Approximately 60,000 hospitalists were working in the United States in 2018.¹ Hospitalist groups work collaboratively because of the shiftwork required for 24/7 patient coverage, and first-rate clinical documentation is essential for quality care.² Thoughtful clinical documentation not only transmits one provider’s clinical reasoning to other providers but is a professional responsibility.³ Hospitalists spend two-thirds of their time in indirect patient-care activities and approximately one quarter of their time on documentation in electronic health records (EHRs).⁴ Despite documentation occupying a substantial portion of the clinician’s time, published literature on the best practices for the documentation of clinical reasoning in hospital medicine or its assessment remains scant.^5-7

Clinical reasoning involves establishing a diagnosis and developing a therapeutic plan that fits the unique circumstances and needs of the patient.⁸ Inpatient providers who admit patients to the hospital end the admission note with their assessment and plan (A&P) after reflecting about a patient’s presenting illness. The A&P generally represents the interpretations, deductions, and clinical reasoning of the inpatient providers; this is the section of the note that fellow physicians concentrate on over others.⁹ The documentation of clinical reasoning in the A&P allows for many to consider how the recorded interpretations relate to their own elucidations resulting in distributed cognition.¹⁰

Disorganized documentation can contribute to cognitive overload and impede thoughtful consideration about the clinical presentation.³ The assessment of clinical documentation may translate into reduced medical errors and improved note quality.^11,12 Studies that have formally evaluated the documentation of clinical reasoning have focused exclusively on medical students.^13-15 The nonexistence of a detailed rubric for evaluating clinical reasoning in the A&Ps of hospitalists represents a missed opportunity for evaluating what hospitalists “do”; if this evolves into a mechanism for offering formative feedback, such professional development would impact the highest level of Miller’s assessment pyramid.¹⁶ We therefore undertook this study to establish a metric to assess the hospitalist providers’ documentation of clinical reasoning in the A&P of an admission note.

Study Design, Setting, and Subjects

This was a retrospective study that reviewed the admission notes of hospitalists for patients admitted over the period of January 2014 and October 2017 at three hospitals in Maryland. One is a community hospital (Hospital A) and two are academic medical centers (Hospital B and Hospital C). Even though these three hospitals are part of one health system, they have distinct cultures and leadership, serve different populations, and are staffed by different provider teams.

The notes of physicians working for the hospitalist groups at each of the three hospitals were the focus of the analysis in this study.

Development of the Documentation Assessment Rubric

A team was assembled to develop the Clinical Reasoning in Admission Note Assessment & PLan (CRANAPL) tool. The CRANAPL was designed to assess the comprehensiveness and thoughtfulness of the clinical reasoning documented in the A&P sections of the notes of patients who were admitted to the hospital with an acute illness. Validity evidence for CRANAPL was summarized on the basis of Messick’s unified validity framework by using four of the five sources of validity: content, response process, internal structure, and relations to other variables.¹⁷

Content Validity

The development team consisted of members who have an average of 10 years of clinical experience in hospital medicine; have studied clinical excellence and clinical reasoning; and have expertise in feedback, assessment, and professional development.^18-22 The development of the CRANAPL tool by the team was informed by a review of the clinical reasoning literature, with particular attention paid to the standards and competencies outlined by the Liaison Committee on Medical Education, the Association of American Medical Colleges, the Accreditation Council on Graduate Medical Education, the Internal Medicine Milestone Project, and the Society of Hospital Medicine.^23-26 For each of these parties, diagnostic reasoning and its impact on clinical decision-making are considered to be a core competency. Several works that heavily influenced the CRANAPL tool’s development were Baker’s Interpretive Summary, Differential Diagnosis, Explanation of Reasoning, And Alternatives (IDEA) assessment tool;¹⁴ King’s Pediatric History and Physical Exam Evaluation (P-HAPEE) rubric;¹⁵ and three other studies related to diagnostic reasoning.^16,27,28 These manuscripts and other works substantively informed the preliminary behavioral-based anchors that formed the initial foundation for the tool under development. The CRANAPL tool was shown to colleagues at other institutions who are leaders on clinical reasoning and was presented at academic conferences in the Division of General Internal Medicine and the Division of Hospital Medicine of our institution. Feedback resulted in iterative revisions. The aforementioned methods established content validity evidence for the CRANAPL tool.

Response Process Validity

Several of the authors pilot-tested earlier iterations on admission notes that were excluded from the sample when refining the CRANAPL tool. The weaknesses and sources of confusion with specific items were addressed by scoring 10 A&Ps individually and then comparing data captured on the tool. This cycle was repeated three times for the iterative enhancement and finalization of the CRANAPL tool. On several occasions when two authors were piloting the near-final CRANAPL tool, a third author interviewed each of the two authors about reactivity while assessing individual items and exploring with probes how their own clinical documentation practices were being considered when scoring the notes. The reasonable and thoughtful answers provided by the two authors as they explained and justified the scores they were selecting during the pilot testing served to confer response process validity evidence.

Finalizing the CRANAPL Tool

The nine-item CRANAPL tool includes elements for problem representation, leading diagnosis, uncertainty, differential diagnosis, plans for diagnosis and treatment, estimated length of stay (LOS), potential for upgrade in status to a higher level of care, and consideration of disposition. Although the final three items are not core clinical reasoning domains in the medical education literature, they represent clinical judgments that are especially relevant for the delivery of the high-quality and cost-effective care of hospitalized patients. Given that the probabilities and estimations of these three elements evolve over the course of any hospitalization on the basis of test results and response to therapy, the documentation of initial expectations on these fronts can facilitate distributed cognition with all individuals becoming wiser from shared insights.¹⁰ The tool uses two- and three-point rating scales, with each number score being clearly defined by specific written criteria (total score range: 0-14; Appendix).

Data Collection

Hospitalists’ admission notes from the three hospitals were used to validate the CRANAPL tool. Admission notes from patients hospitalized to the general medical floors with an admission diagnosis of either fever, syncope/dizziness, or abdominal pain were used. These diagnoses were purposefully examined because they (1) have a wide differential diagnosis, (2) are common presenting symptoms, and (3) are prone to diagnostic errors.^29-32

The centralized EHR system across the three hospitals identified admission notes with one of these primary diagnoses of patients admitted over the period of January 2014 to October 2017. We submitted a request for 650 admission notes to be randomly selected from the centralized institutional records system. The notes were stratified by hospital and diagnosis. The sample size of our study was comparable with that of prior psychometric validation studies.^33,34 Upon reviewing the A&Ps associated with these admissions, 365 notes were excluded for one of three reasons: (1) the note was written by a nurse practitioner, physician assistant, resident, or medical student; (2) the admission diagnosis had been definitively confirmed in the emergency department (eg, abdominal pain due to diverticulitis seen on CT); and (3) the note represented the fourth or more note by any single provider (to sample notes of many providers, no more than three notes written by any single provider were analyzed). A total of 285 admission notes were ultimately included in the sample.

Data were deidentified, and the A&P sections of the admission notes were each copied from the EHR into a unique Word document. Patient and hospital demographic data (including age, gender, race, number of comorbid conditions, LOS, hospital charges, and readmission to the same health system within 30 days) were collected separately from the EHR. Select physician characteristics were also collected from the hospitalist groups at each of the three hospitals, as was the length (word count) of each A&P.

The study was approved by our institutional review board.

Data Analysis

Two authors scored all deidentified A&Ps by using the finalized version of the CRANAPL tool. Prior to using the CRANAPL tool on each of the notes, these raters read each A&P and scored them by using two single-item rating scales: a global clinical reasoning and a global readability/clarity measure. Both of these global scales used three-item Likert scales (below average, average, and above average). These global rating scales collected the reviewers’ gestalt about the quality and clarity of the A&P. The use of gestalt ratings as comparators is supported by other research.³⁵

Descriptive statistics were computed for all variables. Each rater rescored a sample of 48 records (one month after the initial scoring) and intraclass correlations (ICCs) were computed for intrarater reliability. ICCs were calculated for each item and for the CRANAPL total to determine interrater reliability.

The averaged ratings from the two raters were used for all other analyses. For CRANAPL’s internal structure validity evidence, Cronbach’s alpha was calculated as a measure of internal consistency. For relations to other variables validity evidence, CRANAPL total scores were compared with the two global assessment variables with linear regressions.

Bivariate analyses were performed by applying parametric and nonparametric tests as appropriate. A series of multivariate linear regressions, controlling for diagnosis and clustered variance by hospital site, were performed using CRANAPL total as the dependent variable and patient variables as predictors.

All data were analyzed using Stata (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, Texas: StataCorp LP.)

The admission notes of 120 hospitalists were evaluated (Table 1). A total of 39 (33%) physicians were moonlighters with primary appointments outside of the hospitalist division, and 81 (68%) were full-time hospitalists. Among the 120 hospitalists, 48 (40%) were female, 60 (50%) were international medical graduates, and 90 (75%) were of nonwhite race. Most hospitalist physicians (n = 47, 58%) had worked in our health system for less than five years, and 64 hospitalists (53%) devoted greater than 50% of their time to patient care.

Approximately equal numbers of patient admission notes were pulled from each of the three hospitals. The average age of patients was 67.2 (SD 13.6) years, 145 (51%) were female, and 120 (42%) were of nonwhite race. The mean LOS for all patients was 4.0 (SD 3.4) days. A total of 44 (15%) patients were readmitted to the same health system within 30 days of discharge. None of the patients died during the incident hospitalization. The average charge for each of the hospitalizations was $10,646 (SD $9,964).

CRANAPL Data

Figure 1 shows the distribution of the scores given by each rater for each of the nine items. The mean of the total CRANAPL score given by both raters was 6.4 (SD 2.2). Scoring for some items were high (eg, summary statement: 1.5/2), whereas performance on others were low (eg, estimating LOS: 0.1/1 and describing the potential need for upgrade in care: 0.0/1).

Validity of the CRANAPL Tool’s Internal Structure

Cronbach’s alpha, which was used to measure internal consistency within the CRANAPL tool, was 0.43. The ICC, which was applied to measure the interrater reliability for both raters for the total CRANAPL score, was 0.83 (95% CI:  0.76-0.87). The ICC values for intrarater reliability for raters 1 and 2 were 0.73 (95% CI: 0.60-0.83) and 0.73 (95% CI: 0.45-0.86), respectively.

Relations to Other Variables Validity

Associations between CRANAPL total scores, global clinical reasoning, and global scores for note readability/clarity were statistically significant (P < .001), Figure 2.

Eight out of nine CRANAPL variables were statistically significantly different across the three hospitals (P <. 01) when data were analyzed by hospital site. Hospital C had the highest mean score of 7.4 (SD 2.0), followed by Hospital B with a score of 6.6 (SD 2.1), and Hospital A had the lowest total CRANAPL score of 5.2 (SD 1.9). This difference was statistically significant (P < .001). Five variables with respect to admission diagnoses (uncertainty acknowledged, differential diagnosis, plan for diagnosis, plan for treatment, and upgrade plan) were statistically significantly different across notes. Notes for syncope/dizziness generally yielded higher scores than those for abdominal pain and fever.

Factors Associated with High CRANAPL Scores

Table 2 shows the associations between CRANAPL scores and several covariates. Before adjustment, high CRANAPL scores were associated with high word counts of A&Ps (P < .001) and high hospital charges (P < .05). These associations were no longer significant after adjusting for hospital site and admitting diagnoses.

We reviewed the documentation of clinical reasoning in 285 admission notes at three different hospitals written by hospitalist physicians during routine clinical care. To our knowledge, this is the first study that assessed the documentation of hospitalists’ clinical reasoning with real patient notes. Wide variability exists in the documentation of clinical reasoning within the A&Ps of hospitalists’ admission notes. We have provided validity evidence to support the use of the user-friendly CRANAPL tool.

Prior studies have described rubrics for evaluating the clinical reasoning skills of medical students.^14,15 The ICCs for the IDEA rubric used to assess medical students’ documentation of clinical reasoning were fair to moderate (0.29-0.67), whereas the ICC for the CRANAPL tool was high at 0.83. This measure of reliability is similar to that for the P-HAPEE rubric used to assess medical students’ documentation of pediatric history and physical notes.¹⁵ These data are markedly different from the data in previous studies that have found low interrater reliability for psychometric evaluations related to judgment and decision-making.^36-39 CRANAPL was also found to have high intrarater reliability, which shows the reproducibility of an individual’s assessment over time. The strong association between the total CRANAPL score and global clinical reasoning assessment found in the present study is similar to that found in previous studies that have also embedded global rating scales as comparators when assessing clinical reasoning.^13,,15,40,41 Global rating scales represent an overarching structure for comparison given the absence of an accepted method or gold standard for assessing clinical reasoning documentation. High-quality provider notes are defined by clarity, thoroughness, and accuracy;³⁵ and effective documentation promotes communication and the coordination of care among the members of the care team.³

The total CRANAPL scores varied by hospital site with academic hospitals (B and C) scoring higher than the community hospital (A) in our study. Similarly, lengthy A&Ps were associated with high CRANAPL scores (P < .001) prior to adjustment for hospital site. Healthcare providers consider that the thoroughness of documentation denotes quality and attention to detail.^35,42 Comprehensive documentation takes time; the longer notes by academic hospitalists than those by community hospitalists may be attributed to the fewer number of patients generally carried by hospitalists at academic centers than that by hospitalists at community hospitals.⁴³

The documentation of the estimations of LOS, possibility of potential upgrade, and thoughts about disposition were consistently poorly described across all hospital sites and diagnoses. In contrast to CRANAPL, other clinical reasoning rubrics have excluded these items or discussed uncertainty.^14,15,44 These elements represent the forward thinking that may be essential for high-quality progressive care by hospitalists. Physicians’s difficulty in acknowledging uncertainty has been associated with resource overuse, including the excessive ordering of tests, iatrogenic injury, and heavy financial burden on the healthcare system.^45,46 The lack of thoughtful clinical and management reasoning at the time of admission is believed to be associated with medical errors.⁴⁷ If used as a guide, the CRANAPL tool may promote reflection on the part of the admitting physician. The estimations of LOS, potential for upgrade to a higher level of care, and disposition are markers of optimal inpatient care, especially for hospitalists who work in shifts with embedded handoffs. When shared with colleagues (through documentation), there is the potential for distributed cognition¹⁰ to extend throughout the social network of the hospitalist group. The fact that so few providers are currently including these items in their A&P’s show that the providers are either not performing or documenting the ‘reasoning’. Either way, this is an opportunity that has been highlighted by the CRANAPL tool.

Several limitations of this study should be considered. First, the CRANAPL tool may not have captured elements of optimal clinical reasoning documentation. The reliance on multiple methods and an iterative process in the refinement of the CRANAPL tool should have minimized this. Second, this study was conducted across a single healthcare system that uses the same EHR; this EHR or institutional culture may influence documentation practices and behaviors. Given that using the CRANAPL tool to score an A&P is quick and easy, the benefit of giving providers feedback on their notes remains to be seen—here and at other hospitals. Third, our sample size could limit the generalizability of the results and the significance of the associations. However, the sample assessed in our study was significantly larger than that assessed in other studies that have validated clinical reasoning rubrics.^14,15 Fourth, clinical reasoning is a broad and multidimensional construct. The CRANAPL tool focuses exclusively on hospitalists’ documentation of clinical reasoning and therefore does not assess aspects of clinical reasoning occurring in the physicians’ minds. Finally, given our goal to optimally validate the CRANAPL tool, we chose to test the tool on specific presentations that are known to be associated with diagnostic practice variation and errors. We may have observed different results had we chosen a different set of diagnoses from each hospital. Further validity evidence will be established when applying the CRANPL tool to different diagnoses and to notes from other clinical settings.

In conclusion, this study focuses on the development and validation of the CRANAPL tool that assesses how hospitalists document their clinical reasoning in the A&P section of admission notes. Our results show that wide variability exists in the documentation of clinical reasoning by hospitalists within and across hospitals. Given the CRANAPL tool’s ease-of-use and its versatility, hospitalist divisions in academic and nonacademic settings may use the CRANAPL tool to assess and provide feedback on the documentation of hospitalists’ clinical reasoning. Beyond studying whether physicians can be taught to improve their notes with feedback based on the CRANAPL tool, future studies may explore whether enhancing clinical reasoning documentation may be associated with improvements in patient care and clinical outcomes.

Acknowledgments

Dr. Wright is the Anne Gaines and G. Thomas Miller Professor of Medicine which is supported through Hopkins’ Center for Innovative Medicine.

The authors thank Christine Caufield-Noll, MLIS, AHIP (Johns Hopkins Bayview Medical Center, Baltimore, Maryland) for her assistance with this project.

Disclosures

The authors have nothing to disclose.

Approximately 60,000 hospitalists were working in the United States in 2018.¹ Hospitalist groups work collaboratively because of the shiftwork required for 24/7 patient coverage, and first-rate clinical documentation is essential for quality care.² Thoughtful clinical documentation not only transmits one provider’s clinical reasoning to other providers but is a professional responsibility.³ Hospitalists spend two-thirds of their time in indirect patient-care activities and approximately one quarter of their time on documentation in electronic health records (EHRs).⁴ Despite documentation occupying a substantial portion of the clinician’s time, published literature on the best practices for the documentation of clinical reasoning in hospital medicine or its assessment remains scant.^5-7

Clinical reasoning involves establishing a diagnosis and developing a therapeutic plan that fits the unique circumstances and needs of the patient.⁸ Inpatient providers who admit patients to the hospital end the admission note with their assessment and plan (A&P) after reflecting about a patient’s presenting illness. The A&P generally represents the interpretations, deductions, and clinical reasoning of the inpatient providers; this is the section of the note that fellow physicians concentrate on over others.⁹ The documentation of clinical reasoning in the A&P allows for many to consider how the recorded interpretations relate to their own elucidations resulting in distributed cognition.¹⁰

Disorganized documentation can contribute to cognitive overload and impede thoughtful consideration about the clinical presentation.³ The assessment of clinical documentation may translate into reduced medical errors and improved note quality.^11,12 Studies that have formally evaluated the documentation of clinical reasoning have focused exclusively on medical students.^13-15 The nonexistence of a detailed rubric for evaluating clinical reasoning in the A&Ps of hospitalists represents a missed opportunity for evaluating what hospitalists “do”; if this evolves into a mechanism for offering formative feedback, such professional development would impact the highest level of Miller’s assessment pyramid.¹⁶ We therefore undertook this study to establish a metric to assess the hospitalist providers’ documentation of clinical reasoning in the A&P of an admission note.

Study Design, Setting, and Subjects

This was a retrospective study that reviewed the admission notes of hospitalists for patients admitted over the period of January 2014 and October 2017 at three hospitals in Maryland. One is a community hospital (Hospital A) and two are academic medical centers (Hospital B and Hospital C). Even though these three hospitals are part of one health system, they have distinct cultures and leadership, serve different populations, and are staffed by different provider teams.

The notes of physicians working for the hospitalist groups at each of the three hospitals were the focus of the analysis in this study.

Development of the Documentation Assessment Rubric

A team was assembled to develop the Clinical Reasoning in Admission Note Assessment & PLan (CRANAPL) tool. The CRANAPL was designed to assess the comprehensiveness and thoughtfulness of the clinical reasoning documented in the A&P sections of the notes of patients who were admitted to the hospital with an acute illness. Validity evidence for CRANAPL was summarized on the basis of Messick’s unified validity framework by using four of the five sources of validity: content, response process, internal structure, and relations to other variables.¹⁷

Content Validity

The development team consisted of members who have an average of 10 years of clinical experience in hospital medicine; have studied clinical excellence and clinical reasoning; and have expertise in feedback, assessment, and professional development.^18-22 The development of the CRANAPL tool by the team was informed by a review of the clinical reasoning literature, with particular attention paid to the standards and competencies outlined by the Liaison Committee on Medical Education, the Association of American Medical Colleges, the Accreditation Council on Graduate Medical Education, the Internal Medicine Milestone Project, and the Society of Hospital Medicine.^23-26 For each of these parties, diagnostic reasoning and its impact on clinical decision-making are considered to be a core competency. Several works that heavily influenced the CRANAPL tool’s development were Baker’s Interpretive Summary, Differential Diagnosis, Explanation of Reasoning, And Alternatives (IDEA) assessment tool;¹⁴ King’s Pediatric History and Physical Exam Evaluation (P-HAPEE) rubric;¹⁵ and three other studies related to diagnostic reasoning.^16,27,28 These manuscripts and other works substantively informed the preliminary behavioral-based anchors that formed the initial foundation for the tool under development. The CRANAPL tool was shown to colleagues at other institutions who are leaders on clinical reasoning and was presented at academic conferences in the Division of General Internal Medicine and the Division of Hospital Medicine of our institution. Feedback resulted in iterative revisions. The aforementioned methods established content validity evidence for the CRANAPL tool.

