal, and Tdap vaccinations.

Substance use

Patients with combined psychiatric and substance use disorders (“dual diagnosis”) have lower rates of receiving preventive care than patients with either condition alone.¹⁵ Substance use can be behaviorally disinhibiting, leading to increased risk of exposures from sexual contact or other risky activities. The use of illicit substances can provide a nidus for infection depending on the route of administration and can result in negative effects on organ systems, compromising one’s ability to ward off infection.

Patients who use any illicit drugs, regardless of the method of delivery, should be recommended for HAV vaccination. For those with alcohol use disorder and/or chronic liver disease, and/or seeking treatment for substance use, hepatitis B screening and vaccination is recommended.

Case continued

From a substance use perspective, discussion of vaccination status for both hepatitis A and B would be important for Ms. W.

HIV or immunocompromised

Persons with severe mental illness have high rates of HIV, with almost 8 times the risk of exposure, compared with the general population due to myriad reasons, including greater rates of substance abuse, higher risk sexual behavior, and lack of awareness of HIV transmission.^12,13 Patients with mental illness are also at risk of leukopenia and agranulocytosis from certain drugs used to treat their conditions, such as clozapine.

Pregnancy is a challenge for women with mental illness because of the pharmacologic risk and immune-system compromise to the mother and baby. A pregnant woman who has HIV with a CD4 count <200, or has a weakened immune system from an organ transplant or a similar condition, is a candidate for certain vaccines based on the Adult Immunization Schedule (Figure 2). However, these patients should avoid live vaccines, such as the intranasal mist of live influenza, MMR, VZV, and varicella, to avoid illness from these inoculations.
 

Case continued

Ms. W should undergo testing for pregnancy and HIV (and preferably other sexually transmitted infections per general preventive health guidelines) before receiving any live vaccinations.

Occupancy

Aside from direct transmission of bodily fluids, infectious diseases also can spread through droplets/secretions from the throat and respiratory tract. Close quarters or lengthy contact enhances communicability by droplets, and therefore people who reside in a communal living space (eg, individuals in substance use treatment facilities or those who reside in a nursing home) are most susceptible.

The bacterial disease Neisseria meningitidis (meningococcus) can spread through droplets and can cause pneumonia, bacteremia, and meningitis. Vaccination is indicated, and in some states is mandated, for college students who live in residence halls and missed routine vaccination by age 16. Meningococcus conjugate vaccine is administered in 2 doses; each dose may be given at least 2 months apart for those with HIV, asplenia, or persistent complement-related disorders. A single dose may be recommended for travelers to areas where meningococcal disease is hyperendemic or epidemic, military recruits, or microbiologists. For those age ≥55 and older, meningococcal polysaccharide vaccine is recommended over meningococcal conjugate vaccine.

Influenza, MMR, diphtheria, pertussis, and pneumococcus also spread through droplet contact.

Case continued

If Ms. W had not previously received the meningococcus vaccine as part of adolescent immunizations, she could benefit from this vaccine because she plans to enter a residential substance use disorder treatment program.

Tobacco use

Patients with psychiatric illness are twice as likely to smoke compared with the general population.¹⁶ Adult smokers, especially those with chronic lung disease, are at higher risk for influenza and pneumococcal-related illness; they should be vaccinated against these illnesses regardless of age (as discussed in the “Age” section).

Case continued

Because she smokes, Ms. W should receive counseling on vaccinations, such as influenza and pneumonia, to lessen her risk of respiratory illnesses and downstream sepsis.

Conclusion

Ms. W’s case represents an unfortunately all-too-common scenario where her multifaceted biopsychosocial circumstances place her at high risk for vaccine-preventable conditions. Her weight is recorded and laboratory work ordered to evaluate her pregnancy status, blood counts, lipids, complete metabolic panel, lithium level, and HIV status. Fortunately, she had received her series of MMR, meningococcal, and Tdap vaccinations when she was younger. Influenza, HPV, HAV, HBV, and pneumococcal vaccinations were all recommended to her, all of which can be given on the same day (HAV and HBV often are available as a combined vaccine). Ms. W receives a renewal of her psychiatric medications and counseling on healthy living habits (eg, diet and exercise, quitting tobacco and alcohol use, and safe sex practices) and the importance of immunizations.

Vaccination is 1 of the 10 great public health achievements of the 20th century when one considers how immunization of vaccine-preventable diseases has reduced morbidity, mortality, and health-associated costs.¹⁷ As mental health professionals, we can help pass on the direct and indirect benefits of immunizations to an often underserved and undertreated population to help improve their health outcomes and quality of life.

Patients with chronic, severe mental illness live much shorter lives than the general population. The 25-year loss in life expectancy for people with chronic mental illness has been attributed to higher rates of cardiovascular disease driven by increased smoking, obesity, poverty, and poor nutrition.¹ These individuals also face the added burden of struggling with a psychiatric condition that often interferes with their ability to make optimal preventative health decisions, including staying up to date on vaccinations.² A recent review from Toronto, Canada, found that the influenza vaccination rates among homeless adults with mental illness—a population at high risk of respiratory illness—was only 6.7% compared with 31.1% for the general population of Ontario.³

Mental health professionals may serve as the only contacts to offer medical care to this vulnerable population, leading some psychiatric leaders to advocate that psychiatrists be considered primary care providers within accountable care organizations. Because most vaccines are easily available, mental health professionals should know about key immunizations to guide their patients accordingly.

In the United States, approximately 45,000 adults die annually from vaccine-preventable diseases, the majority from influenza.⁴ When combined with the most recent Adult Immunization Schedule and general recommendations adapted from the CDC,^5,6 the mnemonic ARM SHOT allows for a quick assessment of risk factors to guide administration and education about most vaccinations (Table 1). ARM SHOT involves assessing the following components of an individual’s health status and living arrangements to determine one’s risk of contracting communicable diseases:

• Age
• Risk of exposure
• Medical conditions (comorbidities)
• Substance use history
• HIV status or other immunocompromised states
• Occupancy, or living arrangements
• Tobacco use.

We recommend keeping a copy of the Adult Immunization Schedule (age ≥19) and/or the immunization schedule for children and adolescents (age ≤18) close for quick reference. Here, we provide a case and then explore how each component of the ARM SHOT mnemonic applies in decision-making.

Case Evaluating risk, assess needs

Ms. W, age 24, has bipolar I disorder, most recently manic with psychotic features. She presents for follow-up in clinic after a 5-day hospitalization for mania and comorbid alcohol use disorder. Her medical comorbidities include asthma and active tobacco use. She is taking lurasidone, 20 mg/d, and lithium, 900 mg/d. Her case manager is working to place Ms. W in a residential substance use disorder treatment program. Ms. W is on a waiting list to establish care with a primary care physician and has a history of poor engagement with medical services in general; prior attempts to place her with a primary care physician failed.

In advance of Ms. W’s transfer to a residential treatment facility, you have been asked to place a Mantoux screening test for tuberculosis (purified protein derivative), which raises the important question about her susceptibility to infectious diseases in general. To protect Ms. W from preventable diseases for which vaccines are available, you review the ARM SHOT mnemonic to broadly assess her candidacy for vaccinations.

Age

Age may be the most important determinant of a patient’s need for vaccination (Table 2). The CDC immunization schedules account for age-specific risks for diseases, complications, and responses to vaccination (Figure 1).⁶

Influenza vaccination. Adults can have an intramuscular or intradermal inactivated influenza vaccination yearly in the fall or winter, unless they have an allergy to a vaccine component such as egg protein. Those with such an allergy can receive a recombinant influenza vaccine. Until the 2016 to 2017 flu season, an intranasal mist of live, attenuated influenza vaccine was available to healthy, non-pregnant women, ages 2 to 49, without high-risk medical conditions. However, the CDC dropped its recommendation for this vaccine because data showed it did not effectively prevent the flu.⁷ Individuals age ≥65 can receive either the standard- or high-dose inactivated influenza vaccination. The latter contains 4 times the amount of antigen with the intention of triggering a stronger immune response in older adults.

Human papillomavirus (HPV) immunization. The ACIP recommendation⁹ has been for children to receive routine vaccination for the 4 major strains of HPV—strains 6, 11, 16, and 18—starting at ages 11 to 12 to confer protection from HPV-associated diseases, such as genital warts, oropharyngeal cancer, and anal cancer; cancers of the cervix, vulva, and vagina in women; and penile cancer in men. Ideally, the vaccines are administered prior to HPV exposure from sexual contact. The quadrivalent HPV vaccine is safe and is administered as a 3-dose series, with the second and third doses given 2 and 6 months, respectively, after the initial dose. Adolescent girls also have the option of a bivalent HPV vaccine.

In 2016, the FDA approved a 9-valent HPV vaccine, a simpler 2-dose schedule for children ages 9 to 14 (2 doses at least 6 months apart). Leading cancer centers have endorsed this vaccine based on strong comparative data with the 3-dose regimen.¹⁰ For those not previously vaccinated, the HPV vaccine is available for women ages 13 to 26 and for men ages 13 to 21 (although men ages 22 to 26 can receive the vaccine, and it is recommended for men who have sex with men [MSM]). Women do not require Papanicolaou, serum pregnancy, HPV DNA, or HPV antibody tests prior to vaccination. If a woman becomes pregnant, remaining doses of the vaccine should be postponed until after delivery. Women still need to follow recommendations for cervical cancer screening because the HPV vaccine does not cover all genital strains of the virus. For sexually active individuals who might have HPV or genital warts, immunization has no clinical effect except to prevent other HPV strains.

Measles, mumps, and rubella (MMR) vaccine. All adults should receive, at minimum, 1 dose of MMR vaccination unless serological immunity can be verified or if contraindicated. Two doses of the vaccine are recommended for students attending post-high school institutions, health care personnel, and international travelers because they are at higher risk for exposure and transmission of measles and mumps. Individuals born before 1957 are considered immune to measles and mumps. A measles outbreak from December 2014 to February 2015¹¹ highlighted the importance of maintaining one’s immunity status for MMR.

Case continued

Based on Ms. W’s age, she should be offered vaccinations for influenza and opportunities to receive vaccinations for HPV, Tdap (the primary series, a Tdap or Td booster), and MMR, if appropriate and not completed previously.

Risk of exposure

Certain behaviors will increase the risk of exposure to and transmission of diseases communicable by blood and other bodily fluids (Table 3). These behaviors include needle injections (eg, during use of illicit drugs) and sexual activity with multiple partners, including MSM or promiscuity/impulsivity during a manic episode. A common consequence of risky behaviors is comorbid infection of HIV and viral hepatitis for those with substance use disorder or those who engage in high-risk sexual practices.^12,13

Hepatitis B virus (HBV) immunization. Vaccination is one of the most effective ways to prevent HBV infection, which is why it is offered to all health care workers. HBV immunization is a 3-dose series in which the second and third doses are given 1 and 6 months after the initial doses, respectively. In addition to certain medical risk factors or conditions that indicate HBV vaccination, people should be offered the vaccine if they are in a higher risk occupation, travel, are of Asian or Pacific Islander ethnicity from an endemic area, or have any present or suspected sexually transmitted diseases.

Hepatitis A virus (HAV) vaccination. HAV is transmitted via fecal–oral routes, often from contaminated water or food, or through household or sexual contact with an infected person. Individuals should receive the HAV vaccine if they use illicit drugs by any route of administration, work with primates infected with HAV, travel to countries with unknown or high rates of HAV, or have chronic liver disease (ie, hepatitis, alcohol use disorder, or non-alcoholic fatty liver disease) or clotting deficiencies. The CDC Health Information for International Travel, commonly called the “Yellow Book,” publishes vaccination recommendations for those who plan travel to specific countries.¹⁴

Case continued

Ms. W’s history of mania (if such episodes included increased sexual activity) and substance use would make her a candidate for the HBV and HAV vaccinations and could also strengthen our previous recommendation that she receive the HPV vaccination.

Medical conditions

Patients with certain medical conditions may have difficulty fighting infections or become more susceptible to morbidity and mortality from coinfection with vaccine-preventable illnesses. Secondary effects of psychotropic medications that may carry implications for vaccine recommendations (eg, risk of agranulocytosis and impaired cell-medicated immunity with mirtazapine and clozapine or renal impairment from lithium use) are of particular concern in psychiatric patients.²

To help care for these patients, the CDC has developed a “medical conditions” schedule (Figure 2). This schedule makes vaccination recommendations for those with a weakened immune system, including patients with HIV, chronic obstructive pulmonary disease (COPD), diabetes, hepatitis, asplenia, end-stage renal disease, cardiac disease, and pregnancy.

Case continued

Because of Ms. W’s asthma, the CDC schedule recommends ensuring she is up to date on her influenza, pneumococcal, and Tdap vaccinations.

Substance use

Patients with combined psychiatric and substance use disorders (“dual diagnosis”) have lower rates of receiving preventive care than patients with either condition alone.¹⁵ Substance use can be behaviorally disinhibiting, leading to increased risk of exposures from sexual contact or other risky activities. The use of illicit substances can provide a nidus for infection depending on the route of administration and can result in negative effects on organ systems, compromising one’s ability to ward off infection.

Patients who use any illicit drugs, regardless of the method of delivery, should be recommended for HAV vaccination. For those with alcohol use disorder and/or chronic liver disease, and/or seeking treatment for substance use, hepatitis B screening and vaccination is recommended.

Case continued

From a substance use perspective, discussion of vaccination status for both hepatitis A and B would be important for Ms. W.

HIV or immunocompromised

Persons with severe mental illness have high rates of HIV, with almost 8 times the risk of exposure, compared with the general population due to myriad reasons, including greater rates of substance abuse, higher risk sexual behavior, and lack of awareness of HIV transmission.^12,13 Patients with mental illness are also at risk of leukopenia and agranulocytosis from certain drugs used to treat their conditions, such as clozapine.

Pregnancy is a challenge for women with mental illness because of the pharmacologic risk and immune-system compromise to the mother and baby. A pregnant woman who has HIV with a CD4 count <200, or has a weakened immune system from an organ transplant or a similar condition, is a candidate for certain vaccines based on the Adult Immunization Schedule (Figure 2). However, these patients should avoid live vaccines, such as the intranasal mist of live influenza, MMR, VZV, and varicella, to avoid illness from these inoculations.
 

Case continued

Ms. W should undergo testing for pregnancy and HIV (and preferably other sexually transmitted infections per general preventive health guidelines) before receiving any live vaccinations.

Occupancy

Aside from direct transmission of bodily fluids, infectious diseases also can spread through droplets/secretions from the throat and respiratory tract. Close quarters or lengthy contact enhances communicability by droplets, and therefore people who reside in a communal living space (eg, individuals in substance use treatment facilities or those who reside in a nursing home) are most susceptible.

The bacterial disease Neisseria meningitidis (meningococcus) can spread through droplets and can cause pneumonia, bacteremia, and meningitis. Vaccination is indicated, and in some states is mandated, for college students who live in residence halls and missed routine vaccination by age 16. Meningococcus conjugate vaccine is administered in 2 doses; each dose may be given at least 2 months apart for those with HIV, asplenia, or persistent complement-related disorders. A single dose may be recommended for travelers to areas where meningococcal disease is hyperendemic or epidemic, military recruits, or microbiologists. For those age ≥55 and older, meningococcal polysaccharide vaccine is recommended over meningococcal conjugate vaccine.

Influenza, MMR, diphtheria, pertussis, and pneumococcus also spread through droplet contact.

Case continued

If Ms. W had not previously received the meningococcus vaccine as part of adolescent immunizations, she could benefit from this vaccine because she plans to enter a residential substance use disorder treatment program.

Tobacco use

Patients with psychiatric illness are twice as likely to smoke compared with the general population.¹⁶ Adult smokers, especially those with chronic lung disease, are at higher risk for influenza and pneumococcal-related illness; they should be vaccinated against these illnesses regardless of age (as discussed in the “Age” section).

Case continued

Because she smokes, Ms. W should receive counseling on vaccinations, such as influenza and pneumonia, to lessen her risk of respiratory illnesses and downstream sepsis.