Response Process Validity

Several of the authors pilot-tested earlier iterations on admission notes that were excluded from the sample when refining the CRANAPL tool. The weaknesses and sources of confusion with specific items were addressed by scoring 10 A&Ps individually and then comparing data captured on the tool. This cycle was repeated three times for the iterative enhancement and finalization of the CRANAPL tool. On several occasions when two authors were piloting the near-final CRANAPL tool, a third author interviewed each of the two authors about reactivity while assessing individual items and exploring with probes how their own clinical documentation practices were being considered when scoring the notes. The reasonable and thoughtful answers provided by the two authors as they explained and justified the scores they were selecting during the pilot testing served to confer response process validity evidence.

Finalizing the CRANAPL Tool

The nine-item CRANAPL tool includes elements for problem representation, leading diagnosis, uncertainty, differential diagnosis, plans for diagnosis and treatment, estimated length of stay (LOS), potential for upgrade in status to a higher level of care, and consideration of disposition. Although the final three items are not core clinical reasoning domains in the medical education literature, they represent clinical judgments that are especially relevant for the delivery of the high-quality and cost-effective care of hospitalized patients. Given that the probabilities and estimations of these three elements evolve over the course of any hospitalization on the basis of test results and response to therapy, the documentation of initial expectations on these fronts can facilitate distributed cognition with all individuals becoming wiser from shared insights.¹⁰ The tool uses two- and three-point rating scales, with each number score being clearly defined by specific written criteria (total score range: 0-14; Appendix).

Data Collection

Hospitalists’ admission notes from the three hospitals were used to validate the CRANAPL tool. Admission notes from patients hospitalized to the general medical floors with an admission diagnosis of either fever, syncope/dizziness, or abdominal pain were used. These diagnoses were purposefully examined because they (1) have a wide differential diagnosis, (2) are common presenting symptoms, and (3) are prone to diagnostic errors.^29-32

The centralized EHR system across the three hospitals identified admission notes with one of these primary diagnoses of patients admitted over the period of January 2014 to October 2017. We submitted a request for 650 admission notes to be randomly selected from the centralized institutional records system. The notes were stratified by hospital and diagnosis. The sample size of our study was comparable with that of prior psychometric validation studies.^33,34 Upon reviewing the A&Ps associated with these admissions, 365 notes were excluded for one of three reasons: (1) the note was written by a nurse practitioner, physician assistant, resident, or medical student; (2) the admission diagnosis had been definitively confirmed in the emergency department (eg, abdominal pain due to diverticulitis seen on CT); and (3) the note represented the fourth or more note by any single provider (to sample notes of many providers, no more than three notes written by any single provider were analyzed). A total of 285 admission notes were ultimately included in the sample.

Data were deidentified, and the A&P sections of the admission notes were each copied from the EHR into a unique Word document. Patient and hospital demographic data (including age, gender, race, number of comorbid conditions, LOS, hospital charges, and readmission to the same health system within 30 days) were collected separately from the EHR. Select physician characteristics were also collected from the hospitalist groups at each of the three hospitals, as was the length (word count) of each A&P.

The study was approved by our institutional review board.

Data Analysis

Two authors scored all deidentified A&Ps by using the finalized version of the CRANAPL tool. Prior to using the CRANAPL tool on each of the notes, these raters read each A&P and scored them by using two single-item rating scales: a global clinical reasoning and a global readability/clarity measure. Both of these global scales used three-item Likert scales (below average, average, and above average). These global rating scales collected the reviewers’ gestalt about the quality and clarity of the A&P. The use of gestalt ratings as comparators is supported by other research.³⁵

Descriptive statistics were computed for all variables. Each rater rescored a sample of 48 records (one month after the initial scoring) and intraclass correlations (ICCs) were computed for intrarater reliability. ICCs were calculated for each item and for the CRANAPL total to determine interrater reliability.

The averaged ratings from the two raters were used for all other analyses. For CRANAPL’s internal structure validity evidence, Cronbach’s alpha was calculated as a measure of internal consistency. For relations to other variables validity evidence, CRANAPL total scores were compared with the two global assessment variables with linear regressions.

Bivariate analyses were performed by applying parametric and nonparametric tests as appropriate. A series of multivariate linear regressions, controlling for diagnosis and clustered variance by hospital site, were performed using CRANAPL total as the dependent variable and patient variables as predictors.

All data were analyzed using Stata (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, Texas: StataCorp LP.)

The admission notes of 120 hospitalists were evaluated (Table 1). A total of 39 (33%) physicians were moonlighters with primary appointments outside of the hospitalist division, and 81 (68%) were full-time hospitalists. Among the 120 hospitalists, 48 (40%) were female, 60 (50%) were international medical graduates, and 90 (75%) were of nonwhite race. Most hospitalist physicians (n = 47, 58%) had worked in our health system for less than five years, and 64 hospitalists (53%) devoted greater than 50% of their time to patient care.

Approximately equal numbers of patient admission notes were pulled from each of the three hospitals. The average age of patients was 67.2 (SD 13.6) years, 145 (51%) were female, and 120 (42%) were of nonwhite race. The mean LOS for all patients was 4.0 (SD 3.4) days. A total of 44 (15%) patients were readmitted to the same health system within 30 days of discharge. None of the patients died during the incident hospitalization. The average charge for each of the hospitalizations was $10,646 (SD $9,964).

CRANAPL Data

Figure 1 shows the distribution of the scores given by each rater for each of the nine items. The mean of the total CRANAPL score given by both raters was 6.4 (SD 2.2). Scoring for some items were high (eg, summary statement: 1.5/2), whereas performance on others were low (eg, estimating LOS: 0.1/1 and describing the potential need for upgrade in care: 0.0/1).

Validity of the CRANAPL Tool’s Internal Structure

Cronbach’s alpha, which was used to measure internal consistency within the CRANAPL tool, was 0.43. The ICC, which was applied to measure the interrater reliability for both raters for the total CRANAPL score, was 0.83 (95% CI:  0.76-0.87). The ICC values for intrarater reliability for raters 1 and 2 were 0.73 (95% CI: 0.60-0.83) and 0.73 (95% CI: 0.45-0.86), respectively.

Relations to Other Variables Validity

Associations between CRANAPL total scores, global clinical reasoning, and global scores for note readability/clarity were statistically significant (P < .001), Figure 2.

Eight out of nine CRANAPL variables were statistically significantly different across the three hospitals (P <. 01) when data were analyzed by hospital site. Hospital C had the highest mean score of 7.4 (SD 2.0), followed by Hospital B with a score of 6.6 (SD 2.1), and Hospital A had the lowest total CRANAPL score of 5.2 (SD 1.9). This difference was statistically significant (P < .001). Five variables with respect to admission diagnoses (uncertainty acknowledged, differential diagnosis, plan for diagnosis, plan for treatment, and upgrade plan) were statistically significantly different across notes. Notes for syncope/dizziness generally yielded higher scores than those for abdominal pain and fever.

Factors Associated with High CRANAPL Scores

Table 2 shows the associations between CRANAPL scores and several covariates. Before adjustment, high CRANAPL scores were associated with high word counts of A&Ps (P < .001) and high hospital charges (P < .05). These associations were no longer significant after adjusting for hospital site and admitting diagnoses.

We reviewed the documentation of clinical reasoning in 285 admission notes at three different hospitals written by hospitalist physicians during routine clinical care. To our knowledge, this is the first study that assessed the documentation of hospitalists’ clinical reasoning with real patient notes. Wide variability exists in the documentation of clinical reasoning within the A&Ps of hospitalists’ admission notes. We have provided validity evidence to support the use of the user-friendly CRANAPL tool.

Prior studies have described rubrics for evaluating the clinical reasoning skills of medical students.^14,15 The ICCs for the IDEA rubric used to assess medical students’ documentation of clinical reasoning were fair to moderate (0.29-0.67), whereas the ICC for the CRANAPL tool was high at 0.83. This measure of reliability is similar to that for the P-HAPEE rubric used to assess medical students’ documentation of pediatric history and physical notes.¹⁵ These data are markedly different from the data in previous studies that have found low interrater reliability for psychometric evaluations related to judgment and decision-making.^36-39 CRANAPL was also found to have high intrarater reliability, which shows the reproducibility of an individual’s assessment over time. The strong association between the total CRANAPL score and global clinical reasoning assessment found in the present study is similar to that found in previous studies that have also embedded global rating scales as comparators when assessing clinical reasoning.^13,,15,40,41 Global rating scales represent an overarching structure for comparison given the absence of an accepted method or gold standard for assessing clinical reasoning documentation. High-quality provider notes are defined by clarity, thoroughness, and accuracy;³⁵ and effective documentation promotes communication and the coordination of care among the members of the care team.³

The total CRANAPL scores varied by hospital site with academic hospitals (B and C) scoring higher than the community hospital (A) in our study. Similarly, lengthy A&Ps were associated with high CRANAPL scores (P < .001) prior to adjustment for hospital site. Healthcare providers consider that the thoroughness of documentation denotes quality and attention to detail.^35,42 Comprehensive documentation takes time; the longer notes by academic hospitalists than those by community hospitalists may be attributed to the fewer number of patients generally carried by hospitalists at academic centers than that by hospitalists at community hospitals.⁴³

The documentation of the estimations of LOS, possibility of potential upgrade, and thoughts about disposition were consistently poorly described across all hospital sites and diagnoses. In contrast to CRANAPL, other clinical reasoning rubrics have excluded these items or discussed uncertainty.^14,15,44 These elements represent the forward thinking that may be essential for high-quality progressive care by hospitalists. Physicians’s difficulty in acknowledging uncertainty has been associated with resource overuse, including the excessive ordering of tests, iatrogenic injury, and heavy financial burden on the healthcare system.^45,46 The lack of thoughtful clinical and management reasoning at the time of admission is believed to be associated with medical errors.⁴⁷ If used as a guide, the CRANAPL tool may promote reflection on the part of the admitting physician. The estimations of LOS, potential for upgrade to a higher level of care, and disposition are markers of optimal inpatient care, especially for hospitalists who work in shifts with embedded handoffs. When shared with colleagues (through documentation), there is the potential for distributed cognition¹⁰ to extend throughout the social network of the hospitalist group. The fact that so few providers are currently including these items in their A&P’s show that the providers are either not performing or documenting the ‘reasoning’. Either way, this is an opportunity that has been highlighted by the CRANAPL tool.

Several limitations of this study should be considered. First, the CRANAPL tool may not have captured elements of optimal clinical reasoning documentation. The reliance on multiple methods and an iterative process in the refinement of the CRANAPL tool should have minimized this. Second, this study was conducted across a single healthcare system that uses the same EHR; this EHR or institutional culture may influence documentation practices and behaviors. Given that using the CRANAPL tool to score an A&P is quick and easy, the benefit of giving providers feedback on their notes remains to be seen—here and at other hospitals. Third, our sample size could limit the generalizability of the results and the significance of the associations. However, the sample assessed in our study was significantly larger than that assessed in other studies that have validated clinical reasoning rubrics.^14,15 Fourth, clinical reasoning is a broad and multidimensional construct. The CRANAPL tool focuses exclusively on hospitalists’ documentation of clinical reasoning and therefore does not assess aspects of clinical reasoning occurring in the physicians’ minds. Finally, given our goal to optimally validate the CRANAPL tool, we chose to test the tool on specific presentations that are known to be associated with diagnostic practice variation and errors. We may have observed different results had we chosen a different set of diagnoses from each hospital. Further validity evidence will be established when applying the CRANPL tool to different diagnoses and to notes from other clinical settings.

In conclusion, this study focuses on the development and validation of the CRANAPL tool that assesses how hospitalists document their clinical reasoning in the A&P section of admission notes. Our results show that wide variability exists in the documentation of clinical reasoning by hospitalists within and across hospitals. Given the CRANAPL tool’s ease-of-use and its versatility, hospitalist divisions in academic and nonacademic settings may use the CRANAPL tool to assess and provide feedback on the documentation of hospitalists’ clinical reasoning. Beyond studying whether physicians can be taught to improve their notes with feedback based on the CRANAPL tool, future studies may explore whether enhancing clinical reasoning documentation may be associated with improvements in patient care and clinical outcomes.

Acknowledgments

Dr. Wright is the Anne Gaines and G. Thomas Miller Professor of Medicine which is supported through Hopkins’ Center for Innovative Medicine.

The authors thank Christine Caufield-Noll, MLIS, AHIP (Johns Hopkins Bayview Medical Center, Baltimore, Maryland) for her assistance with this project.

Disclosures

The authors have nothing to disclose.

Approximately 60,000 hospitalists were working in the United States in 2018.¹ Hospitalist groups work collaboratively because of the shiftwork required for 24/7 patient coverage, and first-rate clinical documentation is essential for quality care.² Thoughtful clinical documentation not only transmits one provider’s clinical reasoning to other providers but is a professional responsibility.³ Hospitalists spend two-thirds of their time in indirect patient-care activities and approximately one quarter of their time on documentation in electronic health records (EHRs).⁴ Despite documentation occupying a substantial portion of the clinician’s time, published literature on the best practices for the documentation of clinical reasoning in hospital medicine or its assessment remains scant.^5-7

Clinical reasoning involves establishing a diagnosis and developing a therapeutic plan that fits the unique circumstances and needs of the patient.⁸ Inpatient providers who admit patients to the hospital end the admission note with their assessment and plan (A&P) after reflecting about a patient’s presenting illness. The A&P generally represents the interpretations, deductions, and clinical reasoning of the inpatient providers; this is the section of the note that fellow physicians concentrate on over others.⁹ The documentation of clinical reasoning in the A&P allows for many to consider how the recorded interpretations relate to their own elucidations resulting in distributed cognition.¹⁰

Disorganized documentation can contribute to cognitive overload and impede thoughtful consideration about the clinical presentation.³ The assessment of clinical documentation may translate into reduced medical errors and improved note quality.^11,12 Studies that have formally evaluated the documentation of clinical reasoning have focused exclusively on medical students.^13-15 The nonexistence of a detailed rubric for evaluating clinical reasoning in the A&Ps of hospitalists represents a missed opportunity for evaluating what hospitalists “do”; if this evolves into a mechanism for offering formative feedback, such professional development would impact the highest level of Miller’s assessment pyramid.¹⁶ We therefore undertook this study to establish a metric to assess the hospitalist providers’ documentation of clinical reasoning in the A&P of an admission note.

Study Design, Setting, and Subjects

This was a retrospective study that reviewed the admission notes of hospitalists for patients admitted over the period of January 2014 and October 2017 at three hospitals in Maryland. One is a community hospital (Hospital A) and two are academic medical centers (Hospital B and Hospital C). Even though these three hospitals are part of one health system, they have distinct cultures and leadership, serve different populations, and are staffed by different provider teams.

The notes of physicians working for the hospitalist groups at each of the three hospitals were the focus of the analysis in this study.

Development of the Documentation Assessment Rubric

A team was assembled to develop the Clinical Reasoning in Admission Note Assessment & PLan (CRANAPL) tool. The CRANAPL was designed to assess the comprehensiveness and thoughtfulness of the clinical reasoning documented in the A&P sections of the notes of patients who were admitted to the hospital with an acute illness. Validity evidence for CRANAPL was summarized on the basis of Messick’s unified validity framework by using four of the five sources of validity: content, response process, internal structure, and relations to other variables.¹⁷

Content Validity

The development team consisted of members who have an average of 10 years of clinical experience in hospital medicine; have studied clinical excellence and clinical reasoning; and have expertise in feedback, assessment, and professional development.^18-22 The development of the CRANAPL tool by the team was informed by a review of the clinical reasoning literature, with particular attention paid to the standards and competencies outlined by the Liaison Committee on Medical Education, the Association of American Medical Colleges, the Accreditation Council on Graduate Medical Education, the Internal Medicine Milestone Project, and the Society of Hospital Medicine.^23-26 For each of these parties, diagnostic reasoning and its impact on clinical decision-making are considered to be a core competency. Several works that heavily influenced the CRANAPL tool’s development were Baker’s Interpretive Summary, Differential Diagnosis, Explanation of Reasoning, And Alternatives (IDEA) assessment tool;¹⁴ King’s Pediatric History and Physical Exam Evaluation (P-HAPEE) rubric;¹⁵ and three other studies related to diagnostic reasoning.^16,27,28 These manuscripts and other works substantively informed the preliminary behavioral-based anchors that formed the initial foundation for the tool under development. The CRANAPL tool was shown to colleagues at other institutions who are leaders on clinical reasoning and was presented at academic conferences in the Division of General Internal Medicine and the Division of Hospital Medicine of our institution. Feedback resulted in iterative revisions. The aforementioned methods established content validity evidence for the CRANAPL tool.

Response Process Validity

Several of the authors pilot-tested earlier iterations on admission notes that were excluded from the sample when refining the CRANAPL tool. The weaknesses and sources of confusion with specific items were addressed by scoring 10 A&Ps individually and then comparing data captured on the tool. This cycle was repeated three times for the iterative enhancement and finalization of the CRANAPL tool. On several occasions when two authors were piloting the near-final CRANAPL tool, a third author interviewed each of the two authors about reactivity while assessing individual items and exploring with probes how their own clinical documentation practices were being considered when scoring the notes. The reasonable and thoughtful answers provided by the two authors as they explained and justified the scores they were selecting during the pilot testing served to confer response process validity evidence.

Finalizing the CRANAPL Tool

The nine-item CRANAPL tool includes elements for problem representation, leading diagnosis, uncertainty, differential diagnosis, plans for diagnosis and treatment, estimated length of stay (LOS), potential for upgrade in status to a higher level of care, and consideration of disposition. Although the final three items are not core clinical reasoning domains in the medical education literature, they represent clinical judgments that are especially relevant for the delivery of the high-quality and cost-effective care of hospitalized patients. Given that the probabilities and estimations of these three elements evolve over the course of any hospitalization on the basis of test results and response to therapy, the documentation of initial expectations on these fronts can facilitate distributed cognition with all individuals becoming wiser from shared insights.¹⁰ The tool uses two- and three-point rating scales, with each number score being clearly defined by specific written criteria (total score range: 0-14; Appendix).

Data Collection

Hospitalists’ admission notes from the three hospitals were used to validate the CRANAPL tool. Admission notes from patients hospitalized to the general medical floors with an admission diagnosis of either fever, syncope/dizziness, or abdominal pain were used. These diagnoses were purposefully examined because they (1) have a wide differential diagnosis, (2) are common presenting symptoms, and (3) are prone to diagnostic errors.^29-32

The centralized EHR system across the three hospitals identified admission notes with one of these primary diagnoses of patients admitted over the period of January 2014 to October 2017. We submitted a request for 650 admission notes to be randomly selected from the centralized institutional records system. The notes were stratified by hospital and diagnosis. The sample size of our study was comparable with that of prior psychometric validation studies.^33,34 Upon reviewing the A&Ps associated with these admissions, 365 notes were excluded for one of three reasons: (1) the note was written by a nurse practitioner, physician assistant, resident, or medical student; (2) the admission diagnosis had been definitively confirmed in the emergency department (eg, abdominal pain due to diverticulitis seen on CT); and (3) the note represented the fourth or more note by any single provider (to sample notes of many providers, no more than three notes written by any single provider were analyzed). A total of 285 admission notes were ultimately included in the sample.

Data were deidentified, and the A&P sections of the admission notes were each copied from the EHR into a unique Word document. Patient and hospital demographic data (including age, gender, race, number of comorbid conditions, LOS, hospital charges, and readmission to the same health system within 30 days) were collected separately from the EHR. Select physician characteristics were also collected from the hospitalist groups at each of the three hospitals, as was the length (word count) of each A&P.

The study was approved by our institutional review board.

Data Analysis

Two authors scored all deidentified A&Ps by using the finalized version of the CRANAPL tool. Prior to using the CRANAPL tool on each of the notes, these raters read each A&P and scored them by using two single-item rating scales: a global clinical reasoning and a global readability/clarity measure. Both of these global scales used three-item Likert scales (below average, average, and above average). These global rating scales collected the reviewers’ gestalt about the quality and clarity of the A&P. The use of gestalt ratings as comparators is supported by other research.³⁵

Descriptive statistics were computed for all variables. Each rater rescored a sample of 48 records (one month after the initial scoring) and intraclass correlations (ICCs) were computed for intrarater reliability. ICCs were calculated for each item and for the CRANAPL total to determine interrater reliability.

The averaged ratings from the two raters were used for all other analyses. For CRANAPL’s internal structure validity evidence, Cronbach’s alpha was calculated as a measure of internal consistency. For relations to other variables validity evidence, CRANAPL total scores were compared with the two global assessment variables with linear regressions.

Bivariate analyses were performed by applying parametric and nonparametric tests as appropriate. A series of multivariate linear regressions, controlling for diagnosis and clustered variance by hospital site, were performed using CRANAPL total as the dependent variable and patient variables as predictors.

All data were analyzed using Stata (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, Texas: StataCorp LP.)

The admission notes of 120 hospitalists were evaluated (Table 1). A total of 39 (33%) physicians were moonlighters with primary appointments outside of the hospitalist division, and 81 (68%) were full-time hospitalists. Among the 120 hospitalists, 48 (40%) were female, 60 (50%) were international medical graduates, and 90 (75%) were of nonwhite race. Most hospitalist physicians (n = 47, 58%) had worked in our health system for less than five years, and 64 hospitalists (53%) devoted greater than 50% of their time to patient care.

Approximately equal numbers of patient admission notes were pulled from each of the three hospitals. The average age of patients was 67.2 (SD 13.6) years, 145 (51%) were female, and 120 (42%) were of nonwhite race. The mean LOS for all patients was 4.0 (SD 3.4) days. A total of 44 (15%) patients were readmitted to the same health system within 30 days of discharge. None of the patients died during the incident hospitalization. The average charge for each of the hospitalizations was $10,646 (SD $9,964).

CRANAPL Data

Figure 1 shows the distribution of the scores given by each rater for each of the nine items. The mean of the total CRANAPL score given by both raters was 6.4 (SD 2.2). Scoring for some items were high (eg, summary statement: 1.5/2), whereas performance on others were low (eg, estimating LOS: 0.1/1 and describing the potential need for upgrade in care: 0.0/1).

Validity of the CRANAPL Tool’s Internal Structure

Cronbach’s alpha, which was used to measure internal consistency within the CRANAPL tool, was 0.43. The ICC, which was applied to measure the interrater reliability for both raters for the total CRANAPL score, was 0.83 (95% CI:  0.76-0.87). The ICC values for intrarater reliability for raters 1 and 2 were 0.73 (95% CI: 0.60-0.83) and 0.73 (95% CI: 0.45-0.86), respectively.

Relations to Other Variables Validity

Associations between CRANAPL total scores, global clinical reasoning, and global scores for note readability/clarity were statistically significant (P < .001), Figure 2.

Eight out of nine CRANAPL variables were statistically significantly different across the three hospitals (P <. 01) when data were analyzed by hospital site. Hospital C had the highest mean score of 7.4 (SD 2.0), followed by Hospital B with a score of 6.6 (SD 2.1), and Hospital A had the lowest total CRANAPL score of 5.2 (SD 1.9). This difference was statistically significant (P < .001). Five variables with respect to admission diagnoses (uncertainty acknowledged, differential diagnosis, plan for diagnosis, plan for treatment, and upgrade plan) were statistically significantly different across notes. Notes for syncope/dizziness generally yielded higher scores than those for abdominal pain and fever.

Factors Associated with High CRANAPL Scores

Table 2 shows the associations between CRANAPL scores and several covariates. Before adjustment, high CRANAPL scores were associated with high word counts of A&Ps (P < .001) and high hospital charges (P < .05). These associations were no longer significant after adjusting for hospital site and admitting diagnoses.

We reviewed the documentation of clinical reasoning in 285 admission notes at three different hospitals written by hospitalist physicians during routine clinical care. To our knowledge, this is the first study that assessed the documentation of hospitalists’ clinical reasoning with real patient notes. Wide variability exists in the documentation of clinical reasoning within the A&Ps of hospitalists’ admission notes. We have provided validity evidence to support the use of the user-friendly CRANAPL tool.

Prior studies have described rubrics for evaluating the clinical reasoning skills of medical students.^14,15 The ICCs for the IDEA rubric used to assess medical students’ documentation of clinical reasoning were fair to moderate (0.29-0.67), whereas the ICC for the CRANAPL tool was high at 0.83. This measure of reliability is similar to that for the P-HAPEE rubric used to assess medical students’ documentation of pediatric history and physical notes.¹⁵ These data are markedly different from the data in previous studies that have found low interrater reliability for psychometric evaluations related to judgment and decision-making.^36-39 CRANAPL was also found to have high intrarater reliability, which shows the reproducibility of an individual’s assessment over time. The strong association between the total CRANAPL score and global clinical reasoning assessment found in the present study is similar to that found in previous studies that have also embedded global rating scales as comparators when assessing clinical reasoning.^13,,15,40,41 Global rating scales represent an overarching structure for comparison given the absence of an accepted method or gold standard for assessing clinical reasoning documentation. High-quality provider notes are defined by clarity, thoroughness, and accuracy;³⁵ and effective documentation promotes communication and the coordination of care among the members of the care team.³

The total CRANAPL scores varied by hospital site with academic hospitals (B and C) scoring higher than the community hospital (A) in our study. Similarly, lengthy A&Ps were associated with high CRANAPL scores (P < .001) prior to adjustment for hospital site. Healthcare providers consider that the thoroughness of documentation denotes quality and attention to detail.^35,42 Comprehensive documentation takes time; the longer notes by academic hospitalists than those by community hospitalists may be attributed to the fewer number of patients generally carried by hospitalists at academic centers than that by hospitalists at community hospitals.⁴³

The documentation of the estimations of LOS, possibility of potential upgrade, and thoughts about disposition were consistently poorly described across all hospital sites and diagnoses. In contrast to CRANAPL, other clinical reasoning rubrics have excluded these items or discussed uncertainty.^14,15,44 These elements represent the forward thinking that may be essential for high-quality progressive care by hospitalists. Physicians’s difficulty in acknowledging uncertainty has been associated with resource overuse, including the excessive ordering of tests, iatrogenic injury, and heavy financial burden on the healthcare system.^45,46 The lack of thoughtful clinical and management reasoning at the time of admission is believed to be associated with medical errors.⁴⁷ If used as a guide, the CRANAPL tool may promote reflection on the part of the admitting physician. The estimations of LOS, potential for upgrade to a higher level of care, and disposition are markers of optimal inpatient care, especially for hospitalists who work in shifts with embedded handoffs. When shared with colleagues (through documentation), there is the potential for distributed cognition¹⁰ to extend throughout the social network of the hospitalist group. The fact that so few providers are currently including these items in their A&P’s show that the providers are either not performing or documenting the ‘reasoning’. Either way, this is an opportunity that has been highlighted by the CRANAPL tool.

Several limitations of this study should be considered. First, the CRANAPL tool may not have captured elements of optimal clinical reasoning documentation. The reliance on multiple methods and an iterative process in the refinement of the CRANAPL tool should have minimized this. Second, this study was conducted across a single healthcare system that uses the same EHR; this EHR or institutional culture may influence documentation practices and behaviors. Given that using the CRANAPL tool to score an A&P is quick and easy, the benefit of giving providers feedback on their notes remains to be seen—here and at other hospitals. Third, our sample size could limit the generalizability of the results and the significance of the associations. However, the sample assessed in our study was significantly larger than that assessed in other studies that have validated clinical reasoning rubrics.^14,15 Fourth, clinical reasoning is a broad and multidimensional construct. The CRANAPL tool focuses exclusively on hospitalists’ documentation of clinical reasoning and therefore does not assess aspects of clinical reasoning occurring in the physicians’ minds. Finally, given our goal to optimally validate the CRANAPL tool, we chose to test the tool on specific presentations that are known to be associated with diagnostic practice variation and errors. We may have observed different results had we chosen a different set of diagnoses from each hospital. Further validity evidence will be established when applying the CRANPL tool to different diagnoses and to notes from other clinical settings.

In conclusion, this study focuses on the development and validation of the CRANAPL tool that assesses how hospitalists document their clinical reasoning in the A&P section of admission notes. Our results show that wide variability exists in the documentation of clinical reasoning by hospitalists within and across hospitals. Given the CRANAPL tool’s ease-of-use and its versatility, hospitalist divisions in academic and nonacademic settings may use the CRANAPL tool to assess and provide feedback on the documentation of hospitalists’ clinical reasoning. Beyond studying whether physicians can be taught to improve their notes with feedback based on the CRANAPL tool, future studies may explore whether enhancing clinical reasoning documentation may be associated with improvements in patient care and clinical outcomes.

Acknowledgments

Dr. Wright is the Anne Gaines and G. Thomas Miller Professor of Medicine which is supported through Hopkins’ Center for Innovative Medicine.

The authors thank Christine Caufield-Noll, MLIS, AHIP (Johns Hopkins Bayview Medical Center, Baltimore, Maryland) for her assistance with this project.

Disclosures

The authors have nothing to disclose.

A 56-year-old Japanese man with a history of renal transplantation 20 years prior presented to the emergency department (ED) with two months of dyspnea on exertion and one day of fever and chills. The patient was in his usual state of health until two months prior to presentation, when he gradually noticed shortness of breath after sustained or effortful physical activities. The dyspnea improved with rest. Over the following two months, he noticed that the shortness of breath came on with lesser degrees of exertion, such as walking 100 meters. One day before presentation, he developed a fever of 39°C and chills at home, which prompted him to seek ED care. He denied chest pain, cough, leg swelling, or paroxysmal nocturnal dyspnea.

The differential diagnosis of exertional dyspnea progressing over several months includes cardiac, pulmonary, hematologic, and neuromuscular conditions. The patient’s history of renal transplantation prompts consideration of worsening indolent pneumonia (eg, Aspergillus, cytomegalovirus [CMV], or Pneumocystis pneumonia), allograft dysfunction with volume overload, recrudescence of the underlying disease that incited renal failure earlier in life (eg, vasculitis), or a late-onset posttransplantation lymphoproliferative disorder (PTLD). Additionally, acute fever in an immunocompromised patient immediately raises suspicion for infection (eg, pneumonia, enteritis, or urinary tract infection). At this point, it is difficult to know whether the subacute-to-chronic exertional dyspnea and the acute fever are consequences of the same disease or separate, potentially overlapping, processes.

His past medical history was significant for end-stage renal disease due to membranoproliferative glomerular nephropathy (MPGN), for which living, related-donor kidney transplantation was performed 20 years earlier. He also had type 2 diabetes mellitus, hypertension, and basal cell carcinoma of the face, which had been resected three years prior without spread or recurrence. He had no known allergies. Medications included prednisolone 15 mg daily, azathioprine 100 mg daily, and cyclosporine 100 mg daily, as well as amlodipine and candesartan. He lived in Japan with his wife and children. He denied any animal or environmental exposures. He did not smoke cigarettes or drink alcohol and had not traveled recently. His father had diabetes mellitus.

Recrudescence of an underlying autoimmune condition that may have incited MPGN earlier in life is unlikely while taking an immunosuppressive regimen consisting of prednisolone, azathioprine, and cyclosporine. However, these medications do increase susceptibility to infections, lymphoma, and skin cancers. Though he is immunocompromised, the patient is not on prophylaxis for Pneumocystis pneumonia (PCP). PCP in HIV-negative patients is associated with recent glucocorticoid exposure and typically follows an acute-to-subacute course with hypoxemia and respiratory distress. Though the risk of PCP infection is considered highest in the early posttransplantation period (when immunosuppression is most intense), many cases are diagnosed years after transplantation among patients no longer on prophylaxis. The patient has type 2 diabetes mellitus and hypertension, which are known complications of calcineurin inhibitor and steroid therapy and increase the risk of cardiovascular disease. Cardiovascular disease is a major cause of death among renal transplant recipients. Exertional dyspnea may be the presenting symptom of coronary artery disease.

On physical examination, the patient was alert, oriented, and in no acute distress. His temperature was 38.5°C, blood pressure 120/60 mm Hg, heart rate 146 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 93% while breathing ambient air. The conjunctiva were normal without pallor or icterus. There was no cervical lymphadenopathy. Cardiac examination revealed tachycardia with a regular rhythm, normal S1 and S2, and no murmurs, rubs, or gallops. Jugular venous pressure was not elevated, and there was no lower extremity edema. Lungs were clear to auscultation bilaterally. The abdomen was soft, nontender, and nondistended. There was no tenderness over the transplanted kidney and no hepatosplenomegaly.

Dyspnea, fever, and tachycardia may be the sole manifestations of pneumonia in solid organ transplant recipients. The absence of cough or adventitious breath sounds does not eliminate concern for pneumonia. Pathogens that cause indolent pneumonia in immunocompromised patients include viruses (such as typical respiratory viruses and CMV), bacteria (typical organisms, Nocardia, Rhodococcus), and mycobacteria. Fungal causes include Aspergillus, Candida, Cryptococcus, Pneumocystis, and endemic mycoses. A detailed environmental history should be taken, and providers should ascertain which fungal diseases are endemic in the patient’s region of residence. There are no examination features suggesting hypervolemia or anemia. Although there is no hepatosplenomegaly or lymphadenopathy, PTLD often involves extranodal tissues, including the lungs. The incidence of PTLD is highest in the 12 months following transplantation, but it may occur at any time in the posttransplantation course. A complete blood count, comprehensive metabolic panel, lactate dehydrogenase (LDH), and blood and sputum cultures are indicated, along with computed tomography (CT) of the chest.

The leukocyte count was 3,500 cells/mm³, the hemoglobin level 9.0 g/dL, mean corpuscular volume 102 fL, and the platelet count 137,000 cells/mm³. The sodium level was 130 mEq/L, potassium 4.6 mEq/L, blood urea nitrogen 41 mg/dL, and creatinine 3.5 mg/dL. These complete blood count and serum electrolyte results were unchanged from the patient’s baseline values. The serum LDH level was 1,895 IU/L (normal range, 115-245 IU/L). The serum ferritin was 2,114 ng/mL (normal range, 13-277 ng/mL). A chest radiograph revealed diffuse, airspace-filling opacities in the bilateral lung bases. The urinalysis was normal. The patient was admitted and started empirically on intravenous ceftriaxone for potential bacterial pneumonia.

Chronic pancytopenia may result from azathioprine or cyclosporine use, marrow suppression or infiltration by a multisystem disease, or nutritional deficiency. Hemophagocytic lymphohistiocytosis (HLH) triggered by infection, a rheumatologic condition, acquired immunodeficiency, or malignancy can present with fevers, pancytopenia, and elevated ferritin, while splenomegaly may be absent. The euvolemic state, baseline creatinine level, and normal urinalysis argue against allograft dysfunction. The elevated serum ferritin nonspecifically confirms systemic inflammation. LDH, an intracellular enzyme involved in the bidirectional conversion of lactate to pyruvate, is expressed across tissue types. Elevated serum LDH attests to cell destruction, in this case potentially from lung infection (such as PCP) or malignancy (such as PTLD). At this point, the differential diagnosis of fever and pulmonary infiltrates in this patient remains broad.

Azathioprine and cyclosporine were stopped. The patient remained febrile despite the administration of intravenous antibiotics. His hypoxia worsened with an oxygen saturation of 90%-93% on 5 L/min of supplemental oxygen administered by nasal cannula. Noncontrast chest CT obtained on the second hospital day revealed ground-glass opacities in the bilateral lung bases. Blood, sputum, and urine cultures were sterile. As empiric therapies, ganciclovir was started for CMV infection, ciprofloxacin added for atypical pneumonia, and trimethoprim-sulfamethoxazole added for Pneumocystis infection.

These chest imaging findings help prioritize the differential diagnosis. Bibasilar ground-glass opacities are evident, while pulmonary masses, nodules, cavitation, adenopathy, and pleural effusions are absent. The differential diagnosis of multifocal ground-glass opacities on chest imaging includes infectious pneumonia, chronic interstitial lung disease, acute alveolar conditions (eg, cardiogenic pulmonary edema, acute respiratory distress syndrome, diffuse alveolar hemorrhage), or other pathologies (eg, drug toxicity, bronchoalveolar carcinoma, cryptogenic organizing pneumonia).

Infectious pneumonia is the principal concern. A diagnosis of PCP could be unifying, given dyspnea, progressive respiratory failure with hypoxia, and elevated LDH in an immunocompromised patient who is not prescribed PCP prophylaxis. The bilateral lung infiltrates and the absence of thoracic adenopathy or pleural effusions are characteristic of PCP as well. However, caution should be exercised in making specific infectious diagnoses in immunocompromised hosts on the basis of clinical and imaging findings alone. There can be overlap in the radiologic appearance of various infections (eg, CMV pneumonia can also present with bilateral ground-glass infiltrates, with concurrent fever, hypoxia, and pancytopenia). Additionally, more than one pneumonic pathogen may be implicated (eg, acute viral pneumonia superimposed on indolent fungal pneumonia). Polymerase chain reaction (PCR) analysis of respiratory secretions for viruses, serum PCR and serologic testing for herpes viruses, and serum beta-D-glucan and galactomannan assays are indicated. Serum serologic testing for fungi and bacteria such as Nocardia can be helpful, though the negative predictive values of these tests may be reduced in patients with impaired humoral immunity. Timely bronchoalveolar lavage (BAL) with microbiologic and PCR analysis and cytology is advised.

Fever, elevated LDH, cytopenias, and pulmonary infiltrates also raise suspicion for an underlying hematologic malignancy, such as PTLD. However, pulmonary PTLD is seen more often in lung transplant recipients than in patients who have undergone transplantation of other solid organs. In kidney transplant recipients, PTLD most commonly manifests in the allograft itself, gastrointestinal tract, central nervous system, or lymph nodes; lung involvement is less common. Chest imaging in affected patients may reveal nodular or reticulonodular infiltrates of basilar predominance, solitary or multiple masses, cavitating or necrotic lesions, and/or lymphadenopathy. In this patient who has undergone renal transplantation, late-onset PTLD with isolated pulmonary involvement, with only ground-glass opacities on lung imaging, would be an atypical presentation of an uncommon syndrome.

Despite empiric treatment with antibiotics and antiviral agents, the patient’s fever persisted. His respiratory rate increased to 30 breaths per minute. His hypoxia worsened, and he required nasal cannula high-flow oxygen supplementation at 30 L/min with a fraction of inspired oxygen (FiO₂) of 40%. On the fifth hospital day, contrast CT scan of the chest and abdomen showed new infiltrates in the bilateral upper lung fields as well as an area of low density in the tail of the pancreas without a focal mass (Figure 1). At this point, BAL was performed, and fluid PCR analysis returned positive for Pneumocystis jirovecii. CMV direct immunoperoxidase staining of leukocytes with peroxidase-labeled monoclonal antibody (C7-HRP test) was positive at five cells per 7.35 × 10⁴ peripheral blood leukocytes. The serum Epstein-Barr virus (EBV) viral capsid antigen (VCA) IgG was positive, while VCA IgM and EBV nuclear antigen IgG were negative. A bone marrow biopsy revealed mild hemophagocytosis. His serum soluble interleukin-2 (sIL2R) level was elevated at 5,254 U/mL (normal range, 122-496 U/mL). Given the BAL Pneumocystis PCR result, the dose of prednisolone was increased to 30 mg/day, and the patient’s fever subsided. Supplemental oxygen was weaned to an FiO₂ of 35%.

A CMV antigenemia assay returned positive, suggesting prior CMV infection. However, to diagnose CMV pneumonia, the virus must be detected in BAL fluid by PCR or cytologic analysis. CMV infection has been associated with cytopenias, HLH, pancreatic infiltration, and an increased risk for fungal infections and EBV-related PTLD. CMV infection could explain the first phase of this patient’s illness. Serum and BAL PCR for CMV are advised. Meanwhile, EBV testing indicates prior infection but does not distinguish between recent or more distant infection. EBV has been implicated in the pathophysiology of PTLD, as EBV-infected lymphoid tissue may proliferate in a variety of organs under reduced T-cell surveillance. EBV infection or PTLD with resulting immunomodulation may pose other explanations for this patient’s development of PCP infection. Cytologic analysis of the BAL fluid and marrow aspirate for evidence of PTLD is warranted. Finally, CMV, EBV, and PTLD have each been reported to trigger HLH. Though this patient has fevers, mild marrow hemophagocytosis, elevated serum ferritin, and elevated serum IL-2 receptor levels, he does not meet other diagnostic criteria for HLH (such as more pronounced cytopenias, splenomegaly, hypertriglyceridemia, hypofibrinogenemia, and low or absent natural killer T-cell activity). However, HLH may be muted in this patient because he was prescribed cyclosporine, which has been used in HLH treatment protocols.

On the 11^th hospital day, the patient developed hemorrhagic shock due to massive hematemesis and was transferred to the intensive care unit. His hemoglobin level was 5.9 g/dL. A total of 18 units of packed red blood cells were transfused over the following week for ongoing gastrointestinal bleeding. The serum LDH level increased to 4,139 IU/L, and the ferritin level rose to 7,855 ng/mL. The EBV copy level by serum PCR returned at 1 × 10⁶ copies/mL (normal range, less than 2 x 10² copies/mL). The patient was started on methylprednisolone (1 g/day for three days) and transitioned to dexamethasone and cyclosporine for possible EBV-related HLH. Ceftazidime, vancomycin, trimethoprim-sulfamethoxazole, and ciprofloxacin were administered. Amphotericin-B was initiated empirically for potential fungal pneumonia. Ganciclovir was continued. However, the patient remained in shock despite vasopressors and transfusions and died on the 22^nd hospital day.