Conclusion

Ms. W’s case represents an unfortunately all-too-common scenario where her multifaceted biopsychosocial circumstances place her at high risk for vaccine-preventable conditions. Her weight is recorded and laboratory work ordered to evaluate her pregnancy status, blood counts, lipids, complete metabolic panel, lithium level, and HIV status. Fortunately, she had received her series of MMR, meningococcal, and Tdap vaccinations when she was younger. Influenza, HPV, HAV, HBV, and pneumococcal vaccinations were all recommended to her, all of which can be given on the same day (HAV and HBV often are available as a combined vaccine). Ms. W receives a renewal of her psychiatric medications and counseling on healthy living habits (eg, diet and exercise, quitting tobacco and alcohol use, and safe sex practices) and the importance of immunizations.

Vaccination is 1 of the 10 great public health achievements of the 20th century when one considers how immunization of vaccine-preventable diseases has reduced morbidity, mortality, and health-associated costs.¹⁷ As mental health professionals, we can help pass on the direct and indirect benefits of immunizations to an often underserved and undertreated population to help improve their health outcomes and quality of life.

Patients with advanced malignancies may develop pancreatitis during therapy for their cancer. Acute pancreatitis is inflammation of the pancreas. Common symptoms include abdominal pain, nausea, vomiting, shortness of breath, dehydration. Laboratory evidence of acute pancreatitis includes elevations of the amylase and lipase. Mild pancreatitis occurs when there is no organ dysfunction, moderate pancreatitis is associated with one organ dysfunction, and severe pancreatitis is complicated by multiple organ dysfunction. Hypotension, hypocalcemia, or anemia suggest a more severe course of the pancreatitis. In some instances, the pancreatitis may be an adverse reaction to the therapy being given. However, other causes such as hypercalcemia, hypertriglyceridemia, cholelithiasis, and underlying malignancy must be ruled out before ascribing pancreatitis to a specific drug. To date, two classifications systems have been proposed by Trivedi¹ and Badalov² to evaluate the degree to which a drug is responsible for pancreatitis (Table 1). Furthermore, Naranjo and colleagues have proposed a more general method of assessing the causal relationship between drugs and adverse events.³ The Naranjo algorithm is not specific for pancreatitis. Jones and colleagues⁴ reported that 0.1%-2% of acute pancreatitis cases were owing to drugs. In 2015, they listed the older chemotherapy agents associated with pancreatitis. However, more recently, many new agents have been approved for the management of cancers. The newer classes of antineoplastic agents including proteasome inhibitors, immune-modulating agents, tyrosine kinase inhibitors, monoclonal antibodies against programmed cell death-1 (PD-1) and its ligand PD-L1 and antibody-toxin conjugates are now associated with acute pancreatitis.

Methods

We conducted a search in PubMed, Google Scholar, and Micromedex for pancreatitis related to antineoplastic agents, including proteasome inhibitors, immune checkpoint inhibitors, monoclonal antibodies, immune-modulating agents, drug-induced pancreatitis. Terms used for the searches included each specific agent and pancreatitis, immunotherapy and pancreatitis, tyrosine kinase inhibitors and pancreatitis, auto immune pancreatitis, and toxicities of molecular target therapies. Reference lists from the identified manuscripts were reviewed for further studies of pancreatitis as a result of antineoplastic therapy. The most recent search date was February 15, 2017.

The degree to which each agent was associated with inducing pancreatitis was evaluated using the Badalov classification system² in addition to the Naranjo Adverse Drug Reaction (ADR) Probability Scale.³ The Naranjo scale consists of 10 questions with values assigned to each answer. Total scores range from -4 to 13, where 13-9 indicates the reaction is considered definitely attributable to the drug; 8-5, probably attributable; 4-1, possibly attributable; and ≤0, doubtful if attributable.

A total of 67 manuscripts and abstracts were identified. Four manuscripts and 3 abstracts were excluded because they had insufficient information about possible pancreatitis or there was a presence of multiple other agents or conditions that might have caused pancreatitis. In total, 60 publications met inclusion criteria and were evaluated.

Results

Immune checkpoint inhibitors

In a review of toxicities of anti-programmed cell death-1 (PD-1) therapy, pancreatitis was reported to occur in about 1.8% of patients who received nivolumab or pembrolizumab.⁵ The 9 patients with pancreatitis attributed to an immune etiology were treated with corticosteroids. Pancreatitis was grade 2 in 3 patients (1.5-2 times upper limit of normal [ULN]), grade 3 in 4 patients (>2-5 ULN), and grade 4 ( >5 ULN) in 2 patients.

In asymptomatic individuals, pancreatitis has been detected on a positron-emission tomography–computed tomography (CT) scan after anti-PD-1 therapy.⁵ By contrast, there was a case report of a patient treated with nivolumab for lung cancer who developed anorexia, vomiting, and back pain on day 18 of therapy with an elevation of the amylase and lipase levels, but a negative CT.⁶ Later the patient developed a swollen pancreas on CT. Autoimmune pancreatitis comes in two forms. The most common relates to elevated levels of immunoglobulin G4 (IgG4; normal, 135 mg/dL ULN)⁷ The mechanism of immune pancreatitis associated with anti-PD-1 therapy is unknown.

Ipilimumab (an anti-CTLA4 antibody) has been approved by the US Food and Drug Administration (FDA) for the treatment of melanoma. Pancreatitis occurred in 1 patient in a phase 1 trial in pediatric patients.⁹ In a summary of 14 phase 1-3 trials of ipilimumab in advanced melanoma, pancreatitis was reported in fewer than 1% of the patients.¹⁰ In management guidelines for therapy with ipilimumab, pancreatitis may present as an asymptomatic increase in the levels of amylase and lipase, or with fevers, malaise, or abdominal pain. Oral prednisone or dexamethasone were given for the immune pancreatitis, but the decline in enzymes was slow, often taking months.¹¹ In a preclinical model of autoimmune pancreatitis due to the blocking of CTLA4, there was suppression of regulatory T-cell function. The autoimmune pancreatitis responded to cyclosporin or rapamycin but there are no clinical data for these agents.¹² The anti-PD-L1 agent atezolizumab has been associated with acute pancreatitis in 2 of 1,978 patients (0.1%).¹³ A review by Champiat and colleagues on dysimmune toxcities related to immune checkpoint inhibitors includes pancreatitis as an autoimmune complication of such therapies.¹⁴

Blinatumomab is an anti-CD19–directed CD3 T-cell engager that has been approved by the FDA for refractory B-cell acute lymphoblastic leukemia. In August 2016, the maker of the drug, Amgen, advised hematologists and oncologists that since February 2016, 10 patients out of more than 2,000 treated with blinatumomab had developed pancreatitis.¹⁵ Other medications the patients were receiving such as high-dose steroids might have caused or contributed to the pancreatitis. In one case, the pancreatitis improved with stopping blinatumomab but worsened with re-challenge. It is possible that the mechanism of the associated pancreatitis relates to a change in immune checkpoint inhibition. CD19-positive, CD24-high, CD27-positive regulatory B cells are decreased in autoimmune pancreatitis.¹⁶ Treatment with blinatumomab may decrease the CD19-positive cells.

Molecularly targeted agents, including TKIs

Molecularly targeted agents such as tyrosine kinase inhibitors (TKIs) or other kinase inhibitors have been associated with pancreatitis.^{17, 18} In a retrospective study by Tiruman and colleagues,¹⁹ the investigators found 91 patients with pancreatitis on imaging, of whom 15 were receiving molecularly target drugs. The pancreatitis was asymptomatic in 2 patients, but 13 had abdominal pain, many with nausea. Four of the patients also had gallstones, but the drug was deemed to be the cause of the pancreatitis. In 4 of the 9 patients in whom a rechallenge was done with the TKI, the pancreatitis relapsed. The pancreatitis resolved in 14 of the 15 patients; 1 patient died because of progressive cancer before the pancreatitis resolved. The pancreatitis was mild, 7 of the 15 patients had normal pancreatic enzymes and the pancreatitis was diagnosed by radiology.

Ghatlia and colleagues¹⁷ performed a meta-analysis of trials of TKI. They found 9 cases of pancreatitis in patients on sunitinib therapy. Of those, 4 patients were on sunitinib alone, and 5 were on other chemotherapy agents in combination with sunitinib. Eight cases of pancreatitis due to sorafenib were found. Three of the patients were on sorafenib alone, and 5 were on other chemotherapy including 1 on transcatheter embolization (TACE). Three cases of pancreatitis were associated with vandetanib; 2 of those patients had other concurrent chemotherapy. One case of axitinib induced pancreatitis was described.

Pancreatitis was reported in the phase 1 trials of sorafenib and sunitinib. In all, 3 of 69 patients treated with sorafenib had grade 3 pancreatitis and asymptomatic elevations of amylase and lipase levels were present in about 5% of patients receiving sunitinib.^18,19

Other TKIs associated with pancreatitis include pazopanib,^20,21 axitinib,²² and nilotinib.²³ Pezzilli and coleagues²⁴ described 5 patients with pancreatitis on sorafenib, 3 on sunitinib, 6 on nilotinib. It is possible that some of these cases appeared in other reviews. Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, caused a single case of pancreatitis in 9 patients.²⁵

Vemurafenib, a BRAF kinase inhibitor, was associated with pancreatitis in one case. In this case, the pancreatitis resolved on stopping the medication but recurred when vemurafenib rechallenge was attempted.²⁶ There is a report of dabrafenib being associated with pancreatitis in 1 patient.²⁷

Agents that inhibit the TKIs associated with BCR-ABL in chronic myelogenous leukemia are associated with acute pancreatitis. Imatinib-induced pancreatitis was reported in a small number of cases.²⁸ Nilotinib has caused amylase/lipase elevations with and without symptomatic pancreatitis.^29,30 Ponatinib, an inhibitor of BCR-ABL tyrosine kinase, is associated with pancreatitis.³¹ Pancreatitis occurred in 11 of 81 patients treated with ponatinib, and in 8 patients it was described as serious. Further elevation of amylase or lipase levels without clinical pancreatitis was noted in 7 other patients.

Proteosome inhibitors

In 2010, Elouni and colleagues³² reported a case of IV bortezomib-induced pancreatitis, which recurred on rechallenge with bortezomib. This same patient was also reported in an abstract in 2009.³³ In 2009, there was an editorial comment which was added to the end of the abstract that the World Health Organization Adverse Drug Reaction database had 11 reports of bortezomib associated pancreatitis. Talamo and colleagues³⁴ reported a case of bortezomib-induced pancreatitis due to bortezomib that had been administered subcutaneously. At that time, they also summarized 7 previous reports of bortezomib-associated pancreatitis. The mechanism of bortezomib-induced pancreatitis is not known.^35-37

Fotoh and colleagues reported a patient with myeloma who had elevated triglyceride levels after bortezomib therapy.³⁸ In one case of bortezomib-associated pancreatitis, the patient had an elevated triglyceride level, but it was not extremely high.³⁹ Multiple myeloma itself may be associated with hyperlipidemia but only rarely.⁴⁰ Gozetti and colleagues reported a patient who developed hyperlipidemia after two courses of bortezomib;⁴¹ stopping bisphosphonates may be associated with a rise in triglycerides. There was one case of carfilzomib causing pancreatitis during a phase 1 trial.⁴²

Older chemotherapy agents

Reviews of drug-induced pancreatitis have listed many chemotherapy agents which may cause pancreatitis.^1,43 The agent most frequently associated with acute pancreatitis has been asparaginase,⁴⁴ with 2%-16% of patients undergoing asparaginase therapy developing pancreatitis. Asparaginase-related pancreatitis is grade 3 or 4 in 5%-10% of patients, and recurs in 63% of patients on rechallenge. Other chemotherapy agents associated with pancreatitis include: mercaptopurine, cytosine arabinoside, cisplatin, interferon alfa-2b, doxorubicin, tamoxifen, gefitinib, vinorelbine, oxaliplatin, levamisole, methotrexate, azathioprine, 5-fluorouracil, capecitabine, ifosfamide, paclitaxel, and all-trans retinoic acid.

Oxaliplatin carries a 0.1%-2% incidence of drug-induced pancreatitis. In one series of 6 patients, cessation of the agent allowed for resolution of symptoms and decrease in serum lipase and amylase levels.⁴⁵ With capecitabine there are 2 case reports of pancreatitis.⁴⁶ Cases of pancreatitis associated with trifluridine or tipiracil were not present in the literature.

Thalidomide caused severe pancreatitis in a patient when it was used to treat chronic graft-versus-host disease.⁴⁷ This patient suffered recurrent pancreatitis on retreatment with the thalidomide. The authors further referenced two other suspected cases of thalidomide-induced, acute pancreatitis. However, in view of the extensive use of thalidomide for multiple myeloma before the development of lenalidomide, thalidomide-associated pancreatitis would be <1% of patients.

Agents that cause hypertriglyceridemia may cause pancreatitis. This mechanism has been reported as the cause of pancreatitis for everolimus⁴⁸ and tamoxifen.^49,50-52 Everolimus causes elevated triglycerides in 30%-50% of patients. There are case reports and a review of tamoxifen-associated pancreatitis caused by elevated triglycerides.⁵² There has also been a case of temsirolimus-associated pancreatitis,⁵³ another agent that elevates triglycerides.

Pancreatitis associated with hepatic embolization or HIPEC

TACE leads to symptomatic acute pancreatitis in 0.4%-2% of patients, but nonselective TACE (into the hepatic artery and not just feeder vessels), may lead to elevated amylase levels in 15%-40% of patients.^54-56 The risk of pancreatitis would depend on which chemotherapy drug is being infused into the liver. It would also be greater if the chemotherapy has to be infused into a larger part of the liver than into a small portion of the liver. In one patient, severe pancreatitis secondary to TACE occurred after two previous embolizations; prior embolization may have led to occlusion of the previously infused vessels.⁵⁷ Radioembolization with 90Y microspheres was associated with one case of pancreatitis in 112 consecutive patients.⁵⁸ The postembolization syndrome in the first 24 hours after the procedure may involve fever, abdominal pain, nausea, and vomiting due to acute pancreatitis in some instances.

Acute pancreatitis has also been described as a complication of hyperthermic intraperitoneal chemotherapy (HIPEC).^59,60 Two of 13 patients receiving HIPEC for gastric cancer developed pancreatitis.⁵⁹ In 25 patients with colon cancer who were treated with HIPEC, 1 patient had pancreatitis.⁶⁰

Antibody-drug conjugates

Muzaffar and colleagues reported a patient with acute pancreatitis 3 days after starting therapy with ado-trastuzumab emtansine.⁶¹ Urru and colleagues⁶² reported a patient who developed acute pancreatitis after brentuximab vedotin therapy. Ghandi and colleagues⁶³ identified 2 cases of fatal acute pancreatitis with brentuximab vedotin and 6 cases of nonfatal pancreatitis. Two of the nonfatal patients were rechallenged, and 1 developed recurrent pancreatitis. Because abdominal pain may occur in up to 18% of patients receiving brentuximab vedotin, the incidence of pancreatitis may be underestimated with this agent.⁶⁴

In Table 2, ado-trastuzumab emtansine and brentuximab vedotin are listed with incidence and level of association given by the Baldavo² and Naranjo.³ With greater awareness, the incidence of pancreatitis associated with these agents may rise or fall as more data is accumulated. In many instances, there are insufficient numbers of reported cases or insufficient information in single-case reports to complete the entire table.

Discussion

Acute pancreatitis is an uncommon complication of tyrosine kinase inhibitors, other kinase inhibitors, proteasome inhibitors, monoclonal antibody-drug conjugates and anti-PD-1 immunotherapies. As nausea, abdominal pain, emesis are common in patients with cancer on antineoplastic therapy, some patients may have acute pancreatitis which is undiagnosed. It is not clear whether a patient with pancreatitis secondary to a TKI can be safely switched to a different TKI. As more molecularly targeted agents and more monoclonal antibodies targeting PD-L1 and PD-1 are under development, screening for amylase and lipase levels during phase 1/2 testing may prove helpful.