The patient deteriorated despite broad antimicrobial therapy. Laboratory studies revealed EBV viremia and rising serum LDH. Recent EBV infection may have induced PTLD in the gastrointestinal tract, which is a commonly involved site among affected renal transplant patients. Corticosteroids and stress from critical illness can contribute to intestinal mucosal erosion and bleeding from a luminal PTLD lesion. Overall, the patient’s condition was likely explained by EBV infection, which triggered HLH and gastrointestinal PTLD. The resulting immunomodulation increased his risk for PCP infection beyond that conferred by chronic immunosuppression. It is still possible that he had concomitant CMV pneumonia, Aspergillus pneumonia, or even pulmonary PTLD, in addition to the proven PCP diagnosis.

An autopsy was performed. Atypical lymphocytic infiltration and diffuse alveolar damage were shown in the right upper lobe (Figure 2). EBV RNA-positive atypical lymphocytes coexpressing CD20 were demonstrated in multiple organs including the bone marrow, lungs, heart, stomach, adrenal glands, duodenum, ileum, and mesentery (Figure 3). This confirmed the diagnosis of an underlying EBV-positive posttransplant lymphoproliferative disorder. Serum and BAL CMV PCR assays returned negative. Neither CMV nor Aspergillus was identified in autopsy specimens.

A broad differential diagnosis should be considered when acute fever develops in a patient who has undergone solid organ transplantation. Causes may include opportunistic and nonopportunistic infections as well as noninfectious etiologies such as malignancy, organ rejection, inflammatory conditions, and medication toxicity.^1,2 As the discussant noted, more than one infection, or both infection and malignancy, can coexist in immunocompromised patients. For example, while viral pathogens such as EBV, CMV, and respiratory syncytial virus can cause illness due to direct tissue infection, they can also exert indirect effects in transplant recipients: acting as cofactors for and enabling other infections by causing immunosuppression (eg, Aspergillus or PCP developing after CMV infection), triggering graft rejection by upregulating proinflammatory cytokines, and inducing oncogenesis (eg, EBV-related PTLD).^1,3-5

PTLD is a rare but serious complication of solid organ transplantation and immunosuppression. Most cases are driven by EBV infection and subsequent transformation of infected lymphoid tissue in a variety of organs in the context of reduced T-cell surveillance.⁶ The incidence of PTLD varies based on the organ transplanted, ranging from 0.8%-2.5% in those who have undergone renal transplantation to 1.0%-5.5% in liver transplant recipients and 3.0%-10% in lung transplant recipients.³ The incidence has increased over the past decade. This may be due to a greater number of solid organ transplantations being performed, aging of the transplant donor/recipient population, new immunosuppressive regimens, and improved PTLD diagnosis due to superior diagnostic tools and clinician awareness.³ However, the mortality rate among solid organ transplant recipients with PTLD remains high, ranging from 40% to 70%.⁶

Risk factors for PTLD include a greater intensity of T-cell immunosuppression,⁷ history of pretransplant malignancy, recipient EBV seronegativity and donor seropositivity, and younger age at the time of transplantation.^8-10 EBV-related PTLD incidence in solid organ transplant recipients is greatest in the early posttransplantation course (the period of most intense immunosuppression) with over 80% of cases occurring in the first posttransplant year.¹¹

A high index of suspicion for PTLD is warranted in any solid organ transplant recipient who presents with constitutional symptoms, adenopathy, or cytopenias. Clinical suspicion of PTLD can be informed by risk factors, constitutional symptoms, elevated serum LDH, a detectable or rising serum EBV viral load, and radiologic adenopathy or visceral tissue infiltration.¹² The clinical presentation of PTLD is heterogeneous and varies in accordance with the organs affected. Extranodal involvement, such as pulmonary, gastrointestinal, and bone marrow involvement, is more common in PTLD than in other types of lymphoma.¹³ In this patient, the cytopenias, elevated serum LDH level, lung infiltrates, and radiologic pancreatic tail abnormality served as early clues to the presence of underlying PTLD.

The standard approach to diagnosing PTLD is biopsy of a suspicious lesion (adenopathy or an infiltrated visceral organ) with histopathological examination. Pathology may demonstrate distorted tissue architecture, clonal lymphocytes, or EBV-positive lymphocytes.¹⁴ Conventional CT is the most commonly used imaging modality to detect adenopathy or tissue infiltration related to PTLD,³ though 18F-fluorodeoxyglucose position-emission tomography (FDG-PET) is also used. Although FDG-PET has high diagnostic accuracy, with an overall sensitivity of 89% and specificity of 89%, false-negative results have been reported, particularly in cases of early PTLD lesions and diffuse large B-cell lymphoma.¹⁵ The majority of patients with EBV-associated PTLD demonstrate significant elevations in the serum EBV viral load compared with immunosuppressed controls without PTLD.¹⁶ An elevated EBV viral load can support a diagnosis of PTLD, though the absence of EBV viremia does not rule it out.¹⁷ Some transplant centers perform posttransplantation monitoring of the serum EBV viral load to aid in PTLD risk assessment and early diagnosis.

Management of PTLD is patient-specific and may involve reduction of immunosuppressive therapy, rituximab, chemotherapy, surgical excision, and/or radiation.¹³ Reduction of immunosuppression is the cornerstone of treatment.¹⁸ In patients who do not respond to the reduction of immunosuppression, rituximab and immunochemotherapy are second-line treatment options. A prospective, multicenter phase 2 trial (the PTLD-1 trial) demonstrated a complete response rate of 40% among patients with PTLD managed with rituximab.¹⁹

In summary, this case illustrates the importance of maintaining a broad differential diagnosis when acute fever develops in a patient who has undergone solid organ transplantation. The presence of more than one condition should be considered when the clinical presentation cannot be explained by a single diagnosis, as infections and malignancies can coexist in immunocompromised hosts. This case also highlights an unusual clinical presentation of PTLD, which was heralded mainly by its immunomodulatory effects rather than by compatible symptoms or obvious mass lesions.

Carefully reviewing the patient’s medical history and understanding how it sets the stage for the present illness is an essential step in clinical problem solving, because what is past is prologue.

• Fever in solid organ transplant recipients should prompt consideration of a broad differential diagnosis, including infection, malignancy, organ graft rejection, autoimmune disease, and medication toxicity.
• PTLD is a rare but serious complication of organ transplantation. Most cases are driven by EBV infection and transformation of infected lymphocytes in a variety of organs in the context of reduced T-cell surveillance. The clinical presentation can be heterogeneous and varies depending on the organs and tissues involved.
• More than one infection, or both infection and malignancy, can coexist in organ transplant recipients. Viral pathogens can exert direct pathologic effects on tissue but can also exert indirect effects, such as contributing to opportunistic infection susceptibility, graft rejection, and oncogenesis.

Disclosures

The authors have nothing to disclose.

Previous Publication

This case was originally reported in the 121st Okinawa Association of Medical Sciences in 2015 in Okinawa, Japan, and the conference abstracts were covered in The Okinawa Medical Journal. The publication did not provide any detailed, step-by-step analysis of clinical decision-making.

A 56-year-old Japanese man with a history of renal transplantation 20 years prior presented to the emergency department (ED) with two months of dyspnea on exertion and one day of fever and chills. The patient was in his usual state of health until two months prior to presentation, when he gradually noticed shortness of breath after sustained or effortful physical activities. The dyspnea improved with rest. Over the following two months, he noticed that the shortness of breath came on with lesser degrees of exertion, such as walking 100 meters. One day before presentation, he developed a fever of 39°C and chills at home, which prompted him to seek ED care. He denied chest pain, cough, leg swelling, or paroxysmal nocturnal dyspnea.

The differential diagnosis of exertional dyspnea progressing over several months includes cardiac, pulmonary, hematologic, and neuromuscular conditions. The patient’s history of renal transplantation prompts consideration of worsening indolent pneumonia (eg, Aspergillus, cytomegalovirus [CMV], or Pneumocystis pneumonia), allograft dysfunction with volume overload, recrudescence of the underlying disease that incited renal failure earlier in life (eg, vasculitis), or a late-onset posttransplantation lymphoproliferative disorder (PTLD). Additionally, acute fever in an immunocompromised patient immediately raises suspicion for infection (eg, pneumonia, enteritis, or urinary tract infection). At this point, it is difficult to know whether the subacute-to-chronic exertional dyspnea and the acute fever are consequences of the same disease or separate, potentially overlapping, processes.

His past medical history was significant for end-stage renal disease due to membranoproliferative glomerular nephropathy (MPGN), for which living, related-donor kidney transplantation was performed 20 years earlier. He also had type 2 diabetes mellitus, hypertension, and basal cell carcinoma of the face, which had been resected three years prior without spread or recurrence. He had no known allergies. Medications included prednisolone 15 mg daily, azathioprine 100 mg daily, and cyclosporine 100 mg daily, as well as amlodipine and candesartan. He lived in Japan with his wife and children. He denied any animal or environmental exposures. He did not smoke cigarettes or drink alcohol and had not traveled recently. His father had diabetes mellitus.

Recrudescence of an underlying autoimmune condition that may have incited MPGN earlier in life is unlikely while taking an immunosuppressive regimen consisting of prednisolone, azathioprine, and cyclosporine. However, these medications do increase susceptibility to infections, lymphoma, and skin cancers. Though he is immunocompromised, the patient is not on prophylaxis for Pneumocystis pneumonia (PCP). PCP in HIV-negative patients is associated with recent glucocorticoid exposure and typically follows an acute-to-subacute course with hypoxemia and respiratory distress. Though the risk of PCP infection is considered highest in the early posttransplantation period (when immunosuppression is most intense), many cases are diagnosed years after transplantation among patients no longer on prophylaxis. The patient has type 2 diabetes mellitus and hypertension, which are known complications of calcineurin inhibitor and steroid therapy and increase the risk of cardiovascular disease. Cardiovascular disease is a major cause of death among renal transplant recipients. Exertional dyspnea may be the presenting symptom of coronary artery disease.

On physical examination, the patient was alert, oriented, and in no acute distress. His temperature was 38.5°C, blood pressure 120/60 mm Hg, heart rate 146 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 93% while breathing ambient air. The conjunctiva were normal without pallor or icterus. There was no cervical lymphadenopathy. Cardiac examination revealed tachycardia with a regular rhythm, normal S1 and S2, and no murmurs, rubs, or gallops. Jugular venous pressure was not elevated, and there was no lower extremity edema. Lungs were clear to auscultation bilaterally. The abdomen was soft, nontender, and nondistended. There was no tenderness over the transplanted kidney and no hepatosplenomegaly.

Dyspnea, fever, and tachycardia may be the sole manifestations of pneumonia in solid organ transplant recipients. The absence of cough or adventitious breath sounds does not eliminate concern for pneumonia. Pathogens that cause indolent pneumonia in immunocompromised patients include viruses (such as typical respiratory viruses and CMV), bacteria (typical organisms, Nocardia, Rhodococcus), and mycobacteria. Fungal causes include Aspergillus, Candida, Cryptococcus, Pneumocystis, and endemic mycoses. A detailed environmental history should be taken, and providers should ascertain which fungal diseases are endemic in the patient’s region of residence. There are no examination features suggesting hypervolemia or anemia. Although there is no hepatosplenomegaly or lymphadenopathy, PTLD often involves extranodal tissues, including the lungs. The incidence of PTLD is highest in the 12 months following transplantation, but it may occur at any time in the posttransplantation course. A complete blood count, comprehensive metabolic panel, lactate dehydrogenase (LDH), and blood and sputum cultures are indicated, along with computed tomography (CT) of the chest.

The leukocyte count was 3,500 cells/mm³, the hemoglobin level 9.0 g/dL, mean corpuscular volume 102 fL, and the platelet count 137,000 cells/mm³. The sodium level was 130 mEq/L, potassium 4.6 mEq/L, blood urea nitrogen 41 mg/dL, and creatinine 3.5 mg/dL. These complete blood count and serum electrolyte results were unchanged from the patient’s baseline values. The serum LDH level was 1,895 IU/L (normal range, 115-245 IU/L). The serum ferritin was 2,114 ng/mL (normal range, 13-277 ng/mL). A chest radiograph revealed diffuse, airspace-filling opacities in the bilateral lung bases. The urinalysis was normal. The patient was admitted and started empirically on intravenous ceftriaxone for potential bacterial pneumonia.

Chronic pancytopenia may result from azathioprine or cyclosporine use, marrow suppression or infiltration by a multisystem disease, or nutritional deficiency. Hemophagocytic lymphohistiocytosis (HLH) triggered by infection, a rheumatologic condition, acquired immunodeficiency, or malignancy can present with fevers, pancytopenia, and elevated ferritin, while splenomegaly may be absent. The euvolemic state, baseline creatinine level, and normal urinalysis argue against allograft dysfunction. The elevated serum ferritin nonspecifically confirms systemic inflammation. LDH, an intracellular enzyme involved in the bidirectional conversion of lactate to pyruvate, is expressed across tissue types. Elevated serum LDH attests to cell destruction, in this case potentially from lung infection (such as PCP) or malignancy (such as PTLD). At this point, the differential diagnosis of fever and pulmonary infiltrates in this patient remains broad.

Azathioprine and cyclosporine were stopped. The patient remained febrile despite the administration of intravenous antibiotics. His hypoxia worsened with an oxygen saturation of 90%-93% on 5 L/min of supplemental oxygen administered by nasal cannula. Noncontrast chest CT obtained on the second hospital day revealed ground-glass opacities in the bilateral lung bases. Blood, sputum, and urine cultures were sterile. As empiric therapies, ganciclovir was started for CMV infection, ciprofloxacin added for atypical pneumonia, and trimethoprim-sulfamethoxazole added for Pneumocystis infection.

These chest imaging findings help prioritize the differential diagnosis. Bibasilar ground-glass opacities are evident, while pulmonary masses, nodules, cavitation, adenopathy, and pleural effusions are absent. The differential diagnosis of multifocal ground-glass opacities on chest imaging includes infectious pneumonia, chronic interstitial lung disease, acute alveolar conditions (eg, cardiogenic pulmonary edema, acute respiratory distress syndrome, diffuse alveolar hemorrhage), or other pathologies (eg, drug toxicity, bronchoalveolar carcinoma, cryptogenic organizing pneumonia).

Infectious pneumonia is the principal concern. A diagnosis of PCP could be unifying, given dyspnea, progressive respiratory failure with hypoxia, and elevated LDH in an immunocompromised patient who is not prescribed PCP prophylaxis. The bilateral lung infiltrates and the absence of thoracic adenopathy or pleural effusions are characteristic of PCP as well. However, caution should be exercised in making specific infectious diagnoses in immunocompromised hosts on the basis of clinical and imaging findings alone. There can be overlap in the radiologic appearance of various infections (eg, CMV pneumonia can also present with bilateral ground-glass infiltrates, with concurrent fever, hypoxia, and pancytopenia). Additionally, more than one pneumonic pathogen may be implicated (eg, acute viral pneumonia superimposed on indolent fungal pneumonia). Polymerase chain reaction (PCR) analysis of respiratory secretions for viruses, serum PCR and serologic testing for herpes viruses, and serum beta-D-glucan and galactomannan assays are indicated. Serum serologic testing for fungi and bacteria such as Nocardia can be helpful, though the negative predictive values of these tests may be reduced in patients with impaired humoral immunity. Timely bronchoalveolar lavage (BAL) with microbiologic and PCR analysis and cytology is advised.

Fever, elevated LDH, cytopenias, and pulmonary infiltrates also raise suspicion for an underlying hematologic malignancy, such as PTLD. However, pulmonary PTLD is seen more often in lung transplant recipients than in patients who have undergone transplantation of other solid organs. In kidney transplant recipients, PTLD most commonly manifests in the allograft itself, gastrointestinal tract, central nervous system, or lymph nodes; lung involvement is less common. Chest imaging in affected patients may reveal nodular or reticulonodular infiltrates of basilar predominance, solitary or multiple masses, cavitating or necrotic lesions, and/or lymphadenopathy. In this patient who has undergone renal transplantation, late-onset PTLD with isolated pulmonary involvement, with only ground-glass opacities on lung imaging, would be an atypical presentation of an uncommon syndrome.

Despite empiric treatment with antibiotics and antiviral agents, the patient’s fever persisted. His respiratory rate increased to 30 breaths per minute. His hypoxia worsened, and he required nasal cannula high-flow oxygen supplementation at 30 L/min with a fraction of inspired oxygen (FiO₂) of 40%. On the fifth hospital day, contrast CT scan of the chest and abdomen showed new infiltrates in the bilateral upper lung fields as well as an area of low density in the tail of the pancreas without a focal mass (Figure 1). At this point, BAL was performed, and fluid PCR analysis returned positive for Pneumocystis jirovecii. CMV direct immunoperoxidase staining of leukocytes with peroxidase-labeled monoclonal antibody (C7-HRP test) was positive at five cells per 7.35 × 10⁴ peripheral blood leukocytes. The serum Epstein-Barr virus (EBV) viral capsid antigen (VCA) IgG was positive, while VCA IgM and EBV nuclear antigen IgG were negative. A bone marrow biopsy revealed mild hemophagocytosis. His serum soluble interleukin-2 (sIL2R) level was elevated at 5,254 U/mL (normal range, 122-496 U/mL). Given the BAL Pneumocystis PCR result, the dose of prednisolone was increased to 30 mg/day, and the patient’s fever subsided. Supplemental oxygen was weaned to an FiO₂ of 35%.

A CMV antigenemia assay returned positive, suggesting prior CMV infection. However, to diagnose CMV pneumonia, the virus must be detected in BAL fluid by PCR or cytologic analysis. CMV infection has been associated with cytopenias, HLH, pancreatic infiltration, and an increased risk for fungal infections and EBV-related PTLD. CMV infection could explain the first phase of this patient’s illness. Serum and BAL PCR for CMV are advised. Meanwhile, EBV testing indicates prior infection but does not distinguish between recent or more distant infection. EBV has been implicated in the pathophysiology of PTLD, as EBV-infected lymphoid tissue may proliferate in a variety of organs under reduced T-cell surveillance. EBV infection or PTLD with resulting immunomodulation may pose other explanations for this patient’s development of PCP infection. Cytologic analysis of the BAL fluid and marrow aspirate for evidence of PTLD is warranted. Finally, CMV, EBV, and PTLD have each been reported to trigger HLH. Though this patient has fevers, mild marrow hemophagocytosis, elevated serum ferritin, and elevated serum IL-2 receptor levels, he does not meet other diagnostic criteria for HLH (such as more pronounced cytopenias, splenomegaly, hypertriglyceridemia, hypofibrinogenemia, and low or absent natural killer T-cell activity). However, HLH may be muted in this patient because he was prescribed cyclosporine, which has been used in HLH treatment protocols.

On the 11^th hospital day, the patient developed hemorrhagic shock due to massive hematemesis and was transferred to the intensive care unit. His hemoglobin level was 5.9 g/dL. A total of 18 units of packed red blood cells were transfused over the following week for ongoing gastrointestinal bleeding. The serum LDH level increased to 4,139 IU/L, and the ferritin level rose to 7,855 ng/mL. The EBV copy level by serum PCR returned at 1 × 10⁶ copies/mL (normal range, less than 2 x 10² copies/mL). The patient was started on methylprednisolone (1 g/day for three days) and transitioned to dexamethasone and cyclosporine for possible EBV-related HLH. Ceftazidime, vancomycin, trimethoprim-sulfamethoxazole, and ciprofloxacin were administered. Amphotericin-B was initiated empirically for potential fungal pneumonia. Ganciclovir was continued. However, the patient remained in shock despite vasopressors and transfusions and died on the 22^nd hospital day.

The patient deteriorated despite broad antimicrobial therapy. Laboratory studies revealed EBV viremia and rising serum LDH. Recent EBV infection may have induced PTLD in the gastrointestinal tract, which is a commonly involved site among affected renal transplant patients. Corticosteroids and stress from critical illness can contribute to intestinal mucosal erosion and bleeding from a luminal PTLD lesion. Overall, the patient’s condition was likely explained by EBV infection, which triggered HLH and gastrointestinal PTLD. The resulting immunomodulation increased his risk for PCP infection beyond that conferred by chronic immunosuppression. It is still possible that he had concomitant CMV pneumonia, Aspergillus pneumonia, or even pulmonary PTLD, in addition to the proven PCP diagnosis.

An autopsy was performed. Atypical lymphocytic infiltration and diffuse alveolar damage were shown in the right upper lobe (Figure 2). EBV RNA-positive atypical lymphocytes coexpressing CD20 were demonstrated in multiple organs including the bone marrow, lungs, heart, stomach, adrenal glands, duodenum, ileum, and mesentery (Figure 3). This confirmed the diagnosis of an underlying EBV-positive posttransplant lymphoproliferative disorder. Serum and BAL CMV PCR assays returned negative. Neither CMV nor Aspergillus was identified in autopsy specimens.

A broad differential diagnosis should be considered when acute fever develops in a patient who has undergone solid organ transplantation. Causes may include opportunistic and nonopportunistic infections as well as noninfectious etiologies such as malignancy, organ rejection, inflammatory conditions, and medication toxicity.^1,2 As the discussant noted, more than one infection, or both infection and malignancy, can coexist in immunocompromised patients. For example, while viral pathogens such as EBV, CMV, and respiratory syncytial virus can cause illness due to direct tissue infection, they can also exert indirect effects in transplant recipients: acting as cofactors for and enabling other infections by causing immunosuppression (eg, Aspergillus or PCP developing after CMV infection), triggering graft rejection by upregulating proinflammatory cytokines, and inducing oncogenesis (eg, EBV-related PTLD).^1,3-5

PTLD is a rare but serious complication of solid organ transplantation and immunosuppression. Most cases are driven by EBV infection and subsequent transformation of infected lymphoid tissue in a variety of organs in the context of reduced T-cell surveillance.⁶ The incidence of PTLD varies based on the organ transplanted, ranging from 0.8%-2.5% in those who have undergone renal transplantation to 1.0%-5.5% in liver transplant recipients and 3.0%-10% in lung transplant recipients.³ The incidence has increased over the past decade. This may be due to a greater number of solid organ transplantations being performed, aging of the transplant donor/recipient population, new immunosuppressive regimens, and improved PTLD diagnosis due to superior diagnostic tools and clinician awareness.³ However, the mortality rate among solid organ transplant recipients with PTLD remains high, ranging from 40% to 70%.⁶

Risk factors for PTLD include a greater intensity of T-cell immunosuppression,⁷ history of pretransplant malignancy, recipient EBV seronegativity and donor seropositivity, and younger age at the time of transplantation.^8-10 EBV-related PTLD incidence in solid organ transplant recipients is greatest in the early posttransplantation course (the period of most intense immunosuppression) with over 80% of cases occurring in the first posttransplant year.¹¹

A high index of suspicion for PTLD is warranted in any solid organ transplant recipient who presents with constitutional symptoms, adenopathy, or cytopenias. Clinical suspicion of PTLD can be informed by risk factors, constitutional symptoms, elevated serum LDH, a detectable or rising serum EBV viral load, and radiologic adenopathy or visceral tissue infiltration.¹² The clinical presentation of PTLD is heterogeneous and varies in accordance with the organs affected. Extranodal involvement, such as pulmonary, gastrointestinal, and bone marrow involvement, is more common in PTLD than in other types of lymphoma.¹³ In this patient, the cytopenias, elevated serum LDH level, lung infiltrates, and radiologic pancreatic tail abnormality served as early clues to the presence of underlying PTLD.

The standard approach to diagnosing PTLD is biopsy of a suspicious lesion (adenopathy or an infiltrated visceral organ) with histopathological examination. Pathology may demonstrate distorted tissue architecture, clonal lymphocytes, or EBV-positive lymphocytes.¹⁴ Conventional CT is the most commonly used imaging modality to detect adenopathy or tissue infiltration related to PTLD,³ though 18F-fluorodeoxyglucose position-emission tomography (FDG-PET) is also used. Although FDG-PET has high diagnostic accuracy, with an overall sensitivity of 89% and specificity of 89%, false-negative results have been reported, particularly in cases of early PTLD lesions and diffuse large B-cell lymphoma.¹⁵ The majority of patients with EBV-associated PTLD demonstrate significant elevations in the serum EBV viral load compared with immunosuppressed controls without PTLD.¹⁶ An elevated EBV viral load can support a diagnosis of PTLD, though the absence of EBV viremia does not rule it out.¹⁷ Some transplant centers perform posttransplantation monitoring of the serum EBV viral load to aid in PTLD risk assessment and early diagnosis.

Management of PTLD is patient-specific and may involve reduction of immunosuppressive therapy, rituximab, chemotherapy, surgical excision, and/or radiation.¹³ Reduction of immunosuppression is the cornerstone of treatment.¹⁸ In patients who do not respond to the reduction of immunosuppression, rituximab and immunochemotherapy are second-line treatment options. A prospective, multicenter phase 2 trial (the PTLD-1 trial) demonstrated a complete response rate of 40% among patients with PTLD managed with rituximab.¹⁹

In summary, this case illustrates the importance of maintaining a broad differential diagnosis when acute fever develops in a patient who has undergone solid organ transplantation. The presence of more than one condition should be considered when the clinical presentation cannot be explained by a single diagnosis, as infections and malignancies can coexist in immunocompromised hosts. This case also highlights an unusual clinical presentation of PTLD, which was heralded mainly by its immunomodulatory effects rather than by compatible symptoms or obvious mass lesions.

Carefully reviewing the patient’s medical history and understanding how it sets the stage for the present illness is an essential step in clinical problem solving, because what is past is prologue.

• Fever in solid organ transplant recipients should prompt consideration of a broad differential diagnosis, including infection, malignancy, organ graft rejection, autoimmune disease, and medication toxicity.
• PTLD is a rare but serious complication of organ transplantation. Most cases are driven by EBV infection and transformation of infected lymphocytes in a variety of organs in the context of reduced T-cell surveillance. The clinical presentation can be heterogeneous and varies depending on the organs and tissues involved.
• More than one infection, or both infection and malignancy, can coexist in organ transplant recipients. Viral pathogens can exert direct pathologic effects on tissue but can also exert indirect effects, such as contributing to opportunistic infection susceptibility, graft rejection, and oncogenesis.

Disclosures

The authors have nothing to disclose.

Previous Publication

This case was originally reported in the 121st Okinawa Association of Medical Sciences in 2015 in Okinawa, Japan, and the conference abstracts were covered in The Okinawa Medical Journal. The publication did not provide any detailed, step-by-step analysis of clinical decision-making.

A 56-year-old Japanese man with a history of renal transplantation 20 years prior presented to the emergency department (ED) with two months of dyspnea on exertion and one day of fever and chills. The patient was in his usual state of health until two months prior to presentation, when he gradually noticed shortness of breath after sustained or effortful physical activities. The dyspnea improved with rest. Over the following two months, he noticed that the shortness of breath came on with lesser degrees of exertion, such as walking 100 meters. One day before presentation, he developed a fever of 39°C and chills at home, which prompted him to seek ED care. He denied chest pain, cough, leg swelling, or paroxysmal nocturnal dyspnea.

The differential diagnosis of exertional dyspnea progressing over several months includes cardiac, pulmonary, hematologic, and neuromuscular conditions. The patient’s history of renal transplantation prompts consideration of worsening indolent pneumonia (eg, Aspergillus, cytomegalovirus [CMV], or Pneumocystis pneumonia), allograft dysfunction with volume overload, recrudescence of the underlying disease that incited renal failure earlier in life (eg, vasculitis), or a late-onset posttransplantation lymphoproliferative disorder (PTLD). Additionally, acute fever in an immunocompromised patient immediately raises suspicion for infection (eg, pneumonia, enteritis, or urinary tract infection). At this point, it is difficult to know whether the subacute-to-chronic exertional dyspnea and the acute fever are consequences of the same disease or separate, potentially overlapping, processes.

His past medical history was significant for end-stage renal disease due to membranoproliferative glomerular nephropathy (MPGN), for which living, related-donor kidney transplantation was performed 20 years earlier. He also had type 2 diabetes mellitus, hypertension, and basal cell carcinoma of the face, which had been resected three years prior without spread or recurrence. He had no known allergies. Medications included prednisolone 15 mg daily, azathioprine 100 mg daily, and cyclosporine 100 mg daily, as well as amlodipine and candesartan. He lived in Japan with his wife and children. He denied any animal or environmental exposures. He did not smoke cigarettes or drink alcohol and had not traveled recently. His father had diabetes mellitus.

Recrudescence of an underlying autoimmune condition that may have incited MPGN earlier in life is unlikely while taking an immunosuppressive regimen consisting of prednisolone, azathioprine, and cyclosporine. However, these medications do increase susceptibility to infections, lymphoma, and skin cancers. Though he is immunocompromised, the patient is not on prophylaxis for Pneumocystis pneumonia (PCP). PCP in HIV-negative patients is associated with recent glucocorticoid exposure and typically follows an acute-to-subacute course with hypoxemia and respiratory distress. Though the risk of PCP infection is considered highest in the early posttransplantation period (when immunosuppression is most intense), many cases are diagnosed years after transplantation among patients no longer on prophylaxis. The patient has type 2 diabetes mellitus and hypertension, which are known complications of calcineurin inhibitor and steroid therapy and increase the risk of cardiovascular disease. Cardiovascular disease is a major cause of death among renal transplant recipients. Exertional dyspnea may be the presenting symptom of coronary artery disease.

On physical examination, the patient was alert, oriented, and in no acute distress. His temperature was 38.5°C, blood pressure 120/60 mm Hg, heart rate 146 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 93% while breathing ambient air. The conjunctiva were normal without pallor or icterus. There was no cervical lymphadenopathy. Cardiac examination revealed tachycardia with a regular rhythm, normal S1 and S2, and no murmurs, rubs, or gallops. Jugular venous pressure was not elevated, and there was no lower extremity edema. Lungs were clear to auscultation bilaterally. The abdomen was soft, nontender, and nondistended. There was no tenderness over the transplanted kidney and no hepatosplenomegaly.

Dyspnea, fever, and tachycardia may be the sole manifestations of pneumonia in solid organ transplant recipients. The absence of cough or adventitious breath sounds does not eliminate concern for pneumonia. Pathogens that cause indolent pneumonia in immunocompromised patients include viruses (such as typical respiratory viruses and CMV), bacteria (typical organisms, Nocardia, Rhodococcus), and mycobacteria. Fungal causes include Aspergillus, Candida, Cryptococcus, Pneumocystis, and endemic mycoses. A detailed environmental history should be taken, and providers should ascertain which fungal diseases are endemic in the patient’s region of residence. There are no examination features suggesting hypervolemia or anemia. Although there is no hepatosplenomegaly or lymphadenopathy, PTLD often involves extranodal tissues, including the lungs. The incidence of PTLD is highest in the 12 months following transplantation, but it may occur at any time in the posttransplantation course. A complete blood count, comprehensive metabolic panel, lactate dehydrogenase (LDH), and blood and sputum cultures are indicated, along with computed tomography (CT) of the chest.

The leukocyte count was 3,500 cells/mm³, the hemoglobin level 9.0 g/dL, mean corpuscular volume 102 fL, and the platelet count 137,000 cells/mm³. The sodium level was 130 mEq/L, potassium 4.6 mEq/L, blood urea nitrogen 41 mg/dL, and creatinine 3.5 mg/dL. These complete blood count and serum electrolyte results were unchanged from the patient’s baseline values. The serum LDH level was 1,895 IU/L (normal range, 115-245 IU/L). The serum ferritin was 2,114 ng/mL (normal range, 13-277 ng/mL). A chest radiograph revealed diffuse, airspace-filling opacities in the bilateral lung bases. The urinalysis was normal. The patient was admitted and started empirically on intravenous ceftriaxone for potential bacterial pneumonia.

Chronic pancytopenia may result from azathioprine or cyclosporine use, marrow suppression or infiltration by a multisystem disease, or nutritional deficiency. Hemophagocytic lymphohistiocytosis (HLH) triggered by infection, a rheumatologic condition, acquired immunodeficiency, or malignancy can present with fevers, pancytopenia, and elevated ferritin, while splenomegaly may be absent. The euvolemic state, baseline creatinine level, and normal urinalysis argue against allograft dysfunction. The elevated serum ferritin nonspecifically confirms systemic inflammation. LDH, an intracellular enzyme involved in the bidirectional conversion of lactate to pyruvate, is expressed across tissue types. Elevated serum LDH attests to cell destruction, in this case potentially from lung infection (such as PCP) or malignancy (such as PTLD). At this point, the differential diagnosis of fever and pulmonary infiltrates in this patient remains broad.

Azathioprine and cyclosporine were stopped. The patient remained febrile despite the administration of intravenous antibiotics. His hypoxia worsened with an oxygen saturation of 90%-93% on 5 L/min of supplemental oxygen administered by nasal cannula. Noncontrast chest CT obtained on the second hospital day revealed ground-glass opacities in the bilateral lung bases. Blood, sputum, and urine cultures were sterile. As empiric therapies, ganciclovir was started for CMV infection, ciprofloxacin added for atypical pneumonia, and trimethoprim-sulfamethoxazole added for Pneumocystis infection.

These chest imaging findings help prioritize the differential diagnosis. Bibasilar ground-glass opacities are evident, while pulmonary masses, nodules, cavitation, adenopathy, and pleural effusions are absent. The differential diagnosis of multifocal ground-glass opacities on chest imaging includes infectious pneumonia, chronic interstitial lung disease, acute alveolar conditions (eg, cardiogenic pulmonary edema, acute respiratory distress syndrome, diffuse alveolar hemorrhage), or other pathologies (eg, drug toxicity, bronchoalveolar carcinoma, cryptogenic organizing pneumonia).

Infectious pneumonia is the principal concern. A diagnosis of PCP could be unifying, given dyspnea, progressive respiratory failure with hypoxia, and elevated LDH in an immunocompromised patient who is not prescribed PCP prophylaxis. The bilateral lung infiltrates and the absence of thoracic adenopathy or pleural effusions are characteristic of PCP as well. However, caution should be exercised in making specific infectious diagnoses in immunocompromised hosts on the basis of clinical and imaging findings alone. There can be overlap in the radiologic appearance of various infections (eg, CMV pneumonia can also present with bilateral ground-glass infiltrates, with concurrent fever, hypoxia, and pancytopenia). Additionally, more than one pneumonic pathogen may be implicated (eg, acute viral pneumonia superimposed on indolent fungal pneumonia). Polymerase chain reaction (PCR) analysis of respiratory secretions for viruses, serum PCR and serologic testing for herpes viruses, and serum beta-D-glucan and galactomannan assays are indicated. Serum serologic testing for fungi and bacteria such as Nocardia can be helpful, though the negative predictive values of these tests may be reduced in patients with impaired humoral immunity. Timely bronchoalveolar lavage (BAL) with microbiologic and PCR analysis and cytology is advised.

Fever, elevated LDH, cytopenias, and pulmonary infiltrates also raise suspicion for an underlying hematologic malignancy, such as PTLD. However, pulmonary PTLD is seen more often in lung transplant recipients than in patients who have undergone transplantation of other solid organs. In kidney transplant recipients, PTLD most commonly manifests in the allograft itself, gastrointestinal tract, central nervous system, or lymph nodes; lung involvement is less common. Chest imaging in affected patients may reveal nodular or reticulonodular infiltrates of basilar predominance, solitary or multiple masses, cavitating or necrotic lesions, and/or lymphadenopathy. In this patient who has undergone renal transplantation, late-onset PTLD with isolated pulmonary involvement, with only ground-glass opacities on lung imaging, would be an atypical presentation of an uncommon syndrome.

Despite empiric treatment with antibiotics and antiviral agents, the patient’s fever persisted. His respiratory rate increased to 30 breaths per minute. His hypoxia worsened, and he required nasal cannula high-flow oxygen supplementation at 30 L/min with a fraction of inspired oxygen (FiO₂) of 40%. On the fifth hospital day, contrast CT scan of the chest and abdomen showed new infiltrates in the bilateral upper lung fields as well as an area of low density in the tail of the pancreas without a focal mass (Figure 1). At this point, BAL was performed, and fluid PCR analysis returned positive for Pneumocystis jirovecii. CMV direct immunoperoxidase staining of leukocytes with peroxidase-labeled monoclonal antibody (C7-HRP test) was positive at five cells per 7.35 × 10⁴ peripheral blood leukocytes. The serum Epstein-Barr virus (EBV) viral capsid antigen (VCA) IgG was positive, while VCA IgM and EBV nuclear antigen IgG were negative. A bone marrow biopsy revealed mild hemophagocytosis. His serum soluble interleukin-2 (sIL2R) level was elevated at 5,254 U/mL (normal range, 122-496 U/mL). Given the BAL Pneumocystis PCR result, the dose of prednisolone was increased to 30 mg/day, and the patient’s fever subsided. Supplemental oxygen was weaned to an FiO₂ of 35%.

A CMV antigenemia assay returned positive, suggesting prior CMV infection. However, to diagnose CMV pneumonia, the virus must be detected in BAL fluid by PCR or cytologic analysis. CMV infection has been associated with cytopenias, HLH, pancreatic infiltration, and an increased risk for fungal infections and EBV-related PTLD. CMV infection could explain the first phase of this patient’s illness. Serum and BAL PCR for CMV are advised. Meanwhile, EBV testing indicates prior infection but does not distinguish between recent or more distant infection. EBV has been implicated in the pathophysiology of PTLD, as EBV-infected lymphoid tissue may proliferate in a variety of organs under reduced T-cell surveillance. EBV infection or PTLD with resulting immunomodulation may pose other explanations for this patient’s development of PCP infection. Cytologic analysis of the BAL fluid and marrow aspirate for evidence of PTLD is warranted. Finally, CMV, EBV, and PTLD have each been reported to trigger HLH. Though this patient has fevers, mild marrow hemophagocytosis, elevated serum ferritin, and elevated serum IL-2 receptor levels, he does not meet other diagnostic criteria for HLH (such as more pronounced cytopenias, splenomegaly, hypertriglyceridemia, hypofibrinogenemia, and low or absent natural killer T-cell activity). However, HLH may be muted in this patient because he was prescribed cyclosporine, which has been used in HLH treatment protocols.

On the 11^th hospital day, the patient developed hemorrhagic shock due to massive hematemesis and was transferred to the intensive care unit. His hemoglobin level was 5.9 g/dL. A total of 18 units of packed red blood cells were transfused over the following week for ongoing gastrointestinal bleeding. The serum LDH level increased to 4,139 IU/L, and the ferritin level rose to 7,855 ng/mL. The EBV copy level by serum PCR returned at 1 × 10⁶ copies/mL (normal range, less than 2 x 10² copies/mL). The patient was started on methylprednisolone (1 g/day for three days) and transitioned to dexamethasone and cyclosporine for possible EBV-related HLH. Ceftazidime, vancomycin, trimethoprim-sulfamethoxazole, and ciprofloxacin were administered. Amphotericin-B was initiated empirically for potential fungal pneumonia. Ganciclovir was continued. However, the patient remained in shock despite vasopressors and transfusions and died on the 22^nd hospital day.

The patient deteriorated despite broad antimicrobial therapy. Laboratory studies revealed EBV viremia and rising serum LDH. Recent EBV infection may have induced PTLD in the gastrointestinal tract, which is a commonly involved site among affected renal transplant patients. Corticosteroids and stress from critical illness can contribute to intestinal mucosal erosion and bleeding from a luminal PTLD lesion. Overall, the patient’s condition was likely explained by EBV infection, which triggered HLH and gastrointestinal PTLD. The resulting immunomodulation increased his risk for PCP infection beyond that conferred by chronic immunosuppression. It is still possible that he had concomitant CMV pneumonia, Aspergillus pneumonia, or even pulmonary PTLD, in addition to the proven PCP diagnosis.

An autopsy was performed. Atypical lymphocytic infiltration and diffuse alveolar damage were shown in the right upper lobe (Figure 2). EBV RNA-positive atypical lymphocytes coexpressing CD20 were demonstrated in multiple organs including the bone marrow, lungs, heart, stomach, adrenal glands, duodenum, ileum, and mesentery (Figure 3). This confirmed the diagnosis of an underlying EBV-positive posttransplant lymphoproliferative disorder. Serum and BAL CMV PCR assays returned negative. Neither CMV nor Aspergillus was identified in autopsy specimens.