The natural history of cancer-drug–associated pancreatitis may depend on which agent is the cause. Although there are descriptions of the course of autoimmune pancreatitis, these studies have not included pancreatitis associated with anti-PD-L1 or -PD-1 therapies.⁶⁵ It is possible that once an autoimmune pancreatitis has developed, simply stopping the inciting anti-PD-L1 or -PD-1 antibody may not lead to immediate resolution. Therapy with combined immune checkpoint blockade agents (eg, nivolumab and ipilimumab) may cause a higher incidence of pancreatitis than therapy with a single agent.⁶⁶

In a report of 119 patients with melanoma who were treated with nivolumab and ipilimumab, there were 2 cases of acute pancreatitis, though 20% of patients had a grade 3 or higher amylase level, and just over 6% had a grade 3 or higher lipase.⁶⁷ Stopping this type of immunotherapy early for grade 1,2, or 3 rises in pancreatic enzymes might prevent symptomatic pancreatitis from developing, but would stop potentially curative therapy for many patients who would have never developed clinically serious pancreatitis. Patients who suffer immune toxicities with anti-PD-1 therapies may be more apt to obtain some clinical benefit. The development of immune-related toxicities in patients treated with ipilimumab ( an anti CTLA4 antibody) seemed to correlate the tumor regression.⁶⁸ This has also been suggested by the fact that the development of vitiligo correlates with clinical response in melanoma patients treated with nivolumab.⁶⁹ Although clinically significant pancreatitis might be averted by stopping immune therapies earlier, stopping before it is deemed necessary might prevent cancer patients from receiving life-prolonging therapy.

Acute pancreatitis in general is severe in about 25% of cases and is associated with a significant risk of death. Scoring systems such as Ranson criteria and Apache 2 are used to assess the severity of pancreatitis although their utility is debated.⁷⁰ Asparaginase is the chemotherapy agent most frequently associated with pancreatitis. It has been used to treat acute lymphoblastic leukemia for more than 30 years. This allowed for a study of 5,185 children and young adults who received asparaginase to determine what clinical factors and genomic factors were associated with the development of acute pancreatitis in 117 individuals.⁷¹ Further information gathered from programs such as the FDA and the adverse drug reaction program at Northwestern University in Chicago, coupled with the publication of other cases of pancreatitis associated with newer cancer agents may provide more insight into the mechanism causing pancreatitis due to a specific agent. With more cases being published, it may also become possible to determine if there are specific predisposing factors based on the clearance or metabolism of the offending agent or any genetic predisposition for drug-related pancreatitis.

Patients with advanced malignancies may develop pancreatitis during therapy for their cancer. Acute pancreatitis is inflammation of the pancreas. Common symptoms include abdominal pain, nausea, vomiting, shortness of breath, dehydration. Laboratory evidence of acute pancreatitis includes elevations of the amylase and lipase. Mild pancreatitis occurs when there is no organ dysfunction, moderate pancreatitis is associated with one organ dysfunction, and severe pancreatitis is complicated by multiple organ dysfunction. Hypotension, hypocalcemia, or anemia suggest a more severe course of the pancreatitis. In some instances, the pancreatitis may be an adverse reaction to the therapy being given. However, other causes such as hypercalcemia, hypertriglyceridemia, cholelithiasis, and underlying malignancy must be ruled out before ascribing pancreatitis to a specific drug. To date, two classifications systems have been proposed by Trivedi¹ and Badalov² to evaluate the degree to which a drug is responsible for pancreatitis (Table 1). Furthermore, Naranjo and colleagues have proposed a more general method of assessing the causal relationship between drugs and adverse events.³ The Naranjo algorithm is not specific for pancreatitis. Jones and colleagues⁴ reported that 0.1%-2% of acute pancreatitis cases were owing to drugs. In 2015, they listed the older chemotherapy agents associated with pancreatitis. However, more recently, many new agents have been approved for the management of cancers. The newer classes of antineoplastic agents including proteasome inhibitors, immune-modulating agents, tyrosine kinase inhibitors, monoclonal antibodies against programmed cell death-1 (PD-1) and its ligand PD-L1 and antibody-toxin conjugates are now associated with acute pancreatitis.

Methods

We conducted a search in PubMed, Google Scholar, and Micromedex for pancreatitis related to antineoplastic agents, including proteasome inhibitors, immune checkpoint inhibitors, monoclonal antibodies, immune-modulating agents, drug-induced pancreatitis. Terms used for the searches included each specific agent and pancreatitis, immunotherapy and pancreatitis, tyrosine kinase inhibitors and pancreatitis, auto immune pancreatitis, and toxicities of molecular target therapies. Reference lists from the identified manuscripts were reviewed for further studies of pancreatitis as a result of antineoplastic therapy. The most recent search date was February 15, 2017.

The degree to which each agent was associated with inducing pancreatitis was evaluated using the Badalov classification system² in addition to the Naranjo Adverse Drug Reaction (ADR) Probability Scale.³ The Naranjo scale consists of 10 questions with values assigned to each answer. Total scores range from -4 to 13, where 13-9 indicates the reaction is considered definitely attributable to the drug; 8-5, probably attributable; 4-1, possibly attributable; and ≤0, doubtful if attributable.

A total of 67 manuscripts and abstracts were identified. Four manuscripts and 3 abstracts were excluded because they had insufficient information about possible pancreatitis or there was a presence of multiple other agents or conditions that might have caused pancreatitis. In total, 60 publications met inclusion criteria and were evaluated.

Results

Immune checkpoint inhibitors

In a review of toxicities of anti-programmed cell death-1 (PD-1) therapy, pancreatitis was reported to occur in about 1.8% of patients who received nivolumab or pembrolizumab.⁵ The 9 patients with pancreatitis attributed to an immune etiology were treated with corticosteroids. Pancreatitis was grade 2 in 3 patients (1.5-2 times upper limit of normal [ULN]), grade 3 in 4 patients (>2-5 ULN), and grade 4 ( >5 ULN) in 2 patients.

In asymptomatic individuals, pancreatitis has been detected on a positron-emission tomography–computed tomography (CT) scan after anti-PD-1 therapy.⁵ By contrast, there was a case report of a patient treated with nivolumab for lung cancer who developed anorexia, vomiting, and back pain on day 18 of therapy with an elevation of the amylase and lipase levels, but a negative CT.⁶ Later the patient developed a swollen pancreas on CT. Autoimmune pancreatitis comes in two forms. The most common relates to elevated levels of immunoglobulin G4 (IgG4; normal, 135 mg/dL ULN)⁷ The mechanism of immune pancreatitis associated with anti-PD-1 therapy is unknown.

Ipilimumab (an anti-CTLA4 antibody) has been approved by the US Food and Drug Administration (FDA) for the treatment of melanoma. Pancreatitis occurred in 1 patient in a phase 1 trial in pediatric patients.⁹ In a summary of 14 phase 1-3 trials of ipilimumab in advanced melanoma, pancreatitis was reported in fewer than 1% of the patients.¹⁰ In management guidelines for therapy with ipilimumab, pancreatitis may present as an asymptomatic increase in the levels of amylase and lipase, or with fevers, malaise, or abdominal pain. Oral prednisone or dexamethasone were given for the immune pancreatitis, but the decline in enzymes was slow, often taking months.¹¹ In a preclinical model of autoimmune pancreatitis due to the blocking of CTLA4, there was suppression of regulatory T-cell function. The autoimmune pancreatitis responded to cyclosporin or rapamycin but there are no clinical data for these agents.¹² The anti-PD-L1 agent atezolizumab has been associated with acute pancreatitis in 2 of 1,978 patients (0.1%).¹³ A review by Champiat and colleagues on dysimmune toxcities related to immune checkpoint inhibitors includes pancreatitis as an autoimmune complication of such therapies.¹⁴

Blinatumomab is an anti-CD19–directed CD3 T-cell engager that has been approved by the FDA for refractory B-cell acute lymphoblastic leukemia. In August 2016, the maker of the drug, Amgen, advised hematologists and oncologists that since February 2016, 10 patients out of more than 2,000 treated with blinatumomab had developed pancreatitis.¹⁵ Other medications the patients were receiving such as high-dose steroids might have caused or contributed to the pancreatitis. In one case, the pancreatitis improved with stopping blinatumomab but worsened with re-challenge. It is possible that the mechanism of the associated pancreatitis relates to a change in immune checkpoint inhibition. CD19-positive, CD24-high, CD27-positive regulatory B cells are decreased in autoimmune pancreatitis.¹⁶ Treatment with blinatumomab may decrease the CD19-positive cells.

Molecularly targeted agents, including TKIs

Molecularly targeted agents such as tyrosine kinase inhibitors (TKIs) or other kinase inhibitors have been associated with pancreatitis.^{17, 18} In a retrospective study by Tiruman and colleagues,¹⁹ the investigators found 91 patients with pancreatitis on imaging, of whom 15 were receiving molecularly target drugs. The pancreatitis was asymptomatic in 2 patients, but 13 had abdominal pain, many with nausea. Four of the patients also had gallstones, but the drug was deemed to be the cause of the pancreatitis. In 4 of the 9 patients in whom a rechallenge was done with the TKI, the pancreatitis relapsed. The pancreatitis resolved in 14 of the 15 patients; 1 patient died because of progressive cancer before the pancreatitis resolved. The pancreatitis was mild, 7 of the 15 patients had normal pancreatic enzymes and the pancreatitis was diagnosed by radiology.

Ghatlia and colleagues¹⁷ performed a meta-analysis of trials of TKI. They found 9 cases of pancreatitis in patients on sunitinib therapy. Of those, 4 patients were on sunitinib alone, and 5 were on other chemotherapy agents in combination with sunitinib. Eight cases of pancreatitis due to sorafenib were found. Three of the patients were on sorafenib alone, and 5 were on other chemotherapy including 1 on transcatheter embolization (TACE). Three cases of pancreatitis were associated with vandetanib; 2 of those patients had other concurrent chemotherapy. One case of axitinib induced pancreatitis was described.

Pancreatitis was reported in the phase 1 trials of sorafenib and sunitinib. In all, 3 of 69 patients treated with sorafenib had grade 3 pancreatitis and asymptomatic elevations of amylase and lipase levels were present in about 5% of patients receiving sunitinib.^18,19

Other TKIs associated with pancreatitis include pazopanib,^20,21 axitinib,²² and nilotinib.²³ Pezzilli and coleagues²⁴ described 5 patients with pancreatitis on sorafenib, 3 on sunitinib, 6 on nilotinib. It is possible that some of these cases appeared in other reviews. Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, caused a single case of pancreatitis in 9 patients.²⁵

Vemurafenib, a BRAF kinase inhibitor, was associated with pancreatitis in one case. In this case, the pancreatitis resolved on stopping the medication but recurred when vemurafenib rechallenge was attempted.²⁶ There is a report of dabrafenib being associated with pancreatitis in 1 patient.²⁷

Agents that inhibit the TKIs associated with BCR-ABL in chronic myelogenous leukemia are associated with acute pancreatitis. Imatinib-induced pancreatitis was reported in a small number of cases.²⁸ Nilotinib has caused amylase/lipase elevations with and without symptomatic pancreatitis.^29,30 Ponatinib, an inhibitor of BCR-ABL tyrosine kinase, is associated with pancreatitis.³¹ Pancreatitis occurred in 11 of 81 patients treated with ponatinib, and in 8 patients it was described as serious. Further elevation of amylase or lipase levels without clinical pancreatitis was noted in 7 other patients.

Proteosome inhibitors

In 2010, Elouni and colleagues³² reported a case of IV bortezomib-induced pancreatitis, which recurred on rechallenge with bortezomib. This same patient was also reported in an abstract in 2009.³³ In 2009, there was an editorial comment which was added to the end of the abstract that the World Health Organization Adverse Drug Reaction database had 11 reports of bortezomib associated pancreatitis. Talamo and colleagues³⁴ reported a case of bortezomib-induced pancreatitis due to bortezomib that had been administered subcutaneously. At that time, they also summarized 7 previous reports of bortezomib-associated pancreatitis. The mechanism of bortezomib-induced pancreatitis is not known.^35-37

Fotoh and colleagues reported a patient with myeloma who had elevated triglyceride levels after bortezomib therapy.³⁸ In one case of bortezomib-associated pancreatitis, the patient had an elevated triglyceride level, but it was not extremely high.³⁹ Multiple myeloma itself may be associated with hyperlipidemia but only rarely.⁴⁰ Gozetti and colleagues reported a patient who developed hyperlipidemia after two courses of bortezomib;⁴¹ stopping bisphosphonates may be associated with a rise in triglycerides. There was one case of carfilzomib causing pancreatitis during a phase 1 trial.⁴²

Older chemotherapy agents

Reviews of drug-induced pancreatitis have listed many chemotherapy agents which may cause pancreatitis.^1,43 The agent most frequently associated with acute pancreatitis has been asparaginase,⁴⁴ with 2%-16% of patients undergoing asparaginase therapy developing pancreatitis. Asparaginase-related pancreatitis is grade 3 or 4 in 5%-10% of patients, and recurs in 63% of patients on rechallenge. Other chemotherapy agents associated with pancreatitis include: mercaptopurine, cytosine arabinoside, cisplatin, interferon alfa-2b, doxorubicin, tamoxifen, gefitinib, vinorelbine, oxaliplatin, levamisole, methotrexate, azathioprine, 5-fluorouracil, capecitabine, ifosfamide, paclitaxel, and all-trans retinoic acid.

Oxaliplatin carries a 0.1%-2% incidence of drug-induced pancreatitis. In one series of 6 patients, cessation of the agent allowed for resolution of symptoms and decrease in serum lipase and amylase levels.⁴⁵ With capecitabine there are 2 case reports of pancreatitis.⁴⁶ Cases of pancreatitis associated with trifluridine or tipiracil were not present in the literature.

Thalidomide caused severe pancreatitis in a patient when it was used to treat chronic graft-versus-host disease.⁴⁷ This patient suffered recurrent pancreatitis on retreatment with the thalidomide. The authors further referenced two other suspected cases of thalidomide-induced, acute pancreatitis. However, in view of the extensive use of thalidomide for multiple myeloma before the development of lenalidomide, thalidomide-associated pancreatitis would be <1% of patients.

Agents that cause hypertriglyceridemia may cause pancreatitis. This mechanism has been reported as the cause of pancreatitis for everolimus⁴⁸ and tamoxifen.^49,50-52 Everolimus causes elevated triglycerides in 30%-50% of patients. There are case reports and a review of tamoxifen-associated pancreatitis caused by elevated triglycerides.⁵² There has also been a case of temsirolimus-associated pancreatitis,⁵³ another agent that elevates triglycerides.

Pancreatitis associated with hepatic embolization or HIPEC

TACE leads to symptomatic acute pancreatitis in 0.4%-2% of patients, but nonselective TACE (into the hepatic artery and not just feeder vessels), may lead to elevated amylase levels in 15%-40% of patients.^54-56 The risk of pancreatitis would depend on which chemotherapy drug is being infused into the liver. It would also be greater if the chemotherapy has to be infused into a larger part of the liver than into a small portion of the liver. In one patient, severe pancreatitis secondary to TACE occurred after two previous embolizations; prior embolization may have led to occlusion of the previously infused vessels.⁵⁷ Radioembolization with 90Y microspheres was associated with one case of pancreatitis in 112 consecutive patients.⁵⁸ The postembolization syndrome in the first 24 hours after the procedure may involve fever, abdominal pain, nausea, and vomiting due to acute pancreatitis in some instances.