A broad differential diagnosis should be considered when acute fever develops in a patient who has undergone solid organ transplantation. Causes may include opportunistic and nonopportunistic infections as well as noninfectious etiologies such as malignancy, organ rejection, inflammatory conditions, and medication toxicity.^1,2 As the discussant noted, more than one infection, or both infection and malignancy, can coexist in immunocompromised patients. For example, while viral pathogens such as EBV, CMV, and respiratory syncytial virus can cause illness due to direct tissue infection, they can also exert indirect effects in transplant recipients: acting as cofactors for and enabling other infections by causing immunosuppression (eg, Aspergillus or PCP developing after CMV infection), triggering graft rejection by upregulating proinflammatory cytokines, and inducing oncogenesis (eg, EBV-related PTLD).^1,3-5

PTLD is a rare but serious complication of solid organ transplantation and immunosuppression. Most cases are driven by EBV infection and subsequent transformation of infected lymphoid tissue in a variety of organs in the context of reduced T-cell surveillance.⁶ The incidence of PTLD varies based on the organ transplanted, ranging from 0.8%-2.5% in those who have undergone renal transplantation to 1.0%-5.5% in liver transplant recipients and 3.0%-10% in lung transplant recipients.³ The incidence has increased over the past decade. This may be due to a greater number of solid organ transplantations being performed, aging of the transplant donor/recipient population, new immunosuppressive regimens, and improved PTLD diagnosis due to superior diagnostic tools and clinician awareness.³ However, the mortality rate among solid organ transplant recipients with PTLD remains high, ranging from 40% to 70%.⁶

Risk factors for PTLD include a greater intensity of T-cell immunosuppression,⁷ history of pretransplant malignancy, recipient EBV seronegativity and donor seropositivity, and younger age at the time of transplantation.^8-10 EBV-related PTLD incidence in solid organ transplant recipients is greatest in the early posttransplantation course (the period of most intense immunosuppression) with over 80% of cases occurring in the first posttransplant year.¹¹

A high index of suspicion for PTLD is warranted in any solid organ transplant recipient who presents with constitutional symptoms, adenopathy, or cytopenias. Clinical suspicion of PTLD can be informed by risk factors, constitutional symptoms, elevated serum LDH, a detectable or rising serum EBV viral load, and radiologic adenopathy or visceral tissue infiltration.¹² The clinical presentation of PTLD is heterogeneous and varies in accordance with the organs affected. Extranodal involvement, such as pulmonary, gastrointestinal, and bone marrow involvement, is more common in PTLD than in other types of lymphoma.¹³ In this patient, the cytopenias, elevated serum LDH level, lung infiltrates, and radiologic pancreatic tail abnormality served as early clues to the presence of underlying PTLD.

The standard approach to diagnosing PTLD is biopsy of a suspicious lesion (adenopathy or an infiltrated visceral organ) with histopathological examination. Pathology may demonstrate distorted tissue architecture, clonal lymphocytes, or EBV-positive lymphocytes.¹⁴ Conventional CT is the most commonly used imaging modality to detect adenopathy or tissue infiltration related to PTLD,³ though 18F-fluorodeoxyglucose position-emission tomography (FDG-PET) is also used. Although FDG-PET has high diagnostic accuracy, with an overall sensitivity of 89% and specificity of 89%, false-negative results have been reported, particularly in cases of early PTLD lesions and diffuse large B-cell lymphoma.¹⁵ The majority of patients with EBV-associated PTLD demonstrate significant elevations in the serum EBV viral load compared with immunosuppressed controls without PTLD.¹⁶ An elevated EBV viral load can support a diagnosis of PTLD, though the absence of EBV viremia does not rule it out.¹⁷ Some transplant centers perform posttransplantation monitoring of the serum EBV viral load to aid in PTLD risk assessment and early diagnosis.

Management of PTLD is patient-specific and may involve reduction of immunosuppressive therapy, rituximab, chemotherapy, surgical excision, and/or radiation.¹³ Reduction of immunosuppression is the cornerstone of treatment.¹⁸ In patients who do not respond to the reduction of immunosuppression, rituximab and immunochemotherapy are second-line treatment options. A prospective, multicenter phase 2 trial (the PTLD-1 trial) demonstrated a complete response rate of 40% among patients with PTLD managed with rituximab.¹⁹

In summary, this case illustrates the importance of maintaining a broad differential diagnosis when acute fever develops in a patient who has undergone solid organ transplantation. The presence of more than one condition should be considered when the clinical presentation cannot be explained by a single diagnosis, as infections and malignancies can coexist in immunocompromised hosts. This case also highlights an unusual clinical presentation of PTLD, which was heralded mainly by its immunomodulatory effects rather than by compatible symptoms or obvious mass lesions.

Carefully reviewing the patient’s medical history and understanding how it sets the stage for the present illness is an essential step in clinical problem solving, because what is past is prologue.

• Fever in solid organ transplant recipients should prompt consideration of a broad differential diagnosis, including infection, malignancy, organ graft rejection, autoimmune disease, and medication toxicity.
• PTLD is a rare but serious complication of organ transplantation. Most cases are driven by EBV infection and transformation of infected lymphocytes in a variety of organs in the context of reduced T-cell surveillance. The clinical presentation can be heterogeneous and varies depending on the organs and tissues involved.
• More than one infection, or both infection and malignancy, can coexist in organ transplant recipients. Viral pathogens can exert direct pathologic effects on tissue but can also exert indirect effects, such as contributing to opportunistic infection susceptibility, graft rejection, and oncogenesis.

Disclosures

The authors have nothing to disclose.

Previous Publication

This case was originally reported in the 121st Okinawa Association of Medical Sciences in 2015 in Okinawa, Japan, and the conference abstracts were covered in The Okinawa Medical Journal. The publication did not provide any detailed, step-by-step analysis of clinical decision-making.

SAN DIEGO – A novel oral drug for inflammatory bowel disease showed good safety and efficacy data in preliminary clinical trial results.

Among a group of 32 patients with ulcerative colitis, the investigative drug ABX464 showed a decrease in Mayo score of over 50% and a drop in fecal calprotectin to near-normal levels. The safety profile was reassuring, and results were durable at the 9-month mark.

Coauthor Jean-Marc Steens, MD, presented results of the randomized, double-blind, placebo-controlled phase 2a study at the annual Digestive Disease Week^®, and noted that ABX464 is also being investigated as antiviral therapy for individuals with HIV/AIDS.

“Despite the major advances in the last 10 years with the introduction of biologics and [Janus kinase] inhibitors, there is still a huge unmet medical need for these patients,” said Dr. Steens, chief medical officer of Abivax (Paris), in an interview. “Large phase 3 studies with these recent drugs have shown that about two-thirds of the patients show a clinical response during induction, but that half of these responders will lose their response within the next 6-12 months. The safety profile of these drugs also includes severe infections, which is a major concern,” he said.

Dr. Steens presented the findings on behalf of first author Severine Vermeire, MD, chair of the department of chronic diseases, metabolism, and aging at Catholic University, Leuven, Belgium.

ABX464, a small-molecule oral medication, has been evaluated for safety among more than 180 patients with HIV as well as the patients with ulcerative colitis (UC) studied in the current trial. The drug increases expression of the microRNA precursor miR-124, with the result that “the inflammatory brake is applied,” explained Dr. Steens.

In the present study, whose primary outcome was safety, 23 patients with moderate to severe active UC were randomized to ABX464 50 mg once daily, and 9 to placebo. Patients were included if they had failed or were intolerant to immunomodulators, anti–tumor necrosis factor–alpha therapies, vedolizumab, or corticosteroids; the two groups had balanced disease and demographic characteristics. At baseline, patients had a total Mayo score of 6-12, and an endoscopic subscore of 2 or 3.

Three patients withdrew from the ABX464 arm by the end of 8 weeks: one because of adverse events (AEs), one withdrew consent, and the third declined to undergo endoscopy at the 8-week mark.

All treatment-emergent AEs were mild or moderate, with gastrointestinal disorders occurring in eight of the ABX464 patients and two placebo patients (34.8% and 22.2%, respectively.) Five ABX-464 patients (21.7%) experienced nervous system symptoms – mostly headaches, said Dr. Steens. No patients in the placebo arm had headache or other neurological AEs.

By the end of 8 weeks, 30% of the intention-to-treat ABX464 group was in clinical remission, compared with 11% of the placebo group; this was not a statistically significant difference (P = .16). The proportion of ABX464 patients who had a clinical response just missed statistical significance, compared with placebo (61% versus 33%; P = 06).

However, significant endoscopic improvement was seen in the ABX464 arm, with 43% having a Mayo endoscopy subscore of 0 or 1, compared with 11% in the placebo arm (P = .03).

The total Mayo score dropped by 53% in the ABX464 group, compared with 27% in the placebo group (P = .03); a partial Mayo score dropped by 62% for those in the active arm, compared with 32% in the placebo arm (P = .02).

“The major finding from the induction study was that all endpoints were going in the same direction in favor of ABX464, even reaching statistical significance for endoscopy as well, and total and partial Mayo score,” said Dr. Steens.

Patients underwent rectal biopsies at the end of 8 weeks, and miR-124 expression increased more than sevenfold from baseline for those taking ABX464, compared with a small increase in the placebo group (7.69- versus 1.46-fold; P = .004). Expression of miR-124 in total blood also increased – by over 800-fold – at study day 28 for the ABX464 arm. Levels were sustained at more than 700-fold at study day 56 in this group. Placebo arm participants saw an insignificant rise in miR-124 blood levels.

Dr. Steens reported that 22 patients, including 7 who had originally been placebo arm participants, continued into the maintenance phase of the study. Nineteen patients have now had a median of over 400 days of exposure to ABX464, with sustained significant improvement in partial Mayo scores from a baseline of 6 to scores below 2 at 6 and 9 months. Fecal calprotectin scores have dropped from a median 1,044 mcg/g at baseline to 23.5 mcg/g at 9 months.

Next steps include the 12-month assessment, which includes another endoscopy, said Dr. Steens. Also, a phase 2b study is seeking to enroll 232 patients who have moderate to severe ulcerative colitis, with room within the enrollment scheme for new study sites, said Dr. Steens. This larger study will have arms in which the current 50-mg oral dose is doubled and halved, as well as a placebo arm, he said. The medication will also be trialed for Crohn’s disease and rheumatoid arthritis.

The small sample size is an inherent limitation of this early-stage clinical trial, noted Dr. Steens.

Dr. Steens reported being an employee and holding shares in Abivax, which funded the study.

[email protected]

SOURCE: Vermeire S et al. DDW 2019, Abstract 1007.

SAN DIEGO – A novel oral drug for inflammatory bowel disease showed good safety and efficacy data in preliminary clinical trial results.

Among a group of 32 patients with ulcerative colitis, the investigative drug ABX464 showed a decrease in Mayo score of over 50% and a drop in fecal calprotectin to near-normal levels. The safety profile was reassuring, and results were durable at the 9-month mark.

Coauthor Jean-Marc Steens, MD, presented results of the randomized, double-blind, placebo-controlled phase 2a study at the annual Digestive Disease Week^®, and noted that ABX464 is also being investigated as antiviral therapy for individuals with HIV/AIDS.

“Despite the major advances in the last 10 years with the introduction of biologics and [Janus kinase] inhibitors, there is still a huge unmet medical need for these patients,” said Dr. Steens, chief medical officer of Abivax (Paris), in an interview. “Large phase 3 studies with these recent drugs have shown that about two-thirds of the patients show a clinical response during induction, but that half of these responders will lose their response within the next 6-12 months. The safety profile of these drugs also includes severe infections, which is a major concern,” he said.

Dr. Steens presented the findings on behalf of first author Severine Vermeire, MD, chair of the department of chronic diseases, metabolism, and aging at Catholic University, Leuven, Belgium.

ABX464, a small-molecule oral medication, has been evaluated for safety among more than 180 patients with HIV as well as the patients with ulcerative colitis (UC) studied in the current trial. The drug increases expression of the microRNA precursor miR-124, with the result that “the inflammatory brake is applied,” explained Dr. Steens.

In the present study, whose primary outcome was safety, 23 patients with moderate to severe active UC were randomized to ABX464 50 mg once daily, and 9 to placebo. Patients were included if they had failed or were intolerant to immunomodulators, anti–tumor necrosis factor–alpha therapies, vedolizumab, or corticosteroids; the two groups had balanced disease and demographic characteristics. At baseline, patients had a total Mayo score of 6-12, and an endoscopic subscore of 2 or 3.

Three patients withdrew from the ABX464 arm by the end of 8 weeks: one because of adverse events (AEs), one withdrew consent, and the third declined to undergo endoscopy at the 8-week mark.

All treatment-emergent AEs were mild or moderate, with gastrointestinal disorders occurring in eight of the ABX464 patients and two placebo patients (34.8% and 22.2%, respectively.) Five ABX-464 patients (21.7%) experienced nervous system symptoms – mostly headaches, said Dr. Steens. No patients in the placebo arm had headache or other neurological AEs.

By the end of 8 weeks, 30% of the intention-to-treat ABX464 group was in clinical remission, compared with 11% of the placebo group; this was not a statistically significant difference (P = .16). The proportion of ABX464 patients who had a clinical response just missed statistical significance, compared with placebo (61% versus 33%; P = 06).

However, significant endoscopic improvement was seen in the ABX464 arm, with 43% having a Mayo endoscopy subscore of 0 or 1, compared with 11% in the placebo arm (P = .03).

The total Mayo score dropped by 53% in the ABX464 group, compared with 27% in the placebo group (P = .03); a partial Mayo score dropped by 62% for those in the active arm, compared with 32% in the placebo arm (P = .02).

“The major finding from the induction study was that all endpoints were going in the same direction in favor of ABX464, even reaching statistical significance for endoscopy as well, and total and partial Mayo score,” said Dr. Steens.

Patients underwent rectal biopsies at the end of 8 weeks, and miR-124 expression increased more than sevenfold from baseline for those taking ABX464, compared with a small increase in the placebo group (7.69- versus 1.46-fold; P = .004). Expression of miR-124 in total blood also increased – by over 800-fold – at study day 28 for the ABX464 arm. Levels were sustained at more than 700-fold at study day 56 in this group. Placebo arm participants saw an insignificant rise in miR-124 blood levels.

Dr. Steens reported that 22 patients, including 7 who had originally been placebo arm participants, continued into the maintenance phase of the study. Nineteen patients have now had a median of over 400 days of exposure to ABX464, with sustained significant improvement in partial Mayo scores from a baseline of 6 to scores below 2 at 6 and 9 months. Fecal calprotectin scores have dropped from a median 1,044 mcg/g at baseline to 23.5 mcg/g at 9 months.

Next steps include the 12-month assessment, which includes another endoscopy, said Dr. Steens. Also, a phase 2b study is seeking to enroll 232 patients who have moderate to severe ulcerative colitis, with room within the enrollment scheme for new study sites, said Dr. Steens. This larger study will have arms in which the current 50-mg oral dose is doubled and halved, as well as a placebo arm, he said. The medication will also be trialed for Crohn’s disease and rheumatoid arthritis.

The small sample size is an inherent limitation of this early-stage clinical trial, noted Dr. Steens.

Dr. Steens reported being an employee and holding shares in Abivax, which funded the study.

[email protected]

SOURCE: Vermeire S et al. DDW 2019, Abstract 1007.

SAN DIEGO – A novel oral drug for inflammatory bowel disease showed good safety and efficacy data in preliminary clinical trial results.

Among a group of 32 patients with ulcerative colitis, the investigative drug ABX464 showed a decrease in Mayo score of over 50% and a drop in fecal calprotectin to near-normal levels. The safety profile was reassuring, and results were durable at the 9-month mark.

Coauthor Jean-Marc Steens, MD, presented results of the randomized, double-blind, placebo-controlled phase 2a study at the annual Digestive Disease Week^®, and noted that ABX464 is also being investigated as antiviral therapy for individuals with HIV/AIDS.

“Despite the major advances in the last 10 years with the introduction of biologics and [Janus kinase] inhibitors, there is still a huge unmet medical need for these patients,” said Dr. Steens, chief medical officer of Abivax (Paris), in an interview. “Large phase 3 studies with these recent drugs have shown that about two-thirds of the patients show a clinical response during induction, but that half of these responders will lose their response within the next 6-12 months. The safety profile of these drugs also includes severe infections, which is a major concern,” he said.

Dr. Steens presented the findings on behalf of first author Severine Vermeire, MD, chair of the department of chronic diseases, metabolism, and aging at Catholic University, Leuven, Belgium.

ABX464, a small-molecule oral medication, has been evaluated for safety among more than 180 patients with HIV as well as the patients with ulcerative colitis (UC) studied in the current trial. The drug increases expression of the microRNA precursor miR-124, with the result that “the inflammatory brake is applied,” explained Dr. Steens.

In the present study, whose primary outcome was safety, 23 patients with moderate to severe active UC were randomized to ABX464 50 mg once daily, and 9 to placebo. Patients were included if they had failed or were intolerant to immunomodulators, anti–tumor necrosis factor–alpha therapies, vedolizumab, or corticosteroids; the two groups had balanced disease and demographic characteristics. At baseline, patients had a total Mayo score of 6-12, and an endoscopic subscore of 2 or 3.

Three patients withdrew from the ABX464 arm by the end of 8 weeks: one because of adverse events (AEs), one withdrew consent, and the third declined to undergo endoscopy at the 8-week mark.

All treatment-emergent AEs were mild or moderate, with gastrointestinal disorders occurring in eight of the ABX464 patients and two placebo patients (34.8% and 22.2%, respectively.) Five ABX-464 patients (21.7%) experienced nervous system symptoms – mostly headaches, said Dr. Steens. No patients in the placebo arm had headache or other neurological AEs.

By the end of 8 weeks, 30% of the intention-to-treat ABX464 group was in clinical remission, compared with 11% of the placebo group; this was not a statistically significant difference (P = .16). The proportion of ABX464 patients who had a clinical response just missed statistical significance, compared with placebo (61% versus 33%; P = 06).

However, significant endoscopic improvement was seen in the ABX464 arm, with 43% having a Mayo endoscopy subscore of 0 or 1, compared with 11% in the placebo arm (P = .03).

The total Mayo score dropped by 53% in the ABX464 group, compared with 27% in the placebo group (P = .03); a partial Mayo score dropped by 62% for those in the active arm, compared with 32% in the placebo arm (P = .02).

“The major finding from the induction study was that all endpoints were going in the same direction in favor of ABX464, even reaching statistical significance for endoscopy as well, and total and partial Mayo score,” said Dr. Steens.

Patients underwent rectal biopsies at the end of 8 weeks, and miR-124 expression increased more than sevenfold from baseline for those taking ABX464, compared with a small increase in the placebo group (7.69- versus 1.46-fold; P = .004). Expression of miR-124 in total blood also increased – by over 800-fold – at study day 28 for the ABX464 arm. Levels were sustained at more than 700-fold at study day 56 in this group. Placebo arm participants saw an insignificant rise in miR-124 blood levels.

Dr. Steens reported that 22 patients, including 7 who had originally been placebo arm participants, continued into the maintenance phase of the study. Nineteen patients have now had a median of over 400 days of exposure to ABX464, with sustained significant improvement in partial Mayo scores from a baseline of 6 to scores below 2 at 6 and 9 months. Fecal calprotectin scores have dropped from a median 1,044 mcg/g at baseline to 23.5 mcg/g at 9 months.

Next steps include the 12-month assessment, which includes another endoscopy, said Dr. Steens. Also, a phase 2b study is seeking to enroll 232 patients who have moderate to severe ulcerative colitis, with room within the enrollment scheme for new study sites, said Dr. Steens. This larger study will have arms in which the current 50-mg oral dose is doubled and halved, as well as a placebo arm, he said. The medication will also be trialed for Crohn’s disease and rheumatoid arthritis.

The small sample size is an inherent limitation of this early-stage clinical trial, noted Dr. Steens.

Dr. Steens reported being an employee and holding shares in Abivax, which funded the study.

[email protected]

SOURCE: Vermeire S et al. DDW 2019, Abstract 1007.

Inflammatory bowel disease (IBD) treatment remains a challenge in part because care is often fragmented among providers in different specialties, according to the American Gastroenterological Association. To address the need for provider coordination, the AGA has issued a new referral pathway for IBD care, published in Gastroenterology.

“The goal of this pathway is to offer guidance to primary care, emergency department, and gastroenterology providers, by helping identify patients at risk of or diagnosed with IBD and provide direction on initiating appropriate patient referrals,” wrote lead author Jami Kinnucan, MD, of the University of Michigan, Ann Arbor, and members of the AGA workgroup.

In particular, the pathway focuses on gaps in IBD care related to inflammatory issues, mental health, and nutrition. The work group included not only gastroenterologists, but also a primary care physician, mental/behavioral health specialist, registered dietitian/nutritionist, critical care specialist, nurse practitioner, physician group representative, and a patient advocacy representative.

The pathway identifies the top three areas where IBD patients usually present with symptoms: the emergency department, primary care office, and gastroenterology office.

The work group developed a list of key characteristics associated with increased morbidity, established IBD, or IBD-related complications that can be separated into high-risk, moderate-risk, and low-risk groups to help clinicians determine the timing of and need for referrals.

The pathway uses a sample patient presenting with GI symptoms such as bloody diarrhea; GI bleeding; anemia; fecal urgency; fever; abdominal pain; weight loss; and pain, swelling, or redness in the joints. Clinicians then apply the key characteristics to triage the patients into the risk groups.

High-risk characteristics include history of perianal or severe rectal disease, or deep ulcers in the GI mucosa; two or more emergency department visits for GI problems within the past 6 months, severe anemia, inadequate response to outpatient IBD therapy, history of IBD-related surgery, and malnourishment.