Acute pancreatitis has also been described as a complication of hyperthermic intraperitoneal chemotherapy (HIPEC).^59,60 Two of 13 patients receiving HIPEC for gastric cancer developed pancreatitis.⁵⁹ In 25 patients with colon cancer who were treated with HIPEC, 1 patient had pancreatitis.⁶⁰

Antibody-drug conjugates

Muzaffar and colleagues reported a patient with acute pancreatitis 3 days after starting therapy with ado-trastuzumab emtansine.⁶¹ Urru and colleagues⁶² reported a patient who developed acute pancreatitis after brentuximab vedotin therapy. Ghandi and colleagues⁶³ identified 2 cases of fatal acute pancreatitis with brentuximab vedotin and 6 cases of nonfatal pancreatitis. Two of the nonfatal patients were rechallenged, and 1 developed recurrent pancreatitis. Because abdominal pain may occur in up to 18% of patients receiving brentuximab vedotin, the incidence of pancreatitis may be underestimated with this agent.⁶⁴

In Table 2, ado-trastuzumab emtansine and brentuximab vedotin are listed with incidence and level of association given by the Baldavo² and Naranjo.³ With greater awareness, the incidence of pancreatitis associated with these agents may rise or fall as more data is accumulated. In many instances, there are insufficient numbers of reported cases or insufficient information in single-case reports to complete the entire table.

Discussion

Acute pancreatitis is an uncommon complication of tyrosine kinase inhibitors, other kinase inhibitors, proteasome inhibitors, monoclonal antibody-drug conjugates and anti-PD-1 immunotherapies. As nausea, abdominal pain, emesis are common in patients with cancer on antineoplastic therapy, some patients may have acute pancreatitis which is undiagnosed. It is not clear whether a patient with pancreatitis secondary to a TKI can be safely switched to a different TKI. As more molecularly targeted agents and more monoclonal antibodies targeting PD-L1 and PD-1 are under development, screening for amylase and lipase levels during phase 1/2 testing may prove helpful.

The natural history of cancer-drug–associated pancreatitis may depend on which agent is the cause. Although there are descriptions of the course of autoimmune pancreatitis, these studies have not included pancreatitis associated with anti-PD-L1 or -PD-1 therapies.⁶⁵ It is possible that once an autoimmune pancreatitis has developed, simply stopping the inciting anti-PD-L1 or -PD-1 antibody may not lead to immediate resolution. Therapy with combined immune checkpoint blockade agents (eg, nivolumab and ipilimumab) may cause a higher incidence of pancreatitis than therapy with a single agent.⁶⁶

In a report of 119 patients with melanoma who were treated with nivolumab and ipilimumab, there were 2 cases of acute pancreatitis, though 20% of patients had a grade 3 or higher amylase level, and just over 6% had a grade 3 or higher lipase.⁶⁷ Stopping this type of immunotherapy early for grade 1,2, or 3 rises in pancreatic enzymes might prevent symptomatic pancreatitis from developing, but would stop potentially curative therapy for many patients who would have never developed clinically serious pancreatitis. Patients who suffer immune toxicities with anti-PD-1 therapies may be more apt to obtain some clinical benefit. The development of immune-related toxicities in patients treated with ipilimumab ( an anti CTLA4 antibody) seemed to correlate the tumor regression.⁶⁸ This has also been suggested by the fact that the development of vitiligo correlates with clinical response in melanoma patients treated with nivolumab.⁶⁹ Although clinically significant pancreatitis might be averted by stopping immune therapies earlier, stopping before it is deemed necessary might prevent cancer patients from receiving life-prolonging therapy.

Acute pancreatitis in general is severe in about 25% of cases and is associated with a significant risk of death. Scoring systems such as Ranson criteria and Apache 2 are used to assess the severity of pancreatitis although their utility is debated.⁷⁰ Asparaginase is the chemotherapy agent most frequently associated with pancreatitis. It has been used to treat acute lymphoblastic leukemia for more than 30 years. This allowed for a study of 5,185 children and young adults who received asparaginase to determine what clinical factors and genomic factors were associated with the development of acute pancreatitis in 117 individuals.⁷¹ Further information gathered from programs such as the FDA and the adverse drug reaction program at Northwestern University in Chicago, coupled with the publication of other cases of pancreatitis associated with newer cancer agents may provide more insight into the mechanism causing pancreatitis due to a specific agent. With more cases being published, it may also become possible to determine if there are specific predisposing factors based on the clearance or metabolism of the offending agent or any genetic predisposition for drug-related pancreatitis.

Patients with advanced malignancies may develop pancreatitis during therapy for their cancer. Acute pancreatitis is inflammation of the pancreas. Common symptoms include abdominal pain, nausea, vomiting, shortness of breath, dehydration. Laboratory evidence of acute pancreatitis includes elevations of the amylase and lipase. Mild pancreatitis occurs when there is no organ dysfunction, moderate pancreatitis is associated with one organ dysfunction, and severe pancreatitis is complicated by multiple organ dysfunction. Hypotension, hypocalcemia, or anemia suggest a more severe course of the pancreatitis. In some instances, the pancreatitis may be an adverse reaction to the therapy being given. However, other causes such as hypercalcemia, hypertriglyceridemia, cholelithiasis, and underlying malignancy must be ruled out before ascribing pancreatitis to a specific drug. To date, two classifications systems have been proposed by Trivedi¹ and Badalov² to evaluate the degree to which a drug is responsible for pancreatitis (Table 1). Furthermore, Naranjo and colleagues have proposed a more general method of assessing the causal relationship between drugs and adverse events.³ The Naranjo algorithm is not specific for pancreatitis. Jones and colleagues⁴ reported that 0.1%-2% of acute pancreatitis cases were owing to drugs. In 2015, they listed the older chemotherapy agents associated with pancreatitis. However, more recently, many new agents have been approved for the management of cancers. The newer classes of antineoplastic agents including proteasome inhibitors, immune-modulating agents, tyrosine kinase inhibitors, monoclonal antibodies against programmed cell death-1 (PD-1) and its ligand PD-L1 and antibody-toxin conjugates are now associated with acute pancreatitis.

Methods

We conducted a search in PubMed, Google Scholar, and Micromedex for pancreatitis related to antineoplastic agents, including proteasome inhibitors, immune checkpoint inhibitors, monoclonal antibodies, immune-modulating agents, drug-induced pancreatitis. Terms used for the searches included each specific agent and pancreatitis, immunotherapy and pancreatitis, tyrosine kinase inhibitors and pancreatitis, auto immune pancreatitis, and toxicities of molecular target therapies. Reference lists from the identified manuscripts were reviewed for further studies of pancreatitis as a result of antineoplastic therapy. The most recent search date was February 15, 2017.

The degree to which each agent was associated with inducing pancreatitis was evaluated using the Badalov classification system² in addition to the Naranjo Adverse Drug Reaction (ADR) Probability Scale.³ The Naranjo scale consists of 10 questions with values assigned to each answer. Total scores range from -4 to 13, where 13-9 indicates the reaction is considered definitely attributable to the drug; 8-5, probably attributable; 4-1, possibly attributable; and ≤0, doubtful if attributable.

A total of 67 manuscripts and abstracts were identified. Four manuscripts and 3 abstracts were excluded because they had insufficient information about possible pancreatitis or there was a presence of multiple other agents or conditions that might have caused pancreatitis. In total, 60 publications met inclusion criteria and were evaluated.

Results

Immune checkpoint inhibitors

In a review of toxicities of anti-programmed cell death-1 (PD-1) therapy, pancreatitis was reported to occur in about 1.8% of patients who received nivolumab or pembrolizumab.⁵ The 9 patients with pancreatitis attributed to an immune etiology were treated with corticosteroids. Pancreatitis was grade 2 in 3 patients (1.5-2 times upper limit of normal [ULN]), grade 3 in 4 patients (>2-5 ULN), and grade 4 ( >5 ULN) in 2 patients.

In asymptomatic individuals, pancreatitis has been detected on a positron-emission tomography–computed tomography (CT) scan after anti-PD-1 therapy.⁵ By contrast, there was a case report of a patient treated with nivolumab for lung cancer who developed anorexia, vomiting, and back pain on day 18 of therapy with an elevation of the amylase and lipase levels, but a negative CT.⁶ Later the patient developed a swollen pancreas on CT. Autoimmune pancreatitis comes in two forms. The most common relates to elevated levels of immunoglobulin G4 (IgG4; normal, 135 mg/dL ULN)⁷ The mechanism of immune pancreatitis associated with anti-PD-1 therapy is unknown.

Ipilimumab (an anti-CTLA4 antibody) has been approved by the US Food and Drug Administration (FDA) for the treatment of melanoma. Pancreatitis occurred in 1 patient in a phase 1 trial in pediatric patients.⁹ In a summary of 14 phase 1-3 trials of ipilimumab in advanced melanoma, pancreatitis was reported in fewer than 1% of the patients.¹⁰ In management guidelines for therapy with ipilimumab, pancreatitis may present as an asymptomatic increase in the levels of amylase and lipase, or with fevers, malaise, or abdominal pain. Oral prednisone or dexamethasone were given for the immune pancreatitis, but the decline in enzymes was slow, often taking months.¹¹ In a preclinical model of autoimmune pancreatitis due to the blocking of CTLA4, there was suppression of regulatory T-cell function. The autoimmune pancreatitis responded to cyclosporin or rapamycin but there are no clinical data for these agents.¹² The anti-PD-L1 agent atezolizumab has been associated with acute pancreatitis in 2 of 1,978 patients (0.1%).¹³ A review by Champiat and colleagues on dysimmune toxcities related to immune checkpoint inhibitors includes pancreatitis as an autoimmune complication of such therapies.¹⁴

Blinatumomab is an anti-CD19–directed CD3 T-cell engager that has been approved by the FDA for refractory B-cell acute lymphoblastic leukemia. In August 2016, the maker of the drug, Amgen, advised hematologists and oncologists that since February 2016, 10 patients out of more than 2,000 treated with blinatumomab had developed pancreatitis.¹⁵ Other medications the patients were receiving such as high-dose steroids might have caused or contributed to the pancreatitis. In one case, the pancreatitis improved with stopping blinatumomab but worsened with re-challenge. It is possible that the mechanism of the associated pancreatitis relates to a change in immune checkpoint inhibition. CD19-positive, CD24-high, CD27-positive regulatory B cells are decreased in autoimmune pancreatitis.¹⁶ Treatment with blinatumomab may decrease the CD19-positive cells.

Molecularly targeted agents, including TKIs

Molecularly targeted agents such as tyrosine kinase inhibitors (TKIs) or other kinase inhibitors have been associated with pancreatitis.^{17, 18} In a retrospective study by Tiruman and colleagues,¹⁹ the investigators found 91 patients with pancreatitis on imaging, of whom 15 were receiving molecularly target drugs. The pancreatitis was asymptomatic in 2 patients, but 13 had abdominal pain, many with nausea. Four of the patients also had gallstones, but the drug was deemed to be the cause of the pancreatitis. In 4 of the 9 patients in whom a rechallenge was done with the TKI, the pancreatitis relapsed. The pancreatitis resolved in 14 of the 15 patients; 1 patient died because of progressive cancer before the pancreatitis resolved. The pancreatitis was mild, 7 of the 15 patients had normal pancreatic enzymes and the pancreatitis was diagnosed by radiology.

Ghatlia and colleagues¹⁷ performed a meta-analysis of trials of TKI. They found 9 cases of pancreatitis in patients on sunitinib therapy. Of those, 4 patients were on sunitinib alone, and 5 were on other chemotherapy agents in combination with sunitinib. Eight cases of pancreatitis due to sorafenib were found. Three of the patients were on sorafenib alone, and 5 were on other chemotherapy including 1 on transcatheter embolization (TACE). Three cases of pancreatitis were associated with vandetanib; 2 of those patients had other concurrent chemotherapy. One case of axitinib induced pancreatitis was described.

Pancreatitis was reported in the phase 1 trials of sorafenib and sunitinib. In all, 3 of 69 patients treated with sorafenib had grade 3 pancreatitis and asymptomatic elevations of amylase and lipase levels were present in about 5% of patients receiving sunitinib.^18,19

Other TKIs associated with pancreatitis include pazopanib,^20,21 axitinib,²² and nilotinib.²³ Pezzilli and coleagues²⁴ described 5 patients with pancreatitis on sorafenib, 3 on sunitinib, 6 on nilotinib. It is possible that some of these cases appeared in other reviews. Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, caused a single case of pancreatitis in 9 patients.²⁵

Vemurafenib, a BRAF kinase inhibitor, was associated with pancreatitis in one case. In this case, the pancreatitis resolved on stopping the medication but recurred when vemurafenib rechallenge was attempted.²⁶ There is a report of dabrafenib being associated with pancreatitis in 1 patient.²⁷

Agents that inhibit the TKIs associated with BCR-ABL in chronic myelogenous leukemia are associated with acute pancreatitis. Imatinib-induced pancreatitis was reported in a small number of cases.²⁸ Nilotinib has caused amylase/lipase elevations with and without symptomatic pancreatitis.^29,30 Ponatinib, an inhibitor of BCR-ABL tyrosine kinase, is associated with pancreatitis.³¹ Pancreatitis occurred in 11 of 81 patients treated with ponatinib, and in 8 patients it was described as serious. Further elevation of amylase or lipase levels without clinical pancreatitis was noted in 7 other patients.

Proteosome inhibitors

In 2010, Elouni and colleagues³² reported a case of IV bortezomib-induced pancreatitis, which recurred on rechallenge with bortezomib. This same patient was also reported in an abstract in 2009.³³ In 2009, there was an editorial comment which was added to the end of the abstract that the World Health Organization Adverse Drug Reaction database had 11 reports of bortezomib associated pancreatitis. Talamo and colleagues³⁴ reported a case of bortezomib-induced pancreatitis due to bortezomib that had been administered subcutaneously. At that time, they also summarized 7 previous reports of bortezomib-associated pancreatitis. The mechanism of bortezomib-induced pancreatitis is not known.^35-37

Fotoh and colleagues reported a patient with myeloma who had elevated triglyceride levels after bortezomib therapy.³⁸ In one case of bortezomib-associated pancreatitis, the patient had an elevated triglyceride level, but it was not extremely high.³⁹ Multiple myeloma itself may be associated with hyperlipidemia but only rarely.⁴⁰ Gozetti and colleagues reported a patient who developed hyperlipidemia after two courses of bortezomib;⁴¹ stopping bisphosphonates may be associated with a rise in triglycerides. There was one case of carfilzomib causing pancreatitis during a phase 1 trial.⁴²

Older chemotherapy agents

Reviews of drug-induced pancreatitis have listed many chemotherapy agents which may cause pancreatitis.^1,43 The agent most frequently associated with acute pancreatitis has been asparaginase,⁴⁴ with 2%-16% of patients undergoing asparaginase therapy developing pancreatitis. Asparaginase-related pancreatitis is grade 3 or 4 in 5%-10% of patients, and recurs in 63% of patients on rechallenge. Other chemotherapy agents associated with pancreatitis include: mercaptopurine, cytosine arabinoside, cisplatin, interferon alfa-2b, doxorubicin, tamoxifen, gefitinib, vinorelbine, oxaliplatin, levamisole, methotrexate, azathioprine, 5-fluorouracil, capecitabine, ifosfamide, paclitaxel, and all-trans retinoic acid.

Oxaliplatin carries a 0.1%-2% incidence of drug-induced pancreatitis. In one series of 6 patients, cessation of the agent allowed for resolution of symptoms and decrease in serum lipase and amylase levels.⁴⁵ With capecitabine there are 2 case reports of pancreatitis.⁴⁶ Cases of pancreatitis associated with trifluridine or tipiracil were not present in the literature.

Thalidomide caused severe pancreatitis in a patient when it was used to treat chronic graft-versus-host disease.⁴⁷ This patient suffered recurrent pancreatitis on retreatment with the thalidomide. The authors further referenced two other suspected cases of thalidomide-induced, acute pancreatitis. However, in view of the extensive use of thalidomide for multiple myeloma before the development of lenalidomide, thalidomide-associated pancreatitis would be <1% of patients.

Agents that cause hypertriglyceridemia may cause pancreatitis. This mechanism has been reported as the cause of pancreatitis for everolimus⁴⁸ and tamoxifen.^49,50-52 Everolimus causes elevated triglycerides in 30%-50% of patients. There are case reports and a review of tamoxifen-associated pancreatitis caused by elevated triglycerides.⁵² There has also been a case of temsirolimus-associated pancreatitis,⁵³ another agent that elevates triglycerides.

Pancreatitis associated with hepatic embolization or HIPEC

TACE leads to symptomatic acute pancreatitis in 0.4%-2% of patients, but nonselective TACE (into the hepatic artery and not just feeder vessels), may lead to elevated amylase levels in 15%-40% of patients.^54-56 The risk of pancreatitis would depend on which chemotherapy drug is being infused into the liver. It would also be greater if the chemotherapy has to be infused into a larger part of the liver than into a small portion of the liver. In one patient, severe pancreatitis secondary to TACE occurred after two previous embolizations; prior embolization may have led to occlusion of the previously infused vessels.⁵⁷ Radioembolization with 90Y microspheres was associated with one case of pancreatitis in 112 consecutive patients.⁵⁸ The postembolization syndrome in the first 24 hours after the procedure may involve fever, abdominal pain, nausea, and vomiting due to acute pancreatitis in some instances.

Acute pancreatitis has also been described as a complication of hyperthermic intraperitoneal chemotherapy (HIPEC).^59,60 Two of 13 patients receiving HIPEC for gastric cancer developed pancreatitis.⁵⁹ In 25 patients with colon cancer who were treated with HIPEC, 1 patient had pancreatitis.⁶⁰

Antibody-drug conjugates

Muzaffar and colleagues reported a patient with acute pancreatitis 3 days after starting therapy with ado-trastuzumab emtansine.⁶¹ Urru and colleagues⁶² reported a patient who developed acute pancreatitis after brentuximab vedotin therapy. Ghandi and colleagues⁶³ identified 2 cases of fatal acute pancreatitis with brentuximab vedotin and 6 cases of nonfatal pancreatitis. Two of the nonfatal patients were rechallenged, and 1 developed recurrent pancreatitis. Because abdominal pain may occur in up to 18% of patients receiving brentuximab vedotin, the incidence of pancreatitis may be underestimated with this agent.⁶⁴

In Table 2, ado-trastuzumab emtansine and brentuximab vedotin are listed with incidence and level of association given by the Baldavo² and Naranjo.³ With greater awareness, the incidence of pancreatitis associated with these agents may rise or fall as more data is accumulated. In many instances, there are insufficient numbers of reported cases or insufficient information in single-case reports to complete the entire table.

Discussion

Acute pancreatitis is an uncommon complication of tyrosine kinase inhibitors, other kinase inhibitors, proteasome inhibitors, monoclonal antibody-drug conjugates and anti-PD-1 immunotherapies. As nausea, abdominal pain, emesis are common in patients with cancer on antineoplastic therapy, some patients may have acute pancreatitis which is undiagnosed. It is not clear whether a patient with pancreatitis secondary to a TKI can be safely switched to a different TKI. As more molecularly targeted agents and more monoclonal antibodies targeting PD-L1 and PD-1 are under development, screening for amylase and lipase levels during phase 1/2 testing may prove helpful.

The natural history of cancer-drug–associated pancreatitis may depend on which agent is the cause. Although there are descriptions of the course of autoimmune pancreatitis, these studies have not included pancreatitis associated with anti-PD-L1 or -PD-1 therapies.⁶⁵ It is possible that once an autoimmune pancreatitis has developed, simply stopping the inciting anti-PD-L1 or -PD-1 antibody may not lead to immediate resolution. Therapy with combined immune checkpoint blockade agents (eg, nivolumab and ipilimumab) may cause a higher incidence of pancreatitis than therapy with a single agent.⁶⁶

In a report of 119 patients with melanoma who were treated with nivolumab and ipilimumab, there were 2 cases of acute pancreatitis, though 20% of patients had a grade 3 or higher amylase level, and just over 6% had a grade 3 or higher lipase.⁶⁷ Stopping this type of immunotherapy early for grade 1,2, or 3 rises in pancreatic enzymes might prevent symptomatic pancreatitis from developing, but would stop potentially curative therapy for many patients who would have never developed clinically serious pancreatitis. Patients who suffer immune toxicities with anti-PD-1 therapies may be more apt to obtain some clinical benefit. The development of immune-related toxicities in patients treated with ipilimumab ( an anti CTLA4 antibody) seemed to correlate the tumor regression.⁶⁸ This has also been suggested by the fact that the development of vitiligo correlates with clinical response in melanoma patients treated with nivolumab.⁶⁹ Although clinically significant pancreatitis might be averted by stopping immune therapies earlier, stopping before it is deemed necessary might prevent cancer patients from receiving life-prolonging therapy.

Acute pancreatitis in general is severe in about 25% of cases and is associated with a significant risk of death. Scoring systems such as Ranson criteria and Apache 2 are used to assess the severity of pancreatitis although their utility is debated.⁷⁰ Asparaginase is the chemotherapy agent most frequently associated with pancreatitis. It has been used to treat acute lymphoblastic leukemia for more than 30 years. This allowed for a study of 5,185 children and young adults who received asparaginase to determine what clinical factors and genomic factors were associated with the development of acute pancreatitis in 117 individuals.⁷¹ Further information gathered from programs such as the FDA and the adverse drug reaction program at Northwestern University in Chicago, coupled with the publication of other cases of pancreatitis associated with newer cancer agents may provide more insight into the mechanism causing pancreatitis due to a specific agent. With more cases being published, it may also become possible to determine if there are specific predisposing factors based on the clearance or metabolism of the offending agent or any genetic predisposition for drug-related pancreatitis.

Interstitial lung disease (ILD) encompasses a diverse group of disorders that cause inflammation and fibrosis of the lung parenchyma. The clinical manifestations, disease course, management and prognosis of ILD vary depending on the underlying subtype, making accurate classification and diagnosis an important initial step. While a comprehensive list of ILD contains dozens of disorders, the majority of patients will fall into 1 of 3 categories: exposure-related ILD, connective tissue disease-related ILD (CT-ILD), and the idiopathic interstitial pneumonias (Table).

An essential first step in the evaluation of every hospitalized patient with ILD is establishing a diagnosis. A common mistake among clinicians who diagnose patients with ILD is not realizing that ILD is a collection of diseases with different etiologies, natural histories, and treatments. A careful evaluation should be performed in every hospitalized patient with ILD to ensure an accurate diagnosis, ideally in the context of a multidisciplinary conference with pulmonary, radiology, pathology, and other specialties, as appropriate. A multidisciplinary panel of the American Thoracic Society/European Respiratory Society recently published a revised classification of ILD based on a combination of clinical, radiologic, and histopathologic findings, which may aid in refining the diagnosis.¹

There are 3 main scenarios in which the hospital physician will encounter patients with ILD.

Acute presentation of new-onset disease. While many ILDs present insidiously, some cases present acutely and require hospitalization. The most common of these are acute hypersensitivity pneumonitis (HP), CT-ILD (in particular, myositis-related and systemic lupus erythematosus-related), drug-induced ILD (eg, amiodarone, nitrofurantoin), cryptogenic organizing pneumonia (COP), acute eosinophilic pneumonia (AEP), and acute interstitial pneumonia (AIP).

Acute presentation of established (chronic) disease. Patients with chronic forms of ILD can present to the hospital with an acute exacerbation of disease. This can be caused by extra-parenchymal complications, including pulmonary embolism, pneumothorax, and pleural effusion; parenchymal complications such as infectious pneumonia, aspiration pneumonitis, and congestive heart failure; or without an identifiable cause. This latter presentation is most commonly seen in idiopathic pulmonary fibrosis (IPF).^2,3

Elective hospitalization for diagnostic surgical lung biopsy. Patients with ILD may be hospitalized electively for a laparoscopic surgical lung biopsy as part of their diagnostic evaluations.

Physicians caring for a hospitalized ILD patient must be familiar with the clinical presentations, diagnostic approach, medical management, and outpatient follow-up recommended in these 3 settings. We will summarize these areas and provide answers to commonly encountered clinical questions in the hospitalized patient with ILD.

Acute onset (or worsening) of dyspnea is the primary presenting symptom in most patients hospitalized for ILD. This symptom should be further characterized by assessing the degree of dyspnea and the extent of exercise limitation, as both impact overall disease severity and prognosis.⁴ Cough is the second most common symptom, and can be nonproductive, as is common in IPF, or be associated with secretions if parenchymal infection or acute bronchitis is present.⁵ Pleuritic chest pain, pleural effusion, and/or the presence of extrapulmonary features, including dysphagia, joint pain and swelling, or cutaneous thickening may suggest the presence of a CT-ILD. Because most forms of ILD present with only nonspecific symptoms, a careful history and physical examination are essential.

History

A comprehensive patient history is the backbone of diagnosing any ILD. History-taking should focus on severity and temporal progression of symptoms, presence of pre-existing systemic conditions associated with ILD, symptoms of extrapulmonary disease, and exposures to substances that can cause pulmonary injury, including a detailed history of occupations and hobbies, medications, smoking, and familial lung disease.^6-9 Physicians must try to exclude other diagnoses that could result in a similar acute presentation, including congestive heart failure and infection. Considering the complex and extensive recommended history-taking, physicians may find it helpful to use a standardized questionnaire, as provided by the American College of Chest Physicians.¹⁰

Laboratory Testing

All patients presenting to the hospital with a suspected ILD should undergo careful assessment for the presence of connective tissue disease, including patients without clear symptoms because ILD can be the presenting manifestation. We routinely test for antinuclear antibody titer and pattern, rheumatoid factor, anticyclic citrullinated peptide, creatinine kinase, and aldolase as the initial screening panel in most patients, with further testing directed by the findings on history and physical examination. Pulmonary function tests are used routinely to monitor disease progression in the outpatient setting; however, in the hospitalized ILD patient, they are often difficult to perform and have no real diagnostic value. Similarly, arterial blood gas is not routinely used as part of the initial inpatient evaluation.

Imaging

All hospitalized patients with a known or suspected ILD should undergo chest imaging, assuming they are stable enough to do so. While the chest radiograph can provide a low-cost initial assessment of the degree of lung involvement and presence of accompanying abnormalities, computed tomography (CT) scanning is the diagnostic test of choice.¹¹ The pattern and distribution of abnormalities on CT scan can greatly assist with the differential diagnosis in patients presenting with a new ILD, while the presence and pattern of new opacities superimposed on chronic changes can inform the differential and the prognosis of an ILD exacerbation.¹² High-resolution CT provides the most sensitive imaging modality for diffuse ILD. The addition of prone and expiratory images are helpful in differentiating mild lung disease from atelectasis and detecting air trapping, respectively.¹³ However, since pulmonary embolism is a common extraparenchymal finding routinely considered in the differential of a patient presenting with a known or suspected ILD, physicians should consider ordering a CT pulmonary angiogram with additional high-resolution images. Most important, radiographic evaluation should include a review of all available prior chest imaging to assess both the tempo and the nature of radiographic findings.

Bronchoscopy

Bronchoscopy (with bronchoalveolar lavage [BAL], transbronchial lung biopsy [TBLB] and/or transbronchial needle aspiration [TBNA]) is not a routinely used diagnostic tool in the hospitalized ILD patient. However, it should be considered in certain circumstances.⁷ Cell count and differential can be helpful in diagnosing AEP (greater than 40% eosinophilia) or acute HP (greater than 50% lymphocytosis), while the addition of microbiologic and cytologic analysis can assist with the diagnosis of infectious etiologies (including pneumocystis pneumonia) or malignancy.^14,15 Bronchoscopy with BAL has limited sensitivity for many infections and the procedure is associated with a small risk of worsened hypoxemia. Transbronchial lung biopsy, and to a lesser extent TBNA, carry the added risk of pneumothorax and bleeding. In the majority of cases of ILD, TBLB and TBNA have limited diagnostic utility given the small amount of lung tissue sampled. In cases of suspected IPF, where the identification of the histologic pattern is needed for definitive diagnosis, tissue from TBLB cannot be used to make a conclusive diagnosis.^16,17 However, both TBNA and TBLB are useful in the diagnosis of granulomatous disorders, such as sarcoidosis, where the diagnostic yield ranges from 80% to 90% and 50% to 75%, respectively.^18,19

A newer bronchoscopic approach to sampling the lung using a bronchoscopically-placed cryoprobe (termed transbronchial cryobiopsy) has uncertain diagnostic utility and safety in the acute setting. This procedure involves intubation, sedation, and bronchoscopy allowing for the passage of an endobronchial cryoprobe through the bronchoscope and into the periphery of the lung. Several cryobiopies are generally taken from the same pulmonary subsegment. Despite a large number of recent publications on this topic, none of them have provided a clear sense of the diagnostic yield and safety.^20,21 Transbronchial cryobiopsy remains a highly controversial procedure in the clinical setting, and we would not recommend its use until further data are available.²²

Surgical Lung Biopsy

In the outpatient setting, a surgical lung biopsy is often useful when the ILD diagnosis cannot be made from the clinical context and imaging. However, patients presenting with acute respiratory failure from ILD are at greatly increased risk of complications from nonelective biopsy including pneumothorax, hemothorax, acute exacerbation of ILD, ICU admission, mechanical ventilation, and in-hospital mortality.^23,24 Acute histological findings can also make it difficult to appreciate the underlying pattern of fibrosis, reducing the diagnostic utility.^25-27 In our experience, surgical lung biopsy rarely alters the treatment of ILD patients presenting in acute respiratory failure. We believe that surgical lung biopsy should be reserved for the rare hospitalized patients in whom the clinician believes the results would clearly change management and that the substantial risk is worth taking.^5,28

The inpatient management of ILD is a large topic and difficult to comprehensively cover in a single review. Therefore, in this section, we will review 6 key management questions that address both general and specific treatment decisions that frequently arise in the care of hospitalized ILD patients (Figure).

When should hospitalized ILD patients be treated with antibiotics?

Infection and acute presentations of ILD have many similar clinical and radiographic features, making it difficult to distinguish between the two, or exclude infection as the causative role in an acute exacerbation.² In many ILD patients, the risk of infection is higher than in the general population, due to the acute and chronic use of immunosuppression. Until firm guidelines on the use of antibiotics in hospitalized patients with acute respiratory symptoms are available, we recommend considering the empiric use of antibiotics in ILD patients in respiratory failure, in addition to a thorough infectious workup.

When should hospitalized ILD patients be treated with corticosteroids?

Clinical experience supports the use of corticosteroids in the acute management of most rapidly progressive ILDs presenting with respiratory failure, including AEP, COP, acute HP, drug-induced ILD, and some cases of CT-ILD. Patients with AEP tend to respond rapidly to corticosteroids. In a series of 137 patients with AEP, 127 (92%) received corticosteroids, with defervescence and improved dyspnea within 48 to 72 hours and resolution of all symptoms after a median of 7 (4 to 10) days.²⁹ Cryptogenic organizing pneumonia is similarly corticosteroid-responsive, with patients typically started on doses of 1mg/kg of prednisone followed by a slow taper due to the risk of relapse.³⁰ For the majority of acute CT-ILD, oral prednisone is the initial treatment, often in combination with a second immunosuppressive agent such as mycophenolate.

No proven therapies are available for acute exacerbations of IPF (AE-IPF), including the use of corticosteroids. The most recent international guidelines on the management of AE-IPF conditionally recommends the use of corticosteroids, although this recommendation is largely based on anecdotal reports and clearly states that randomized studies are needed.³ When corticosteroids are used, we recommend high doses (eg, 1 to 2 mg/kg of prednisone) with close clinical monitoring. Consider stopping corticosteroids after 3 to 5 days if there is no evidence of clinical improvement. Prolonged courses of corticosteroids should be avoided.

What additional pharmacologic therapies should be considered in the treatment of hospitalized ILD patients?

Immunomodulators. Patients presenting acutely with a new-onset ILD or with an acute exacerbation of a chronic ILD often receive corticosteroids, sometimes in concert with an immunomodulator. This is most commonly seen in the acute management of CTD- ILD and in chronic HP, where mycophenolate mofetil, and to a lesser extent, cyclophosphamide and azathioprine for CT-ILD are used in combination with corticosteroids. The rationale for this is both therapeutic synergy and a desire to limit the long-term exposure to corticosteroids. Similarly, multiple observational cohort studies have investigated the role of combination or tandem immunosuppression in the treatment AE-IPF. Although cyclosporine, cyclophosphamide, azathioprine, rituximab and tacrolimus have all been studied, their efficacy remains uncertain.³ Until these therapies are better studied, they have no routine role in the management of AE-IPF.