Moderate-risk characteristics include anemia without clinical symptoms, chronic corticosteroid use, and no emergency department or other GI medical visits within the past year.

Low-risk characteristics include chronic narcotic use, one or more comorbidities (such as heart failure, active hepatitis B, oncologic malignancy, lupus, GI infections, primary sclerosing cholangitis, viral hepatitis, and celiac disease), one or more relevant mental health conditions (such as depression, anxiety, or chronic pain), and nonadherence to IBD medical therapies.

“Referrals should be based on the highest level of risk present, in the event that a patient has characteristics that fall in more than one risk category,” the work group wrote.

To further guide clinicians in referring patients with possible or diagnosed IBD to gastroenterology specialists and to mental health and nutrition specialists, the work group developed an IBD Characteristics Assessment Checklist and a Referral Feedback form to accompany the pathway.

The checklist is designed for use by any health care professional to help identify whether a patient needs to be referred based on the key characteristics; the feedback form gives gastroenterologists a template to communicate with referring physicians about comanagement strategies for the patient.

The pathway also includes more details on how clinicians can tackle barriers to mental health and nutrition care for IBD patients.

“Until further evaluations are conducted, the work group encourages the immediate use of the pathway to begin addressing the needed improvements for IBD care coordination and communication between the different IBD providers,” the authors wrote.

Dr. Kinnucan disclosed serving as a consultant for AbbVie, Janssen, and Pfizer and serving on the Patient Education Committee of the Crohn’s and Colitis Foundation.

SOURCE: Kinnucan J et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.03.064.

Inflammatory bowel disease (IBD) treatment remains a challenge in part because care is often fragmented among providers in different specialties, according to the American Gastroenterological Association. To address the need for provider coordination, the AGA has issued a new referral pathway for IBD care, published in Gastroenterology.

“The goal of this pathway is to offer guidance to primary care, emergency department, and gastroenterology providers, by helping identify patients at risk of or diagnosed with IBD and provide direction on initiating appropriate patient referrals,” wrote lead author Jami Kinnucan, MD, of the University of Michigan, Ann Arbor, and members of the AGA workgroup.

In particular, the pathway focuses on gaps in IBD care related to inflammatory issues, mental health, and nutrition. The work group included not only gastroenterologists, but also a primary care physician, mental/behavioral health specialist, registered dietitian/nutritionist, critical care specialist, nurse practitioner, physician group representative, and a patient advocacy representative.

The pathway identifies the top three areas where IBD patients usually present with symptoms: the emergency department, primary care office, and gastroenterology office.

The work group developed a list of key characteristics associated with increased morbidity, established IBD, or IBD-related complications that can be separated into high-risk, moderate-risk, and low-risk groups to help clinicians determine the timing of and need for referrals.

The pathway uses a sample patient presenting with GI symptoms such as bloody diarrhea; GI bleeding; anemia; fecal urgency; fever; abdominal pain; weight loss; and pain, swelling, or redness in the joints. Clinicians then apply the key characteristics to triage the patients into the risk groups.

High-risk characteristics include history of perianal or severe rectal disease, or deep ulcers in the GI mucosa; two or more emergency department visits for GI problems within the past 6 months, severe anemia, inadequate response to outpatient IBD therapy, history of IBD-related surgery, and malnourishment.

Moderate-risk characteristics include anemia without clinical symptoms, chronic corticosteroid use, and no emergency department or other GI medical visits within the past year.

Low-risk characteristics include chronic narcotic use, one or more comorbidities (such as heart failure, active hepatitis B, oncologic malignancy, lupus, GI infections, primary sclerosing cholangitis, viral hepatitis, and celiac disease), one or more relevant mental health conditions (such as depression, anxiety, or chronic pain), and nonadherence to IBD medical therapies.

“Referrals should be based on the highest level of risk present, in the event that a patient has characteristics that fall in more than one risk category,” the work group wrote.

To further guide clinicians in referring patients with possible or diagnosed IBD to gastroenterology specialists and to mental health and nutrition specialists, the work group developed an IBD Characteristics Assessment Checklist and a Referral Feedback form to accompany the pathway.

The checklist is designed for use by any health care professional to help identify whether a patient needs to be referred based on the key characteristics; the feedback form gives gastroenterologists a template to communicate with referring physicians about comanagement strategies for the patient.

The pathway also includes more details on how clinicians can tackle barriers to mental health and nutrition care for IBD patients.

“Until further evaluations are conducted, the work group encourages the immediate use of the pathway to begin addressing the needed improvements for IBD care coordination and communication between the different IBD providers,” the authors wrote.

Dr. Kinnucan disclosed serving as a consultant for AbbVie, Janssen, and Pfizer and serving on the Patient Education Committee of the Crohn’s and Colitis Foundation.

SOURCE: Kinnucan J et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.03.064.

Inflammatory bowel disease (IBD) treatment remains a challenge in part because care is often fragmented among providers in different specialties, according to the American Gastroenterological Association. To address the need for provider coordination, the AGA has issued a new referral pathway for IBD care, published in Gastroenterology.

“The goal of this pathway is to offer guidance to primary care, emergency department, and gastroenterology providers, by helping identify patients at risk of or diagnosed with IBD and provide direction on initiating appropriate patient referrals,” wrote lead author Jami Kinnucan, MD, of the University of Michigan, Ann Arbor, and members of the AGA workgroup.

In particular, the pathway focuses on gaps in IBD care related to inflammatory issues, mental health, and nutrition. The work group included not only gastroenterologists, but also a primary care physician, mental/behavioral health specialist, registered dietitian/nutritionist, critical care specialist, nurse practitioner, physician group representative, and a patient advocacy representative.

The pathway identifies the top three areas where IBD patients usually present with symptoms: the emergency department, primary care office, and gastroenterology office.

The work group developed a list of key characteristics associated with increased morbidity, established IBD, or IBD-related complications that can be separated into high-risk, moderate-risk, and low-risk groups to help clinicians determine the timing of and need for referrals.

The pathway uses a sample patient presenting with GI symptoms such as bloody diarrhea; GI bleeding; anemia; fecal urgency; fever; abdominal pain; weight loss; and pain, swelling, or redness in the joints. Clinicians then apply the key characteristics to triage the patients into the risk groups.

High-risk characteristics include history of perianal or severe rectal disease, or deep ulcers in the GI mucosa; two or more emergency department visits for GI problems within the past 6 months, severe anemia, inadequate response to outpatient IBD therapy, history of IBD-related surgery, and malnourishment.

Moderate-risk characteristics include anemia without clinical symptoms, chronic corticosteroid use, and no emergency department or other GI medical visits within the past year.

Low-risk characteristics include chronic narcotic use, one or more comorbidities (such as heart failure, active hepatitis B, oncologic malignancy, lupus, GI infections, primary sclerosing cholangitis, viral hepatitis, and celiac disease), one or more relevant mental health conditions (such as depression, anxiety, or chronic pain), and nonadherence to IBD medical therapies.

“Referrals should be based on the highest level of risk present, in the event that a patient has characteristics that fall in more than one risk category,” the work group wrote.

To further guide clinicians in referring patients with possible or diagnosed IBD to gastroenterology specialists and to mental health and nutrition specialists, the work group developed an IBD Characteristics Assessment Checklist and a Referral Feedback form to accompany the pathway.

The checklist is designed for use by any health care professional to help identify whether a patient needs to be referred based on the key characteristics; the feedback form gives gastroenterologists a template to communicate with referring physicians about comanagement strategies for the patient.

The pathway also includes more details on how clinicians can tackle barriers to mental health and nutrition care for IBD patients.

“Until further evaluations are conducted, the work group encourages the immediate use of the pathway to begin addressing the needed improvements for IBD care coordination and communication between the different IBD providers,” the authors wrote.

Dr. Kinnucan disclosed serving as a consultant for AbbVie, Janssen, and Pfizer and serving on the Patient Education Committee of the Crohn’s and Colitis Foundation.

SOURCE: Kinnucan J et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.03.064.

SAN FRANCISCO – Patients with alcohol use disorder reported a substantial decrease in drinking days, drinks per drinking day, and cravings in an ongoing trial of psilocybin at New York University.

M. Alexander Otto/MDedge News

“If this keeps going the way it looks like it’s going, I think it will lead to a large phase 3 trial that could be part of getting psilocybin rescheduled” from a schedule I drug, said NYU psychiatrist and lead investigator Kelley O’Donnell, MD, PhD.

The work builds on positive results from the 1950s and 1960s of LSD for alcoholism, before LSD research was largely abandoned. Researchers such as Dr. O’Donnell are revisiting the approach, but with psilocybin because, among other reasons, it has less stigma and a shorter duration that allows for outpatient use (J Psychopharmacol. 2012 Jul;26[7]:994-1002). The Drug Enforcement Administration currently classifies psilocybin, the psychoactive ingredient in hallucinogenic, or “magic” mushrooms, as schedule I. The results found by Dr. O’Donnell’s team and other factors, such as the low risk of abuse tied to the use of psilocybin, are leading some researchers to suggest that the drug should be reclassified to “no more restrictively than schedule IV” (Neuropsychopharm. 2018 Nov;142:143-66).

Dr. O’Donnell’s presentation was part of a recurring theme at the annual meeting of the American Psychiatric Association – the transformation of what were once considered street drugs into therapeutic tools. Favorable results also were reported for 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, for posttraumatic stress disorder; ketamine for depression and suicidality; and marijuana for pain and other problems.

Concerning psilocybin for alcohol use disorder (AUD), Dr. O’Donnell said: “Some people have really profound psychological experiences that shift the way they think about themselves and the way alcohol is affecting their relationships. Therapy can work with that shift in meaning [to create] lasting change.”

Many people “say that they get exactly what they needed.” Sometimes, patients revisit a past trauma but with a greater openness and flexibility – and a growing sense of peace. “They access affective states they just don’t have access to normally,” she said.

Dr. O’Donnell recalled a man who said, after his trip: “Okay, I’m done. I’ve seen my true place in the world, and alcohol is interfering with my ability to take that place. I don’t need it, anymore.”

In another case, a woman hallucinated that she was sitting on a throne ascending through the universe, surrounded by the faces and voices of people she knew telling her she is a valuable and worthwhile person, and could take her place within the center of her universe without the sense of defectiveness and shame that often triggered her drinking. Happy little beer bottles told her: “We don’t need to be the enemy. We don’t need to be a part of your life,” Dr. O’Donnell said.

She and her team are pitting psilocybin against diphenhydramine as a control in the NYU AUD trial.

People are randomized, then undergo therapy focused equally on their alcohol use and preparing them for the drug experience. At week 4, they take their study medication – either 25 mg per 70 kg psilocybin or 50 mg diphenhydramine ­– in a relaxed living room–like setting, with classical or world music in the background. The study team avoids music with words in English. Two therapists, usually a man and a woman, are there as guides. The experience lasts a few hours; patients are debriefed afterward.

Patients undergo another round of counseling to understand the meaning of the experience, followed by a second dose, either 40 mg per 70 kg psilocybin or 100 mg diphenhydramine, at week 8. Patients are debriefed again and undergo a third month of counseling.

The results have not yet been unblinded, but Dr. O’Donnell and her team did find that, among their first 56 subjects, more intense mystical experiences, as gauged by the self-reported Mystical Experience Questionnaire (MEQ), correlated with greater treatment success.

Patients fill out the MEQ 8 hours after their dose, rating dimensions such as ego dissolution, oceanic boundlessness, joy, compassion, and openness. The maximum score is 1, the lowest 0, meaning no mystical effects. The median score among the 56 subjects was 0.26. The 30 or so patients who scored at or above that mark after their first medication session – as a group, their mean first MEQ score was 0.65 – reported a smaller percentage of drinking days at week 12 than those who scored below 0.26 (19% vs. 40%; P less than .05), with fewer drinks per drinking day (2.63 vs. 7.01; P less than .01); and lower craving (8.43 vs. 13.86 points on 30-point Penn Alcohol Craving Scale, P less than .01).

The groups were evenly matched at baseline. Both reported drinking an average of 3 out of 4 days, with an mean of 7.5 drinks per drinking day and a craving score of about 18. No differences were found in anxiety and depression scores, which were minimal in both groups.

More than half the subjects were men; the mean age was 46; and subjects were fairly well educated, reporting an average of 17 school years.

Dr. O’Donnell said she’s seen a range of experiences on psilocybin, but that bad trips are rare. Benzodiazepines are kept on hand, however, to help people who get too anxious, and an atypical antipsychotic is on hand to reverse hallucinatory effects.

Her team hopes to enroll 100 subjects and plans for follow-up past 12 weeks. Both Denver and Oakland, Calif., recently decriminalized psilocybin.

The work is being funded by the Heffter Research Institute. Dr. O’Donnell had no disclosures.

[email protected]

SAN FRANCISCO – Patients with alcohol use disorder reported a substantial decrease in drinking days, drinks per drinking day, and cravings in an ongoing trial of psilocybin at New York University.

M. Alexander Otto/MDedge News

“If this keeps going the way it looks like it’s going, I think it will lead to a large phase 3 trial that could be part of getting psilocybin rescheduled” from a schedule I drug, said NYU psychiatrist and lead investigator Kelley O’Donnell, MD, PhD.

The work builds on positive results from the 1950s and 1960s of LSD for alcoholism, before LSD research was largely abandoned. Researchers such as Dr. O’Donnell are revisiting the approach, but with psilocybin because, among other reasons, it has less stigma and a shorter duration that allows for outpatient use (J Psychopharmacol. 2012 Jul;26[7]:994-1002). The Drug Enforcement Administration currently classifies psilocybin, the psychoactive ingredient in hallucinogenic, or “magic” mushrooms, as schedule I. The results found by Dr. O’Donnell’s team and other factors, such as the low risk of abuse tied to the use of psilocybin, are leading some researchers to suggest that the drug should be reclassified to “no more restrictively than schedule IV” (Neuropsychopharm. 2018 Nov;142:143-66).

Dr. O’Donnell’s presentation was part of a recurring theme at the annual meeting of the American Psychiatric Association – the transformation of what were once considered street drugs into therapeutic tools. Favorable results also were reported for 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, for posttraumatic stress disorder; ketamine for depression and suicidality; and marijuana for pain and other problems.

Concerning psilocybin for alcohol use disorder (AUD), Dr. O’Donnell said: “Some people have really profound psychological experiences that shift the way they think about themselves and the way alcohol is affecting their relationships. Therapy can work with that shift in meaning [to create] lasting change.”

Many people “say that they get exactly what they needed.” Sometimes, patients revisit a past trauma but with a greater openness and flexibility – and a growing sense of peace. “They access affective states they just don’t have access to normally,” she said.

Dr. O’Donnell recalled a man who said, after his trip: “Okay, I’m done. I’ve seen my true place in the world, and alcohol is interfering with my ability to take that place. I don’t need it, anymore.”

In another case, a woman hallucinated that she was sitting on a throne ascending through the universe, surrounded by the faces and voices of people she knew telling her she is a valuable and worthwhile person, and could take her place within the center of her universe without the sense of defectiveness and shame that often triggered her drinking. Happy little beer bottles told her: “We don’t need to be the enemy. We don’t need to be a part of your life,” Dr. O’Donnell said.

She and her team are pitting psilocybin against diphenhydramine as a control in the NYU AUD trial.

People are randomized, then undergo therapy focused equally on their alcohol use and preparing them for the drug experience. At week 4, they take their study medication – either 25 mg per 70 kg psilocybin or 50 mg diphenhydramine ­– in a relaxed living room–like setting, with classical or world music in the background. The study team avoids music with words in English. Two therapists, usually a man and a woman, are there as guides. The experience lasts a few hours; patients are debriefed afterward.

Patients undergo another round of counseling to understand the meaning of the experience, followed by a second dose, either 40 mg per 70 kg psilocybin or 100 mg diphenhydramine, at week 8. Patients are debriefed again and undergo a third month of counseling.

The results have not yet been unblinded, but Dr. O’Donnell and her team did find that, among their first 56 subjects, more intense mystical experiences, as gauged by the self-reported Mystical Experience Questionnaire (MEQ), correlated with greater treatment success.

Patients fill out the MEQ 8 hours after their dose, rating dimensions such as ego dissolution, oceanic boundlessness, joy, compassion, and openness. The maximum score is 1, the lowest 0, meaning no mystical effects. The median score among the 56 subjects was 0.26. The 30 or so patients who scored at or above that mark after their first medication session – as a group, their mean first MEQ score was 0.65 – reported a smaller percentage of drinking days at week 12 than those who scored below 0.26 (19% vs. 40%; P less than .05), with fewer drinks per drinking day (2.63 vs. 7.01; P less than .01); and lower craving (8.43 vs. 13.86 points on 30-point Penn Alcohol Craving Scale, P less than .01).

The groups were evenly matched at baseline. Both reported drinking an average of 3 out of 4 days, with an mean of 7.5 drinks per drinking day and a craving score of about 18. No differences were found in anxiety and depression scores, which were minimal in both groups.

More than half the subjects were men; the mean age was 46; and subjects were fairly well educated, reporting an average of 17 school years.

Dr. O’Donnell said she’s seen a range of experiences on psilocybin, but that bad trips are rare. Benzodiazepines are kept on hand, however, to help people who get too anxious, and an atypical antipsychotic is on hand to reverse hallucinatory effects.

Her team hopes to enroll 100 subjects and plans for follow-up past 12 weeks. Both Denver and Oakland, Calif., recently decriminalized psilocybin.

The work is being funded by the Heffter Research Institute. Dr. O’Donnell had no disclosures.

[email protected]

SAN FRANCISCO – Patients with alcohol use disorder reported a substantial decrease in drinking days, drinks per drinking day, and cravings in an ongoing trial of psilocybin at New York University.

M. Alexander Otto/MDedge News

“If this keeps going the way it looks like it’s going, I think it will lead to a large phase 3 trial that could be part of getting psilocybin rescheduled” from a schedule I drug, said NYU psychiatrist and lead investigator Kelley O’Donnell, MD, PhD.

The work builds on positive results from the 1950s and 1960s of LSD for alcoholism, before LSD research was largely abandoned. Researchers such as Dr. O’Donnell are revisiting the approach, but with psilocybin because, among other reasons, it has less stigma and a shorter duration that allows for outpatient use (J Psychopharmacol. 2012 Jul;26[7]:994-1002). The Drug Enforcement Administration currently classifies psilocybin, the psychoactive ingredient in hallucinogenic, or “magic” mushrooms, as schedule I. The results found by Dr. O’Donnell’s team and other factors, such as the low risk of abuse tied to the use of psilocybin, are leading some researchers to suggest that the drug should be reclassified to “no more restrictively than schedule IV” (Neuropsychopharm. 2018 Nov;142:143-66).

Dr. O’Donnell’s presentation was part of a recurring theme at the annual meeting of the American Psychiatric Association – the transformation of what were once considered street drugs into therapeutic tools. Favorable results also were reported for 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, for posttraumatic stress disorder; ketamine for depression and suicidality; and marijuana for pain and other problems.

Concerning psilocybin for alcohol use disorder (AUD), Dr. O’Donnell said: “Some people have really profound psychological experiences that shift the way they think about themselves and the way alcohol is affecting their relationships. Therapy can work with that shift in meaning [to create] lasting change.”

Many people “say that they get exactly what they needed.” Sometimes, patients revisit a past trauma but with a greater openness and flexibility – and a growing sense of peace. “They access affective states they just don’t have access to normally,” she said.

Dr. O’Donnell recalled a man who said, after his trip: “Okay, I’m done. I’ve seen my true place in the world, and alcohol is interfering with my ability to take that place. I don’t need it, anymore.”

In another case, a woman hallucinated that she was sitting on a throne ascending through the universe, surrounded by the faces and voices of people she knew telling her she is a valuable and worthwhile person, and could take her place within the center of her universe without the sense of defectiveness and shame that often triggered her drinking. Happy little beer bottles told her: “We don’t need to be the enemy. We don’t need to be a part of your life,” Dr. O’Donnell said.

She and her team are pitting psilocybin against diphenhydramine as a control in the NYU AUD trial.

People are randomized, then undergo therapy focused equally on their alcohol use and preparing them for the drug experience. At week 4, they take their study medication – either 25 mg per 70 kg psilocybin or 50 mg diphenhydramine ­– in a relaxed living room–like setting, with classical or world music in the background. The study team avoids music with words in English. Two therapists, usually a man and a woman, are there as guides. The experience lasts a few hours; patients are debriefed afterward.

Patients undergo another round of counseling to understand the meaning of the experience, followed by a second dose, either 40 mg per 70 kg psilocybin or 100 mg diphenhydramine, at week 8. Patients are debriefed again and undergo a third month of counseling.

The results have not yet been unblinded, but Dr. O’Donnell and her team did find that, among their first 56 subjects, more intense mystical experiences, as gauged by the self-reported Mystical Experience Questionnaire (MEQ), correlated with greater treatment success.