Antifibrotics. Nintedanib and pirfenidone are 2 antifibrotic agents approved for the treatment of IPF. Clinical trials suggest that, in addition to slowing disease progression, these therapies may help prevent AE-IPF. The data are most robust in studies of nintedanib. A phase 2 trial with 432 subjects demonstrated a delay in time to the first investigator-reported acute exacerbation.³¹ Two follow-up phase 3 trials showed a reduction in centrally adjudicated AE-IPF in the pooled nintedanib groups compared to placebo.³² An initial phase 2 trial of pirfenidone showed a reduction in acute exacerbations in patients on pirfenidone, but this finding was not replicated in follow-up studies.^33-35 Because of their potential role in preventing acute exacerbations and emerging evidence to suggest that continuation of antifibrotics may lead to better outcomes during an acute exacerbation, these drugs should not generally be stopped during a hospitalization for ILD. However, no evidence supports their initiation during acute exacerbations, and we do not recommend starting antifibrotics in the hospitalized setting for newly diagnosed patients. Starting and stopping antifibrotics should be reserved for outpatient management.

When should noninvasive and mechanical ventilation be considered?

We recommend carefully considering the use of noninvasive ventilation (NIV) and intubation in every ILD patient in respiratory distress, as an acutely reversible process may be present. In patients requiring mechanical ventilation, every effort should be made to minimize potential damage by reducing the fraction of inspired oxygen (to prevent potential hyperoxic injury) and reducing tidal volumes (to minimize barotrauma). Patients with a chronic ILD, particularly IPF, who require NIV or mechanical ventilation will generally have poor outcomes.

Studies suggest that NIV prevents mechanical ventilation in only the minority of patients presenting with an AE-IPF and is associated with high in-hospital mortality and a median survival following hospital discharge of only 60 days.^36-38 The majority of patients with IPF requiring mechanical ventilation will not survive the intensive care unit. In a series of 23 patients presenting with acute respiratory failure and IPF, 22 of the 23 patients died while receiving mechanical ventilation, with a median survival of 3 days. In a more recent study of 34 patients with acute respiratory failure and IPF, 15 subjects underwent mechanical ventilation with an in-hospital mortality rate of 100%.³⁹ Given the overall poor survival associated with AE-IPF, mechanical ventilation should be carefully considered with the patient and family as part of an overall goals-of-care conversation prior to initiation.

When should hospitalized ILD patients be referred for inpatient lung transplant evaluation?

A subset of hospitalized patients with ILD will not respond to supportive and pharmacologic care, particularly those with advanced lung fibrosis. In these cases, lung transplantation may be the only remaining treatment option. This is particularly true for patients presenting with IPF, and it is 1 of the most common indications for lung transplantation. Patients with respiratory failure and ILD should be evaluated early in the hospital course for transplantation or considered for transfer to a transplant center. General contraindications to transplant are age older than 70 years, underweight or elevated BMI (generally higher than 30), malignancy within the last 2 years (with the exception of cutaneous squamous and basal cell tumors), untreatable major organ dysfunction other than the lung, noncurable chronic extrapulmonary infection (chronic active viral hepatitis B, hepatitis C, human immunodeficiency virus), significant chest wall deformity, untreatable psychiatric or psychologic disease, substance addiction within the last 6 months, or lack of dependable social support.⁴⁰ In select patients with ILD and gas exchange abnormalities, mechanical ventilation or extracorporeal membrane oxygenation may be used to bridge a patient to lung transplantation.⁴¹

What should you tell your ILD patient to expect at discharge?

Accurate diagnosis is important not only for acute inpatient management, but for informing long-term prognosis. Acute-onset ILD tends to be more reversible, to be responsive to medical therapy, and to have a more favorable overall outcome. On the other hand, acute exacerbations of established ILD, particularly IPF, can have a more unfavorable and treatment-refractory course. Once a diagnosis is established, it is important both to provide patients with information and ensure appropriate outpatient follow-up. The Pulmonary Fibrosis Foundation (the largest U.S. advocacy and support organization for patients with ILD) provides information on ILD to patients and families and can serve as an important educational source.⁴² Prior to discharge, it is important to evaluate the oxygen needs of patients at rest and with exertion. Referral to an ILD center at discharge is important whenever possible, to monitor clinical symptoms and lung function, initiate or assess response to treatment, and provide supportive care, including oxygen therapy, pulmonary rehabilitation, and outpatient lung transplant referral.

ILD is a group of heterogeneous disorders characterized by lung inflammation and fibrosis. Although the onset of disease is typically insidious, patients can present acutely requiring hospitalization. Inpatient management varies significantly depending on ILD subtype, and, therefore, accurate diagnosis is key in determining treatment and prognosis. As we develop an improved understanding of the mechanisms of acute presentations of ILD, and our approaches to detection and treatment improve as a result of clinical trials, we anticipate continued modifications to this shared framework.

Disclosure

Dr. Collard reports personal fees from Alkermes, aTyr Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Global Blood Therapeutics, Genoa, ImmuneWorks, Moerae Matrix, Navitor, Parexel, Patara, Pharma Capital Partners, Prometic, Takeda, Toray, and Xfibra, outside the submitted work. Drs. Farrand and Shah report no financial conflicts of interest.

Interstitial lung disease (ILD) encompasses a diverse group of disorders that cause inflammation and fibrosis of the lung parenchyma. The clinical manifestations, disease course, management and prognosis of ILD vary depending on the underlying subtype, making accurate classification and diagnosis an important initial step. While a comprehensive list of ILD contains dozens of disorders, the majority of patients will fall into 1 of 3 categories: exposure-related ILD, connective tissue disease-related ILD (CT-ILD), and the idiopathic interstitial pneumonias (Table).

An essential first step in the evaluation of every hospitalized patient with ILD is establishing a diagnosis. A common mistake among clinicians who diagnose patients with ILD is not realizing that ILD is a collection of diseases with different etiologies, natural histories, and treatments. A careful evaluation should be performed in every hospitalized patient with ILD to ensure an accurate diagnosis, ideally in the context of a multidisciplinary conference with pulmonary, radiology, pathology, and other specialties, as appropriate. A multidisciplinary panel of the American Thoracic Society/European Respiratory Society recently published a revised classification of ILD based on a combination of clinical, radiologic, and histopathologic findings, which may aid in refining the diagnosis.¹

There are 3 main scenarios in which the hospital physician will encounter patients with ILD.

Acute presentation of new-onset disease. While many ILDs present insidiously, some cases present acutely and require hospitalization. The most common of these are acute hypersensitivity pneumonitis (HP), CT-ILD (in particular, myositis-related and systemic lupus erythematosus-related), drug-induced ILD (eg, amiodarone, nitrofurantoin), cryptogenic organizing pneumonia (COP), acute eosinophilic pneumonia (AEP), and acute interstitial pneumonia (AIP).

Acute presentation of established (chronic) disease. Patients with chronic forms of ILD can present to the hospital with an acute exacerbation of disease. This can be caused by extra-parenchymal complications, including pulmonary embolism, pneumothorax, and pleural effusion; parenchymal complications such as infectious pneumonia, aspiration pneumonitis, and congestive heart failure; or without an identifiable cause. This latter presentation is most commonly seen in idiopathic pulmonary fibrosis (IPF).^2,3

Elective hospitalization for diagnostic surgical lung biopsy. Patients with ILD may be hospitalized electively for a laparoscopic surgical lung biopsy as part of their diagnostic evaluations.

Physicians caring for a hospitalized ILD patient must be familiar with the clinical presentations, diagnostic approach, medical management, and outpatient follow-up recommended in these 3 settings. We will summarize these areas and provide answers to commonly encountered clinical questions in the hospitalized patient with ILD.

Acute onset (or worsening) of dyspnea is the primary presenting symptom in most patients hospitalized for ILD. This symptom should be further characterized by assessing the degree of dyspnea and the extent of exercise limitation, as both impact overall disease severity and prognosis.⁴ Cough is the second most common symptom, and can be nonproductive, as is common in IPF, or be associated with secretions if parenchymal infection or acute bronchitis is present.⁵ Pleuritic chest pain, pleural effusion, and/or the presence of extrapulmonary features, including dysphagia, joint pain and swelling, or cutaneous thickening may suggest the presence of a CT-ILD. Because most forms of ILD present with only nonspecific symptoms, a careful history and physical examination are essential.

History

A comprehensive patient history is the backbone of diagnosing any ILD. History-taking should focus on severity and temporal progression of symptoms, presence of pre-existing systemic conditions associated with ILD, symptoms of extrapulmonary disease, and exposures to substances that can cause pulmonary injury, including a detailed history of occupations and hobbies, medications, smoking, and familial lung disease.^6-9 Physicians must try to exclude other diagnoses that could result in a similar acute presentation, including congestive heart failure and infection. Considering the complex and extensive recommended history-taking, physicians may find it helpful to use a standardized questionnaire, as provided by the American College of Chest Physicians.¹⁰

Laboratory Testing

All patients presenting to the hospital with a suspected ILD should undergo careful assessment for the presence of connective tissue disease, including patients without clear symptoms because ILD can be the presenting manifestation. We routinely test for antinuclear antibody titer and pattern, rheumatoid factor, anticyclic citrullinated peptide, creatinine kinase, and aldolase as the initial screening panel in most patients, with further testing directed by the findings on history and physical examination. Pulmonary function tests are used routinely to monitor disease progression in the outpatient setting; however, in the hospitalized ILD patient, they are often difficult to perform and have no real diagnostic value. Similarly, arterial blood gas is not routinely used as part of the initial inpatient evaluation.

Imaging

All hospitalized patients with a known or suspected ILD should undergo chest imaging, assuming they are stable enough to do so. While the chest radiograph can provide a low-cost initial assessment of the degree of lung involvement and presence of accompanying abnormalities, computed tomography (CT) scanning is the diagnostic test of choice.¹¹ The pattern and distribution of abnormalities on CT scan can greatly assist with the differential diagnosis in patients presenting with a new ILD, while the presence and pattern of new opacities superimposed on chronic changes can inform the differential and the prognosis of an ILD exacerbation.¹² High-resolution CT provides the most sensitive imaging modality for diffuse ILD. The addition of prone and expiratory images are helpful in differentiating mild lung disease from atelectasis and detecting air trapping, respectively.¹³ However, since pulmonary embolism is a common extraparenchymal finding routinely considered in the differential of a patient presenting with a known or suspected ILD, physicians should consider ordering a CT pulmonary angiogram with additional high-resolution images. Most important, radiographic evaluation should include a review of all available prior chest imaging to assess both the tempo and the nature of radiographic findings.

Bronchoscopy

Bronchoscopy (with bronchoalveolar lavage [BAL], transbronchial lung biopsy [TBLB] and/or transbronchial needle aspiration [TBNA]) is not a routinely used diagnostic tool in the hospitalized ILD patient. However, it should be considered in certain circumstances.⁷ Cell count and differential can be helpful in diagnosing AEP (greater than 40% eosinophilia) or acute HP (greater than 50% lymphocytosis), while the addition of microbiologic and cytologic analysis can assist with the diagnosis of infectious etiologies (including pneumocystis pneumonia) or malignancy.^14,15 Bronchoscopy with BAL has limited sensitivity for many infections and the procedure is associated with a small risk of worsened hypoxemia. Transbronchial lung biopsy, and to a lesser extent TBNA, carry the added risk of pneumothorax and bleeding. In the majority of cases of ILD, TBLB and TBNA have limited diagnostic utility given the small amount of lung tissue sampled. In cases of suspected IPF, where the identification of the histologic pattern is needed for definitive diagnosis, tissue from TBLB cannot be used to make a conclusive diagnosis.^16,17 However, both TBNA and TBLB are useful in the diagnosis of granulomatous disorders, such as sarcoidosis, where the diagnostic yield ranges from 80% to 90% and 50% to 75%, respectively.^18,19

A newer bronchoscopic approach to sampling the lung using a bronchoscopically-placed cryoprobe (termed transbronchial cryobiopsy) has uncertain diagnostic utility and safety in the acute setting. This procedure involves intubation, sedation, and bronchoscopy allowing for the passage of an endobronchial cryoprobe through the bronchoscope and into the periphery of the lung. Several cryobiopies are generally taken from the same pulmonary subsegment. Despite a large number of recent publications on this topic, none of them have provided a clear sense of the diagnostic yield and safety.^20,21 Transbronchial cryobiopsy remains a highly controversial procedure in the clinical setting, and we would not recommend its use until further data are available.²²

Surgical Lung Biopsy

In the outpatient setting, a surgical lung biopsy is often useful when the ILD diagnosis cannot be made from the clinical context and imaging. However, patients presenting with acute respiratory failure from ILD are at greatly increased risk of complications from nonelective biopsy including pneumothorax, hemothorax, acute exacerbation of ILD, ICU admission, mechanical ventilation, and in-hospital mortality.^23,24 Acute histological findings can also make it difficult to appreciate the underlying pattern of fibrosis, reducing the diagnostic utility.^25-27 In our experience, surgical lung biopsy rarely alters the treatment of ILD patients presenting in acute respiratory failure. We believe that surgical lung biopsy should be reserved for the rare hospitalized patients in whom the clinician believes the results would clearly change management and that the substantial risk is worth taking.^5,28

The inpatient management of ILD is a large topic and difficult to comprehensively cover in a single review. Therefore, in this section, we will review 6 key management questions that address both general and specific treatment decisions that frequently arise in the care of hospitalized ILD patients (Figure).

When should hospitalized ILD patients be treated with antibiotics?

Infection and acute presentations of ILD have many similar clinical and radiographic features, making it difficult to distinguish between the two, or exclude infection as the causative role in an acute exacerbation.² In many ILD patients, the risk of infection is higher than in the general population, due to the acute and chronic use of immunosuppression. Until firm guidelines on the use of antibiotics in hospitalized patients with acute respiratory symptoms are available, we recommend considering the empiric use of antibiotics in ILD patients in respiratory failure, in addition to a thorough infectious workup.

When should hospitalized ILD patients be treated with corticosteroids?

Clinical experience supports the use of corticosteroids in the acute management of most rapidly progressive ILDs presenting with respiratory failure, including AEP, COP, acute HP, drug-induced ILD, and some cases of CT-ILD. Patients with AEP tend to respond rapidly to corticosteroids. In a series of 137 patients with AEP, 127 (92%) received corticosteroids, with defervescence and improved dyspnea within 48 to 72 hours and resolution of all symptoms after a median of 7 (4 to 10) days.²⁹ Cryptogenic organizing pneumonia is similarly corticosteroid-responsive, with patients typically started on doses of 1mg/kg of prednisone followed by a slow taper due to the risk of relapse.³⁰ For the majority of acute CT-ILD, oral prednisone is the initial treatment, often in combination with a second immunosuppressive agent such as mycophenolate.

No proven therapies are available for acute exacerbations of IPF (AE-IPF), including the use of corticosteroids. The most recent international guidelines on the management of AE-IPF conditionally recommends the use of corticosteroids, although this recommendation is largely based on anecdotal reports and clearly states that randomized studies are needed.³ When corticosteroids are used, we recommend high doses (eg, 1 to 2 mg/kg of prednisone) with close clinical monitoring. Consider stopping corticosteroids after 3 to 5 days if there is no evidence of clinical improvement. Prolonged courses of corticosteroids should be avoided.

What additional pharmacologic therapies should be considered in the treatment of hospitalized ILD patients?

Immunomodulators. Patients presenting acutely with a new-onset ILD or with an acute exacerbation of a chronic ILD often receive corticosteroids, sometimes in concert with an immunomodulator. This is most commonly seen in the acute management of CTD- ILD and in chronic HP, where mycophenolate mofetil, and to a lesser extent, cyclophosphamide and azathioprine for CT-ILD are used in combination with corticosteroids. The rationale for this is both therapeutic synergy and a desire to limit the long-term exposure to corticosteroids. Similarly, multiple observational cohort studies have investigated the role of combination or tandem immunosuppression in the treatment AE-IPF. Although cyclosporine, cyclophosphamide, azathioprine, rituximab and tacrolimus have all been studied, their efficacy remains uncertain.³ Until these therapies are better studied, they have no routine role in the management of AE-IPF.

Antifibrotics. Nintedanib and pirfenidone are 2 antifibrotic agents approved for the treatment of IPF. Clinical trials suggest that, in addition to slowing disease progression, these therapies may help prevent AE-IPF. The data are most robust in studies of nintedanib. A phase 2 trial with 432 subjects demonstrated a delay in time to the first investigator-reported acute exacerbation.³¹ Two follow-up phase 3 trials showed a reduction in centrally adjudicated AE-IPF in the pooled nintedanib groups compared to placebo.³² An initial phase 2 trial of pirfenidone showed a reduction in acute exacerbations in patients on pirfenidone, but this finding was not replicated in follow-up studies.^33-35 Because of their potential role in preventing acute exacerbations and emerging evidence to suggest that continuation of antifibrotics may lead to better outcomes during an acute exacerbation, these drugs should not generally be stopped during a hospitalization for ILD. However, no evidence supports their initiation during acute exacerbations, and we do not recommend starting antifibrotics in the hospitalized setting for newly diagnosed patients. Starting and stopping antifibrotics should be reserved for outpatient management.

When should noninvasive and mechanical ventilation be considered?

We recommend carefully considering the use of noninvasive ventilation (NIV) and intubation in every ILD patient in respiratory distress, as an acutely reversible process may be present. In patients requiring mechanical ventilation, every effort should be made to minimize potential damage by reducing the fraction of inspired oxygen (to prevent potential hyperoxic injury) and reducing tidal volumes (to minimize barotrauma). Patients with a chronic ILD, particularly IPF, who require NIV or mechanical ventilation will generally have poor outcomes.

Studies suggest that NIV prevents mechanical ventilation in only the minority of patients presenting with an AE-IPF and is associated with high in-hospital mortality and a median survival following hospital discharge of only 60 days.^36-38 The majority of patients with IPF requiring mechanical ventilation will not survive the intensive care unit. In a series of 23 patients presenting with acute respiratory failure and IPF, 22 of the 23 patients died while receiving mechanical ventilation, with a median survival of 3 days. In a more recent study of 34 patients with acute respiratory failure and IPF, 15 subjects underwent mechanical ventilation with an in-hospital mortality rate of 100%.³⁹ Given the overall poor survival associated with AE-IPF, mechanical ventilation should be carefully considered with the patient and family as part of an overall goals-of-care conversation prior to initiation.

When should hospitalized ILD patients be referred for inpatient lung transplant evaluation?

A subset of hospitalized patients with ILD will not respond to supportive and pharmacologic care, particularly those with advanced lung fibrosis. In these cases, lung transplantation may be the only remaining treatment option. This is particularly true for patients presenting with IPF, and it is 1 of the most common indications for lung transplantation. Patients with respiratory failure and ILD should be evaluated early in the hospital course for transplantation or considered for transfer to a transplant center. General contraindications to transplant are age older than 70 years, underweight or elevated BMI (generally higher than 30), malignancy within the last 2 years (with the exception of cutaneous squamous and basal cell tumors), untreatable major organ dysfunction other than the lung, noncurable chronic extrapulmonary infection (chronic active viral hepatitis B, hepatitis C, human immunodeficiency virus), significant chest wall deformity, untreatable psychiatric or psychologic disease, substance addiction within the last 6 months, or lack of dependable social support.⁴⁰ In select patients with ILD and gas exchange abnormalities, mechanical ventilation or extracorporeal membrane oxygenation may be used to bridge a patient to lung transplantation.⁴¹

What should you tell your ILD patient to expect at discharge?

Accurate diagnosis is important not only for acute inpatient management, but for informing long-term prognosis. Acute-onset ILD tends to be more reversible, to be responsive to medical therapy, and to have a more favorable overall outcome. On the other hand, acute exacerbations of established ILD, particularly IPF, can have a more unfavorable and treatment-refractory course. Once a diagnosis is established, it is important both to provide patients with information and ensure appropriate outpatient follow-up. The Pulmonary Fibrosis Foundation (the largest U.S. advocacy and support organization for patients with ILD) provides information on ILD to patients and families and can serve as an important educational source.⁴² Prior to discharge, it is important to evaluate the oxygen needs of patients at rest and with exertion. Referral to an ILD center at discharge is important whenever possible, to monitor clinical symptoms and lung function, initiate or assess response to treatment, and provide supportive care, including oxygen therapy, pulmonary rehabilitation, and outpatient lung transplant referral.

ILD is a group of heterogeneous disorders characterized by lung inflammation and fibrosis. Although the onset of disease is typically insidious, patients can present acutely requiring hospitalization. Inpatient management varies significantly depending on ILD subtype, and, therefore, accurate diagnosis is key in determining treatment and prognosis. As we develop an improved understanding of the mechanisms of acute presentations of ILD, and our approaches to detection and treatment improve as a result of clinical trials, we anticipate continued modifications to this shared framework.

Disclosure

Dr. Collard reports personal fees from Alkermes, aTyr Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Global Blood Therapeutics, Genoa, ImmuneWorks, Moerae Matrix, Navitor, Parexel, Patara, Pharma Capital Partners, Prometic, Takeda, Toray, and Xfibra, outside the submitted work. Drs. Farrand and Shah report no financial conflicts of interest.

Interstitial lung disease (ILD) encompasses a diverse group of disorders that cause inflammation and fibrosis of the lung parenchyma. The clinical manifestations, disease course, management and prognosis of ILD vary depending on the underlying subtype, making accurate classification and diagnosis an important initial step. While a comprehensive list of ILD contains dozens of disorders, the majority of patients will fall into 1 of 3 categories: exposure-related ILD, connective tissue disease-related ILD (CT-ILD), and the idiopathic interstitial pneumonias (Table).

An essential first step in the evaluation of every hospitalized patient with ILD is establishing a diagnosis. A common mistake among clinicians who diagnose patients with ILD is not realizing that ILD is a collection of diseases with different etiologies, natural histories, and treatments. A careful evaluation should be performed in every hospitalized patient with ILD to ensure an accurate diagnosis, ideally in the context of a multidisciplinary conference with pulmonary, radiology, pathology, and other specialties, as appropriate. A multidisciplinary panel of the American Thoracic Society/European Respiratory Society recently published a revised classification of ILD based on a combination of clinical, radiologic, and histopathologic findings, which may aid in refining the diagnosis.¹

There are 3 main scenarios in which the hospital physician will encounter patients with ILD.

Acute presentation of new-onset disease. While many ILDs present insidiously, some cases present acutely and require hospitalization. The most common of these are acute hypersensitivity pneumonitis (HP), CT-ILD (in particular, myositis-related and systemic lupus erythematosus-related), drug-induced ILD (eg, amiodarone, nitrofurantoin), cryptogenic organizing pneumonia (COP), acute eosinophilic pneumonia (AEP), and acute interstitial pneumonia (AIP).

Acute presentation of established (chronic) disease. Patients with chronic forms of ILD can present to the hospital with an acute exacerbation of disease. This can be caused by extra-parenchymal complications, including pulmonary embolism, pneumothorax, and pleural effusion; parenchymal complications such as infectious pneumonia, aspiration pneumonitis, and congestive heart failure; or without an identifiable cause. This latter presentation is most commonly seen in idiopathic pulmonary fibrosis (IPF).^2,3

Elective hospitalization for diagnostic surgical lung biopsy. Patients with ILD may be hospitalized electively for a laparoscopic surgical lung biopsy as part of their diagnostic evaluations.

Physicians caring for a hospitalized ILD patient must be familiar with the clinical presentations, diagnostic approach, medical management, and outpatient follow-up recommended in these 3 settings. We will summarize these areas and provide answers to commonly encountered clinical questions in the hospitalized patient with ILD.

Acute onset (or worsening) of dyspnea is the primary presenting symptom in most patients hospitalized for ILD. This symptom should be further characterized by assessing the degree of dyspnea and the extent of exercise limitation, as both impact overall disease severity and prognosis.⁴ Cough is the second most common symptom, and can be nonproductive, as is common in IPF, or be associated with secretions if parenchymal infection or acute bronchitis is present.⁵ Pleuritic chest pain, pleural effusion, and/or the presence of extrapulmonary features, including dysphagia, joint pain and swelling, or cutaneous thickening may suggest the presence of a CT-ILD. Because most forms of ILD present with only nonspecific symptoms, a careful history and physical examination are essential.

History

A comprehensive patient history is the backbone of diagnosing any ILD. History-taking should focus on severity and temporal progression of symptoms, presence of pre-existing systemic conditions associated with ILD, symptoms of extrapulmonary disease, and exposures to substances that can cause pulmonary injury, including a detailed history of occupations and hobbies, medications, smoking, and familial lung disease.^6-9 Physicians must try to exclude other diagnoses that could result in a similar acute presentation, including congestive heart failure and infection. Considering the complex and extensive recommended history-taking, physicians may find it helpful to use a standardized questionnaire, as provided by the American College of Chest Physicians.¹⁰

Laboratory Testing

All patients presenting to the hospital with a suspected ILD should undergo careful assessment for the presence of connective tissue disease, including patients without clear symptoms because ILD can be the presenting manifestation. We routinely test for antinuclear antibody titer and pattern, rheumatoid factor, anticyclic citrullinated peptide, creatinine kinase, and aldolase as the initial screening panel in most patients, with further testing directed by the findings on history and physical examination. Pulmonary function tests are used routinely to monitor disease progression in the outpatient setting; however, in the hospitalized ILD patient, they are often difficult to perform and have no real diagnostic value. Similarly, arterial blood gas is not routinely used as part of the initial inpatient evaluation.

Imaging

All hospitalized patients with a known or suspected ILD should undergo chest imaging, assuming they are stable enough to do so. While the chest radiograph can provide a low-cost initial assessment of the degree of lung involvement and presence of accompanying abnormalities, computed tomography (CT) scanning is the diagnostic test of choice.¹¹ The pattern and distribution of abnormalities on CT scan can greatly assist with the differential diagnosis in patients presenting with a new ILD, while the presence and pattern of new opacities superimposed on chronic changes can inform the differential and the prognosis of an ILD exacerbation.¹² High-resolution CT provides the most sensitive imaging modality for diffuse ILD. The addition of prone and expiratory images are helpful in differentiating mild lung disease from atelectasis and detecting air trapping, respectively.¹³ However, since pulmonary embolism is a common extraparenchymal finding routinely considered in the differential of a patient presenting with a known or suspected ILD, physicians should consider ordering a CT pulmonary angiogram with additional high-resolution images. Most important, radiographic evaluation should include a review of all available prior chest imaging to assess both the tempo and the nature of radiographic findings.

Bronchoscopy

Bronchoscopy (with bronchoalveolar lavage [BAL], transbronchial lung biopsy [TBLB] and/or transbronchial needle aspiration [TBNA]) is not a routinely used diagnostic tool in the hospitalized ILD patient. However, it should be considered in certain circumstances.⁷ Cell count and differential can be helpful in diagnosing AEP (greater than 40% eosinophilia) or acute HP (greater than 50% lymphocytosis), while the addition of microbiologic and cytologic analysis can assist with the diagnosis of infectious etiologies (including pneumocystis pneumonia) or malignancy.^14,15 Bronchoscopy with BAL has limited sensitivity for many infections and the procedure is associated with a small risk of worsened hypoxemia. Transbronchial lung biopsy, and to a lesser extent TBNA, carry the added risk of pneumothorax and bleeding. In the majority of cases of ILD, TBLB and TBNA have limited diagnostic utility given the small amount of lung tissue sampled. In cases of suspected IPF, where the identification of the histologic pattern is needed for definitive diagnosis, tissue from TBLB cannot be used to make a conclusive diagnosis.^16,17 However, both TBNA and TBLB are useful in the diagnosis of granulomatous disorders, such as sarcoidosis, where the diagnostic yield ranges from 80% to 90% and 50% to 75%, respectively.^18,19

A newer bronchoscopic approach to sampling the lung using a bronchoscopically-placed cryoprobe (termed transbronchial cryobiopsy) has uncertain diagnostic utility and safety in the acute setting. This procedure involves intubation, sedation, and bronchoscopy allowing for the passage of an endobronchial cryoprobe through the bronchoscope and into the periphery of the lung. Several cryobiopies are generally taken from the same pulmonary subsegment. Despite a large number of recent publications on this topic, none of them have provided a clear sense of the diagnostic yield and safety.^20,21 Transbronchial cryobiopsy remains a highly controversial procedure in the clinical setting, and we would not recommend its use until further data are available.²²

Surgical Lung Biopsy

In the outpatient setting, a surgical lung biopsy is often useful when the ILD diagnosis cannot be made from the clinical context and imaging. However, patients presenting with acute respiratory failure from ILD are at greatly increased risk of complications from nonelective biopsy including pneumothorax, hemothorax, acute exacerbation of ILD, ICU admission, mechanical ventilation, and in-hospital mortality.^23,24 Acute histological findings can also make it difficult to appreciate the underlying pattern of fibrosis, reducing the diagnostic utility.^25-27 In our experience, surgical lung biopsy rarely alters the treatment of ILD patients presenting in acute respiratory failure. We believe that surgical lung biopsy should be reserved for the rare hospitalized patients in whom the clinician believes the results would clearly change management and that the substantial risk is worth taking.^5,28

The inpatient management of ILD is a large topic and difficult to comprehensively cover in a single review. Therefore, in this section, we will review 6 key management questions that address both general and specific treatment decisions that frequently arise in the care of hospitalized ILD patients (Figure).

When should hospitalized ILD patients be treated with antibiotics?

Infection and acute presentations of ILD have many similar clinical and radiographic features, making it difficult to distinguish between the two, or exclude infection as the causative role in an acute exacerbation.² In many ILD patients, the risk of infection is higher than in the general population, due to the acute and chronic use of immunosuppression. Until firm guidelines on the use of antibiotics in hospitalized patients with acute respiratory symptoms are available, we recommend considering the empiric use of antibiotics in ILD patients in respiratory failure, in addition to a thorough infectious workup.

When should hospitalized ILD patients be treated with corticosteroids?

Clinical experience supports the use of corticosteroids in the acute management of most rapidly progressive ILDs presenting with respiratory failure, including AEP, COP, acute HP, drug-induced ILD, and some cases of CT-ILD. Patients with AEP tend to respond rapidly to corticosteroids. In a series of 137 patients with AEP, 127 (92%) received corticosteroids, with defervescence and improved dyspnea within 48 to 72 hours and resolution of all symptoms after a median of 7 (4 to 10) days.²⁹ Cryptogenic organizing pneumonia is similarly corticosteroid-responsive, with patients typically started on doses of 1mg/kg of prednisone followed by a slow taper due to the risk of relapse.³⁰ For the majority of acute CT-ILD, oral prednisone is the initial treatment, often in combination with a second immunosuppressive agent such as mycophenolate.

No proven therapies are available for acute exacerbations of IPF (AE-IPF), including the use of corticosteroids. The most recent international guidelines on the management of AE-IPF conditionally recommends the use of corticosteroids, although this recommendation is largely based on anecdotal reports and clearly states that randomized studies are needed.³ When corticosteroids are used, we recommend high doses (eg, 1 to 2 mg/kg of prednisone) with close clinical monitoring. Consider stopping corticosteroids after 3 to 5 days if there is no evidence of clinical improvement. Prolonged courses of corticosteroids should be avoided.

What additional pharmacologic therapies should be considered in the treatment of hospitalized ILD patients?

Immunomodulators. Patients presenting acutely with a new-onset ILD or with an acute exacerbation of a chronic ILD often receive corticosteroids, sometimes in concert with an immunomodulator. This is most commonly seen in the acute management of CTD- ILD and in chronic HP, where mycophenolate mofetil, and to a lesser extent, cyclophosphamide and azathioprine for CT-ILD are used in combination with corticosteroids. The rationale for this is both therapeutic synergy and a desire to limit the long-term exposure to corticosteroids. Similarly, multiple observational cohort studies have investigated the role of combination or tandem immunosuppression in the treatment AE-IPF. Although cyclosporine, cyclophosphamide, azathioprine, rituximab and tacrolimus have all been studied, their efficacy remains uncertain.³ Until these therapies are better studied, they have no routine role in the management of AE-IPF.

Antifibrotics. Nintedanib and pirfenidone are 2 antifibrotic agents approved for the treatment of IPF. Clinical trials suggest that, in addition to slowing disease progression, these therapies may help prevent AE-IPF. The data are most robust in studies of nintedanib. A phase 2 trial with 432 subjects demonstrated a delay in time to the first investigator-reported acute exacerbation.³¹ Two follow-up phase 3 trials showed a reduction in centrally adjudicated AE-IPF in the pooled nintedanib groups compared to placebo.³² An initial phase 2 trial of pirfenidone showed a reduction in acute exacerbations in patients on pirfenidone, but this finding was not replicated in follow-up studies.^33-35 Because of their potential role in preventing acute exacerbations and emerging evidence to suggest that continuation of antifibrotics may lead to better outcomes during an acute exacerbation, these drugs should not generally be stopped during a hospitalization for ILD. However, no evidence supports their initiation during acute exacerbations, and we do not recommend starting antifibrotics in the hospitalized setting for newly diagnosed patients. Starting and stopping antifibrotics should be reserved for outpatient management.

When should noninvasive and mechanical ventilation be considered?

We recommend carefully considering the use of noninvasive ventilation (NIV) and intubation in every ILD patient in respiratory distress, as an acutely reversible process may be present. In patients requiring mechanical ventilation, every effort should be made to minimize potential damage by reducing the fraction of inspired oxygen (to prevent potential hyperoxic injury) and reducing tidal volumes (to minimize barotrauma). Patients with a chronic ILD, particularly IPF, who require NIV or mechanical ventilation will generally have poor outcomes.

Studies suggest that NIV prevents mechanical ventilation in only the minority of patients presenting with an AE-IPF and is associated with high in-hospital mortality and a median survival following hospital discharge of only 60 days.^36-38 The majority of patients with IPF requiring mechanical ventilation will not survive the intensive care unit. In a series of 23 patients presenting with acute respiratory failure and IPF, 22 of the 23 patients died while receiving mechanical ventilation, with a median survival of 3 days. In a more recent study of 34 patients with acute respiratory failure and IPF, 15 subjects underwent mechanical ventilation with an in-hospital mortality rate of 100%.³⁹ Given the overall poor survival associated with AE-IPF, mechanical ventilation should be carefully considered with the patient and family as part of an overall goals-of-care conversation prior to initiation.

When should hospitalized ILD patients be referred for inpatient lung transplant evaluation?

A subset of hospitalized patients with ILD will not respond to supportive and pharmacologic care, particularly those with advanced lung fibrosis. In these cases, lung transplantation may be the only remaining treatment option. This is particularly true for patients presenting with IPF, and it is 1 of the most common indications for lung transplantation. Patients with respiratory failure and ILD should be evaluated early in the hospital course for transplantation or considered for transfer to a transplant center. General contraindications to transplant are age older than 70 years, underweight or elevated BMI (generally higher than 30), malignancy within the last 2 years (with the exception of cutaneous squamous and basal cell tumors), untreatable major organ dysfunction other than the lung, noncurable chronic extrapulmonary infection (chronic active viral hepatitis B, hepatitis C, human immunodeficiency virus), significant chest wall deformity, untreatable psychiatric or psychologic disease, substance addiction within the last 6 months, or lack of dependable social support.⁴⁰ In select patients with ILD and gas exchange abnormalities, mechanical ventilation or extracorporeal membrane oxygenation may be used to bridge a patient to lung transplantation.⁴¹

What should you tell your ILD patient to expect at discharge?

Accurate diagnosis is important not only for acute inpatient management, but for informing long-term prognosis. Acute-onset ILD tends to be more reversible, to be responsive to medical therapy, and to have a more favorable overall outcome. On the other hand, acute exacerbations of established ILD, particularly IPF, can have a more unfavorable and treatment-refractory course. Once a diagnosis is established, it is important both to provide patients with information and ensure appropriate outpatient follow-up. The Pulmonary Fibrosis Foundation (the largest U.S. advocacy and support organization for patients with ILD) provides information on ILD to patients and families and can serve as an important educational source.⁴² Prior to discharge, it is important to evaluate the oxygen needs of patients at rest and with exertion. Referral to an ILD center at discharge is important whenever possible, to monitor clinical symptoms and lung function, initiate or assess response to treatment, and provide supportive care, including oxygen therapy, pulmonary rehabilitation, and outpatient lung transplant referral.

ILD is a group of heterogeneous disorders characterized by lung inflammation and fibrosis. Although the onset of disease is typically insidious, patients can present acutely requiring hospitalization. Inpatient management varies significantly depending on ILD subtype, and, therefore, accurate diagnosis is key in determining treatment and prognosis. As we develop an improved understanding of the mechanisms of acute presentations of ILD, and our approaches to detection and treatment improve as a result of clinical trials, we anticipate continued modifications to this shared framework.

Disclosure

Dr. Collard reports personal fees from Alkermes, aTyr Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Global Blood Therapeutics, Genoa, ImmuneWorks, Moerae Matrix, Navitor, Parexel, Patara, Pharma Capital Partners, Prometic, Takeda, Toray, and Xfibra, outside the submitted work. Drs. Farrand and Shah report no financial conflicts of interest.

As it does annually, the Centers for Medicare & Medicaid Services (CMS) has announced changes to the resource-based relative value scale (RBRVS) physician payment system. This system is not static, and each year the CMS identifies codes to review that appear to be either overvalued or undervalued. While the CMS leads this process, the American Medical Association (AMA), working in conjunction with national medical specialty societies, provides annual recommended updates and changes to the CMS via its AMA/Specialty Society RVS Update Committee (RUC).

RVUs defined

Relative value units (RVUs), assigned to most codes found in the AMA’s Current Procedural Terminology (CPT) book, are calculated based on 3 elements: physician work, practice expense, and malpractice cost. For Medicare reimbursement purposes, these elements are adjusted by the current geographic index, and this adjusted RVU is then multiplied by the Medicare calculated annual conversion factor (in fiscal year 2017, that amount is $35.8887) to determine the final allowable for any given provider.

Commercial payers who use the RBRVS system for reimbursement usually calculate their own conversion factors, which they may or may not publish. Such calculation can be based on a percentage increase over the Medicare rate or other factors.

In-office hysteroscopy procedure reimbursement increases

This year, some notable increases and decreases in the practice expense element will impact payment to ObGyn practices. The best news is that for practices in which clinicians have been removing polyps or performing endometrial sampling or a full dilation and curettage (D & C) using a hysteroscope in the office, practice expense reimbursement now will improve dramatically. The practice expense RVU for CPT code 58558, Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C, has been increased more than 450% in this setting, with an increase from 6.11 in 2016 to 33.82 as of January 2, 2017, which reduces to a 237% increase when the change to the total RVU is calculated.

More new-found income. The only other procedure showing at least a 10% increase in reimbursement in the office setting is the professional component for the ultrasonic guidance for aspiration of ova.

When your reimbursements will decrease

Unfortunately, reimbursement has also been decreased for some CPT code procedures. The urodynamic study code 51784, Electromyography studies (EMG) of anal or urethral sphincter, other than needle, any technique, has decreased in RVU value by about 64%. This is due to cutting by half the physician work, practice expense, and malpractice cost RVU elements. Although hit with a somewhat smaller decrease, code 58562, Hysteroscopy, surgical; with removal of impacted foreign body, also suffered a decrease in all 3 RVU elements in the office setting, amounting to about a 19% decrease.

In the facility setting, the RVU for the code for vaginoplasty has been increased by 10%, but 11 procedures have lost between 11% and 19% of their previous RVU levels in this setting, and more than half are for hysteroscopic procedures. The complete list of codes that have incurred at least a 10% RVU change in 2017 are listed in TABLES 1 and 2 according to place of service.

Related article:
GYN coding changes to note for your maximized reimbursement

What’s up next for review and possible adjustment

Finally, as a reminder to all providers, the CMS has identified 3 procedure codes that are potentially misvalued due to their being reported more than 50% of the time with an evaluation and management (E/M) service. These codes represent 0-day procedures and will be evaluated during 2017:

• 57150, Irrigation of vagina and/or application of medicament for treatment of bacterial, parasitic, or fungoid disease
• 57160, Fitting and insertion of pessary or other intravaginal support device
• 58100, Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure).

The CMS has made it clear that all 0-day procedure codes include evaluation services on the date of service, including the decision to do the procedure. If the CMS examination of data finds that the documentation does not support a separate and significant E/M service at the time of the procedure, the agency will consider adjusting the physician work component. All providers should therefore examine their reporting of an E/M service with 0-day procedures to ensure that the documentation clearly supports doing so.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

As it does annually, the Centers for Medicare & Medicaid Services (CMS) has announced changes to the resource-based relative value scale (RBRVS) physician payment system. This system is not static, and each year the CMS identifies codes to review that appear to be either overvalued or undervalued. While the CMS leads this process, the American Medical Association (AMA), working in conjunction with national medical specialty societies, provides annual recommended updates and changes to the CMS via its AMA/Specialty Society RVS Update Committee (RUC).

RVUs defined

Relative value units (RVUs), assigned to most codes found in the AMA’s Current Procedural Terminology (CPT) book, are calculated based on 3 elements: physician work, practice expense, and malpractice cost. For Medicare reimbursement purposes, these elements are adjusted by the current geographic index, and this adjusted RVU is then multiplied by the Medicare calculated annual conversion factor (in fiscal year 2017, that amount is $35.8887) to determine the final allowable for any given provider.

Commercial payers who use the RBRVS system for reimbursement usually calculate their own conversion factors, which they may or may not publish. Such calculation can be based on a percentage increase over the Medicare rate or other factors.

In-office hysteroscopy procedure reimbursement increases

This year, some notable increases and decreases in the practice expense element will impact payment to ObGyn practices. The best news is that for practices in which clinicians have been removing polyps or performing endometrial sampling or a full dilation and curettage (D & C) using a hysteroscope in the office, practice expense reimbursement now will improve dramatically. The practice expense RVU for CPT code 58558, Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C, has been increased more than 450% in this setting, with an increase from 6.11 in 2016 to 33.82 as of January 2, 2017, which reduces to a 237% increase when the change to the total RVU is calculated.

More new-found income. The only other procedure showing at least a 10% increase in reimbursement in the office setting is the professional component for the ultrasonic guidance for aspiration of ova.

When your reimbursements will decrease

Unfortunately, reimbursement has also been decreased for some CPT code procedures. The urodynamic study code 51784, Electromyography studies (EMG) of anal or urethral sphincter, other than needle, any technique, has decreased in RVU value by about 64%. This is due to cutting by half the physician work, practice expense, and malpractice cost RVU elements. Although hit with a somewhat smaller decrease, code 58562, Hysteroscopy, surgical; with removal of impacted foreign body, also suffered a decrease in all 3 RVU elements in the office setting, amounting to about a 19% decrease.

In the facility setting, the RVU for the code for vaginoplasty has been increased by 10%, but 11 procedures have lost between 11% and 19% of their previous RVU levels in this setting, and more than half are for hysteroscopic procedures. The complete list of codes that have incurred at least a 10% RVU change in 2017 are listed in TABLES 1 and 2 according to place of service.

Related article:
GYN coding changes to note for your maximized reimbursement

What’s up next for review and possible adjustment

Finally, as a reminder to all providers, the CMS has identified 3 procedure codes that are potentially misvalued due to their being reported more than 50% of the time with an evaluation and management (E/M) service. These codes represent 0-day procedures and will be evaluated during 2017:

• 57150, Irrigation of vagina and/or application of medicament for treatment of bacterial, parasitic, or fungoid disease
• 57160, Fitting and insertion of pessary or other intravaginal support device
• 58100, Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure).

The CMS has made it clear that all 0-day procedure codes include evaluation services on the date of service, including the decision to do the procedure. If the CMS examination of data finds that the documentation does not support a separate and significant E/M service at the time of the procedure, the agency will consider adjusting the physician work component. All providers should therefore examine their reporting of an E/M service with 0-day procedures to ensure that the documentation clearly supports doing so.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

As it does annually, the Centers for Medicare & Medicaid Services (CMS) has announced changes to the resource-based relative value scale (RBRVS) physician payment system. This system is not static, and each year the CMS identifies codes to review that appear to be either overvalued or undervalued. While the CMS leads this process, the American Medical Association (AMA), working in conjunction with national medical specialty societies, provides annual recommended updates and changes to the CMS via its AMA/Specialty Society RVS Update Committee (RUC).

RVUs defined

Relative value units (RVUs), assigned to most codes found in the AMA’s Current Procedural Terminology (CPT) book, are calculated based on 3 elements: physician work, practice expense, and malpractice cost. For Medicare reimbursement purposes, these elements are adjusted by the current geographic index, and this adjusted RVU is then multiplied by the Medicare calculated annual conversion factor (in fiscal year 2017, that amount is $35.8887) to determine the final allowable for any given provider.

Commercial payers who use the RBRVS system for reimbursement usually calculate their own conversion factors, which they may or may not publish. Such calculation can be based on a percentage increase over the Medicare rate or other factors.

In-office hysteroscopy procedure reimbursement increases

This year, some notable increases and decreases in the practice expense element will impact payment to ObGyn practices. The best news is that for practices in which clinicians have been removing polyps or performing endometrial sampling or a full dilation and curettage (D & C) using a hysteroscope in the office, practice expense reimbursement now will improve dramatically. The practice expense RVU for CPT code 58558, Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C, has been increased more than 450% in this setting, with an increase from 6.11 in 2016 to 33.82 as of January 2, 2017, which reduces to a 237% increase when the change to the total RVU is calculated.

More new-found income. The only other procedure showing at least a 10% increase in reimbursement in the office setting is the professional component for the ultrasonic guidance for aspiration of ova.

When your reimbursements will decrease

Unfortunately, reimbursement has also been decreased for some CPT code procedures. The urodynamic study code 51784, Electromyography studies (EMG) of anal or urethral sphincter, other than needle, any technique, has decreased in RVU value by about 64%. This is due to cutting by half the physician work, practice expense, and malpractice cost RVU elements. Although hit with a somewhat smaller decrease, code 58562, Hysteroscopy, surgical; with removal of impacted foreign body, also suffered a decrease in all 3 RVU elements in the office setting, amounting to about a 19% decrease.

In the facility setting, the RVU for the code for vaginoplasty has been increased by 10%, but 11 procedures have lost between 11% and 19% of their previous RVU levels in this setting, and more than half are for hysteroscopic procedures. The complete list of codes that have incurred at least a 10% RVU change in 2017 are listed in TABLES 1 and 2 according to place of service.

Related article:
GYN coding changes to note for your maximized reimbursement

What’s up next for review and possible adjustment

Finally, as a reminder to all providers, the CMS has identified 3 procedure codes that are potentially misvalued due to their being reported more than 50% of the time with an evaluation and management (E/M) service. These codes represent 0-day procedures and will be evaluated during 2017:

• 57150, Irrigation of vagina and/or application of medicament for treatment of bacterial, parasitic, or fungoid disease
• 57160, Fitting and insertion of pessary or other intravaginal support device
• 58100, Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure).

The CMS has made it clear that all 0-day procedure codes include evaluation services on the date of service, including the decision to do the procedure. If the CMS examination of data finds that the documentation does not support a separate and significant E/M service at the time of the procedure, the agency will consider adjusting the physician work component. All providers should therefore examine their reporting of an E/M service with 0-day procedures to ensure that the documentation clearly supports doing so.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.