Patients fill out the MEQ 8 hours after their dose, rating dimensions such as ego dissolution, oceanic boundlessness, joy, compassion, and openness. The maximum score is 1, the lowest 0, meaning no mystical effects. The median score among the 56 subjects was 0.26. The 30 or so patients who scored at or above that mark after their first medication session – as a group, their mean first MEQ score was 0.65 – reported a smaller percentage of drinking days at week 12 than those who scored below 0.26 (19% vs. 40%; P less than .05), with fewer drinks per drinking day (2.63 vs. 7.01; P less than .01); and lower craving (8.43 vs. 13.86 points on 30-point Penn Alcohol Craving Scale, P less than .01).

The groups were evenly matched at baseline. Both reported drinking an average of 3 out of 4 days, with an mean of 7.5 drinks per drinking day and a craving score of about 18. No differences were found in anxiety and depression scores, which were minimal in both groups.

More than half the subjects were men; the mean age was 46; and subjects were fairly well educated, reporting an average of 17 school years.

Dr. O’Donnell said she’s seen a range of experiences on psilocybin, but that bad trips are rare. Benzodiazepines are kept on hand, however, to help people who get too anxious, and an atypical antipsychotic is on hand to reverse hallucinatory effects.

Her team hopes to enroll 100 subjects and plans for follow-up past 12 weeks. Both Denver and Oakland, Calif., recently decriminalized psilocybin.

The work is being funded by the Heffter Research Institute. Dr. O’Donnell had no disclosures.

[email protected]

Measles cases in the United States have topped 1,000 for the first time since 1992, according to the Centers for Disease Control and Prevention.

The 41 new cases reported for the week ending June 6 bring the total for the year to 1,022, the CDC reported June 10, and that is more than any year since 1992, when there were 2,237 cases.

Idaho and Virginia reported their first cases of 2019, which makes a total of 28 states with measles cases this year. The Idaho case was reported in Latah County and is the state’s first since 2001. In Virginia, health officials are investigating possible contacts with an infected individual at Dulles International Airport and two other locations on June 2 and 4.

Outbreaks in Georgia, Maryland, and Michigan have ended, while seven others continue in California (Butte, Los Angeles, and Sacramento Counties), New York (Rockland County and New York City), Pennsylvania, and Washington, the CDC said. New York City has the largest outbreak this year with 509 cases through June 3, most of them occurring in Brooklyn.

[email protected]

Measles cases in the United States have topped 1,000 for the first time since 1992, according to the Centers for Disease Control and Prevention.

The 41 new cases reported for the week ending June 6 bring the total for the year to 1,022, the CDC reported June 10, and that is more than any year since 1992, when there were 2,237 cases.

Idaho and Virginia reported their first cases of 2019, which makes a total of 28 states with measles cases this year. The Idaho case was reported in Latah County and is the state’s first since 2001. In Virginia, health officials are investigating possible contacts with an infected individual at Dulles International Airport and two other locations on June 2 and 4.

Outbreaks in Georgia, Maryland, and Michigan have ended, while seven others continue in California (Butte, Los Angeles, and Sacramento Counties), New York (Rockland County and New York City), Pennsylvania, and Washington, the CDC said. New York City has the largest outbreak this year with 509 cases through June 3, most of them occurring in Brooklyn.

[email protected]

Measles cases in the United States have topped 1,000 for the first time since 1992, according to the Centers for Disease Control and Prevention.

The 41 new cases reported for the week ending June 6 bring the total for the year to 1,022, the CDC reported June 10, and that is more than any year since 1992, when there were 2,237 cases.

Idaho and Virginia reported their first cases of 2019, which makes a total of 28 states with measles cases this year. The Idaho case was reported in Latah County and is the state’s first since 2001. In Virginia, health officials are investigating possible contacts with an infected individual at Dulles International Airport and two other locations on June 2 and 4.

Outbreaks in Georgia, Maryland, and Michigan have ended, while seven others continue in California (Butte, Los Angeles, and Sacramento Counties), New York (Rockland County and New York City), Pennsylvania, and Washington, the CDC said. New York City has the largest outbreak this year with 509 cases through June 3, most of them occurring in Brooklyn.

[email protected]

The Food and Drug Administration has granted accelerated approval to Polivy (polatuzumab vedotin-piiq), in conjunction with bendamustine and a rituximab product, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have undergone at least two prior therapies.

The FDA approval is based on results of an open-label, multicenter clinical trial of 80 patients with DLBCL who had undergone at least one prior regimen. Patients received either Polivy plus bendamustine and rituximab or only bendamustine and rituximab for six 21-day cycles. At the completion of therapy, 40% of patients who received Polivy in conjunction with bendamustine and rituximab achieved a complete response, compared with 18% of patients who received only bendamustine and rituximab; total response was 63% in those who received Polivy and 25% in those who did not.

The most common adverse events included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. Serious adverse events occurred in 64% of patients, most commonly from infection; the most common cause for treatment discontinuation was cytopenia.

The recommended dose of Polivy is 1.8 mg/kg as an intravenous infusion over 90 minutes every 21 days for six cycles in combination with bendamustine and a rituximab product, the FDA said. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has granted accelerated approval to Polivy (polatuzumab vedotin-piiq), in conjunction with bendamustine and a rituximab product, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have undergone at least two prior therapies.

The FDA approval is based on results of an open-label, multicenter clinical trial of 80 patients with DLBCL who had undergone at least one prior regimen. Patients received either Polivy plus bendamustine and rituximab or only bendamustine and rituximab for six 21-day cycles. At the completion of therapy, 40% of patients who received Polivy in conjunction with bendamustine and rituximab achieved a complete response, compared with 18% of patients who received only bendamustine and rituximab; total response was 63% in those who received Polivy and 25% in those who did not.

The most common adverse events included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. Serious adverse events occurred in 64% of patients, most commonly from infection; the most common cause for treatment discontinuation was cytopenia.

The recommended dose of Polivy is 1.8 mg/kg as an intravenous infusion over 90 minutes every 21 days for six cycles in combination with bendamustine and a rituximab product, the FDA said. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has granted accelerated approval to Polivy (polatuzumab vedotin-piiq), in conjunction with bendamustine and a rituximab product, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have undergone at least two prior therapies.

The FDA approval is based on results of an open-label, multicenter clinical trial of 80 patients with DLBCL who had undergone at least one prior regimen. Patients received either Polivy plus bendamustine and rituximab or only bendamustine and rituximab for six 21-day cycles. At the completion of therapy, 40% of patients who received Polivy in conjunction with bendamustine and rituximab achieved a complete response, compared with 18% of patients who received only bendamustine and rituximab; total response was 63% in those who received Polivy and 25% in those who did not.

The most common adverse events included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. Serious adverse events occurred in 64% of patients, most commonly from infection; the most common cause for treatment discontinuation was cytopenia.

The recommended dose of Polivy is 1.8 mg/kg as an intravenous infusion over 90 minutes every 21 days for six cycles in combination with bendamustine and a rituximab product, the FDA said. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated.

Find the full press release on the FDA website.

[email protected]

WASHINGTON – Having unmet social needs plays a key role in raising the risk of cardiovascular disease among immigrant, socially isolated, and low-income populations, according to a study.

Jennifer Reising/MDege News

“Although there have been great medical interventions and our technology keeps improving, we can’t prevent the burden of cardiovascular disease. It’s the social factors that are playing this role,” said Ana Palacio, MD, MPH, of the University of Miami during her presentation of the study findings at the annual meeting of the Society of General Internal Medicine.

“We need to address issues at the patient’s home, such as food, isolation, and transportation, to help them prevent cardiovascular risk,” she added.

The study was designed to determine how patient-reported social determinants of health (SDH) had an effect on the Framingham risk score (FRS). Researchers also wanted to assess the relationship between the SDH score and individual risk factors for cardiovascular health, including blood pressure, hemoglobin A_1c, LDL cholesterol, body mass index, tobacco use, and physical activity.

Results showed that several SDH factors significantly increase the FRS score, including being born outside of the United States, living alone, having a high social isolation score, and having a low geocoded-based median household income (P less than .01). The calculated SDH score ranged from 0 to 59.

Higher SDH scores were associated with high FRS scores in the areas of poor blood pressure and diabetes control. Additionally, those who had financial strain, poor health literacy, stress, lack of education, and a low median household income were more likely to have a sedentary lifestyle. Black or Hispanic patients who were born outside the United States and had low median household income were at a higher risk of obesity.

The retrospective cohort study originally involved 11,113 primary care patients who received care at the University of Miami Health System between Sept. 16, 2016 and Sept. 10, 2017 and answered an SDH survey. Of this group, 2,876 patients completed the electronic health record data to compile a score. This population had a mean age of 53.8 years and was 61% female; 38% were Hispanic and 9% were black. The mean household income was $53,677 and 87% reported speaking English.

The study examined a total of 11 self-reported and census-based SDH factors. The self-reported factors were race/ethnicity, education, financial strain, stress, tobacco use and physical activity, social isolation, years living in the United States, health literacy, and delayed care. The remaining factors were based on an area deprivation index and census-driven median household income.

“The most surprising finding was how much weight the social factors have in adding to the Framingham risk score, in taking a patient from a medium score to a higher score because of their social environment,” said Dr. Palacio.

The study was funded by the Precision Medicine and Health Disparities Collaborative and was supported by the National Institute on Minority Health and Health Disparities and National Human Genome Research Institute of the National Institutes of Health.
 

WASHINGTON – Having unmet social needs plays a key role in raising the risk of cardiovascular disease among immigrant, socially isolated, and low-income populations, according to a study.

Jennifer Reising/MDege News

“Although there have been great medical interventions and our technology keeps improving, we can’t prevent the burden of cardiovascular disease. It’s the social factors that are playing this role,” said Ana Palacio, MD, MPH, of the University of Miami during her presentation of the study findings at the annual meeting of the Society of General Internal Medicine.

“We need to address issues at the patient’s home, such as food, isolation, and transportation, to help them prevent cardiovascular risk,” she added.

The study was designed to determine how patient-reported social determinants of health (SDH) had an effect on the Framingham risk score (FRS). Researchers also wanted to assess the relationship between the SDH score and individual risk factors for cardiovascular health, including blood pressure, hemoglobin A_1c, LDL cholesterol, body mass index, tobacco use, and physical activity.

Results showed that several SDH factors significantly increase the FRS score, including being born outside of the United States, living alone, having a high social isolation score, and having a low geocoded-based median household income (P less than .01). The calculated SDH score ranged from 0 to 59.

Higher SDH scores were associated with high FRS scores in the areas of poor blood pressure and diabetes control. Additionally, those who had financial strain, poor health literacy, stress, lack of education, and a low median household income were more likely to have a sedentary lifestyle. Black or Hispanic patients who were born outside the United States and had low median household income were at a higher risk of obesity.

The retrospective cohort study originally involved 11,113 primary care patients who received care at the University of Miami Health System between Sept. 16, 2016 and Sept. 10, 2017 and answered an SDH survey. Of this group, 2,876 patients completed the electronic health record data to compile a score. This population had a mean age of 53.8 years and was 61% female; 38% were Hispanic and 9% were black. The mean household income was $53,677 and 87% reported speaking English.

The study examined a total of 11 self-reported and census-based SDH factors. The self-reported factors were race/ethnicity, education, financial strain, stress, tobacco use and physical activity, social isolation, years living in the United States, health literacy, and delayed care. The remaining factors were based on an area deprivation index and census-driven median household income.

“The most surprising finding was how much weight the social factors have in adding to the Framingham risk score, in taking a patient from a medium score to a higher score because of their social environment,” said Dr. Palacio.

The study was funded by the Precision Medicine and Health Disparities Collaborative and was supported by the National Institute on Minority Health and Health Disparities and National Human Genome Research Institute of the National Institutes of Health.
 

WASHINGTON – Having unmet social needs plays a key role in raising the risk of cardiovascular disease among immigrant, socially isolated, and low-income populations, according to a study.

Jennifer Reising/MDege News

“Although there have been great medical interventions and our technology keeps improving, we can’t prevent the burden of cardiovascular disease. It’s the social factors that are playing this role,” said Ana Palacio, MD, MPH, of the University of Miami during her presentation of the study findings at the annual meeting of the Society of General Internal Medicine.

“We need to address issues at the patient’s home, such as food, isolation, and transportation, to help them prevent cardiovascular risk,” she added.

The study was designed to determine how patient-reported social determinants of health (SDH) had an effect on the Framingham risk score (FRS). Researchers also wanted to assess the relationship between the SDH score and individual risk factors for cardiovascular health, including blood pressure, hemoglobin A_1c, LDL cholesterol, body mass index, tobacco use, and physical activity.

Results showed that several SDH factors significantly increase the FRS score, including being born outside of the United States, living alone, having a high social isolation score, and having a low geocoded-based median household income (P less than .01). The calculated SDH score ranged from 0 to 59.

Higher SDH scores were associated with high FRS scores in the areas of poor blood pressure and diabetes control. Additionally, those who had financial strain, poor health literacy, stress, lack of education, and a low median household income were more likely to have a sedentary lifestyle. Black or Hispanic patients who were born outside the United States and had low median household income were at a higher risk of obesity.

The retrospective cohort study originally involved 11,113 primary care patients who received care at the University of Miami Health System between Sept. 16, 2016 and Sept. 10, 2017 and answered an SDH survey. Of this group, 2,876 patients completed the electronic health record data to compile a score. This population had a mean age of 53.8 years and was 61% female; 38% were Hispanic and 9% were black. The mean household income was $53,677 and 87% reported speaking English.

The study examined a total of 11 self-reported and census-based SDH factors. The self-reported factors were race/ethnicity, education, financial strain, stress, tobacco use and physical activity, social isolation, years living in the United States, health literacy, and delayed care. The remaining factors were based on an area deprivation index and census-driven median household income.

“The most surprising finding was how much weight the social factors have in adding to the Framingham risk score, in taking a patient from a medium score to a higher score because of their social environment,” said Dr. Palacio.

The study was funded by the Precision Medicine and Health Disparities Collaborative and was supported by the National Institute on Minority Health and Health Disparities and National Human Genome Research Institute of the National Institutes of Health.
 

The investigational oral Janus kinase (JAK) inhibitor upadacitinib has shown promise as a monotherapy treatment option for patients with active rheumatoid arthritis despite treatment with methotrexate, based on results from the phase 3 SELECT-MONOTHERAPY trial.

“The SELECT-MONOTHERAPY trial showed that patients who were having an inadequate response to methotrexate could be switched to oral upadacitinib monotherapy (15 mg or 30 mg) once a day, with improvements in clinical signs and symptoms, physical function, and quality of life measures, compared with patients who continued on their previous methotrexate dose,” Josef S. Smolen, MD, of the Medical University of Vienna, and his colleagues wrote in the Lancet.

The phase 3, double-blind, placebo-controlled trial randomized 648 RA patients with active disease despite methotrexate therapy from 138 sites in 24 countries.

Higher proportions of patients receiving upadacitinib 15 mg and 30 mg versus continued methotrexate achieved the primary endpoints of the proportion of patients achieving a 20% improvement in American College of Rheumatology (ACR 20) criteria at 14 weeks and the proportion achieving low disease activity defined as a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) of 3.2 or lower.

An ACR 20 response was achieved by 89 (41%) of 216 patients (95% confidence interval, 35%-48%) in the continued methotrexate group, 147 (68%) of 217 patients (95% CI, 62%-74%) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (95% CI, 65%-77%) receiving upadacitinib 30 mg (P less than .0001 for both doses vs. continued methotrexate).

A DAS28-CRP score of 3.2 or lower was met by 42 (19%) of 216 (95% CI, 14%-25%) receiving methotrexate, 97 (45%) of 217 (95% CI, 38%-51%) receiving upadacitinib 15 mg, and 114 (53%) of 215 (95% CI, 46%-60%) receiving upadacitinib 30 mg (P less than .0001 for both doses vs. continued methotrexate).

The investigators noted that responses were observed with both 15-mg and 30-mg doses of upadacitinib, although numerically higher responses were seen with the 30-mg dose.

“Whether the 15-mg or the 30-mg dose is the more appropriate one for patients who switch from methotrexate to upadacitinib will have to be established in conjunction with data from the other phase 3 upadacitinib trials,” they wrote.

Treatment-emergent adverse events were reported at similar frequencies across the arms (n = 102 with methotrexate; n = 103 with upadacitinib 15 mg; n = 105 with upadacitinib 30 mg).

Serious adverse events were reported in 11 (5%) of 217 patients in the upadacitinib 15 mg arm, 6 (3%) of 216 patients in the continued methotrexate arm, and 6 (3%) of 215 patients in the upadacitinib 30 mg arm.

“This favorable benefit-risk profile of upadacitinib monotherapy has the potential to provide a treatment option for patients who are intolerant to methotrexate or who prefer a treatment without the need for concomitant [conventional synthetic] DMARDs,” the authors wrote.

The study was funded by AbbVie. Dr. Smolen and most authors reported financial ties to AbbVie and other companies marketing rheumatoid arthritis treatments. Five authors are employees of AbbVie.

SOURCE: Smolen JS et al. Lancet. 2019;393[10188]:2303-11. doi: 10.1016/S0140-6736(19)30419-2

The investigational oral Janus kinase (JAK) inhibitor upadacitinib has shown promise as a monotherapy treatment option for patients with active rheumatoid arthritis despite treatment with methotrexate, based on results from the phase 3 SELECT-MONOTHERAPY trial.

“The SELECT-MONOTHERAPY trial showed that patients who were having an inadequate response to methotrexate could be switched to oral upadacitinib monotherapy (15 mg or 30 mg) once a day, with improvements in clinical signs and symptoms, physical function, and quality of life measures, compared with patients who continued on their previous methotrexate dose,” Josef S. Smolen, MD, of the Medical University of Vienna, and his colleagues wrote in the Lancet.

The phase 3, double-blind, placebo-controlled trial randomized 648 RA patients with active disease despite methotrexate therapy from 138 sites in 24 countries.

Higher proportions of patients receiving upadacitinib 15 mg and 30 mg versus continued methotrexate achieved the primary endpoints of the proportion of patients achieving a 20% improvement in American College of Rheumatology (ACR 20) criteria at 14 weeks and the proportion achieving low disease activity defined as a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) of 3.2 or lower.

An ACR 20 response was achieved by 89 (41%) of 216 patients (95% confidence interval, 35%-48%) in the continued methotrexate group, 147 (68%) of 217 patients (95% CI, 62%-74%) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (95% CI, 65%-77%) receiving upadacitinib 30 mg (P less than .0001 for both doses vs. continued methotrexate).

A DAS28-CRP score of 3.2 or lower was met by 42 (19%) of 216 (95% CI, 14%-25%) receiving methotrexate, 97 (45%) of 217 (95% CI, 38%-51%) receiving upadacitinib 15 mg, and 114 (53%) of 215 (95% CI, 46%-60%) receiving upadacitinib 30 mg (P less than .0001 for both doses vs. continued methotrexate).

The investigators noted that responses were observed with both 15-mg and 30-mg doses of upadacitinib, although numerically higher responses were seen with the 30-mg dose.

“Whether the 15-mg or the 30-mg dose is the more appropriate one for patients who switch from methotrexate to upadacitinib will have to be established in conjunction with data from the other phase 3 upadacitinib trials,” they wrote.

Treatment-emergent adverse events were reported at similar frequencies across the arms (n = 102 with methotrexate; n = 103 with upadacitinib 15 mg; n = 105 with upadacitinib 30 mg).

Serious adverse events were reported in 11 (5%) of 217 patients in the upadacitinib 15 mg arm, 6 (3%) of 216 patients in the continued methotrexate arm, and 6 (3%) of 215 patients in the upadacitinib 30 mg arm.

“This favorable benefit-risk profile of upadacitinib monotherapy has the potential to provide a treatment option for patients who are intolerant to methotrexate or who prefer a treatment without the need for concomitant [conventional synthetic] DMARDs,” the authors wrote.

The study was funded by AbbVie. Dr. Smolen and most authors reported financial ties to AbbVie and other companies marketing rheumatoid arthritis treatments. Five authors are employees of AbbVie.

SOURCE: Smolen JS et al. Lancet. 2019;393[10188]:2303-11. doi: 10.1016/S0140-6736(19)30419-2

The investigational oral Janus kinase (JAK) inhibitor upadacitinib has shown promise as a monotherapy treatment option for patients with active rheumatoid arthritis despite treatment with methotrexate, based on results from the phase 3 SELECT-MONOTHERAPY trial.

“The SELECT-MONOTHERAPY trial showed that patients who were having an inadequate response to methotrexate could be switched to oral upadacitinib monotherapy (15 mg or 30 mg) once a day, with improvements in clinical signs and symptoms, physical function, and quality of life measures, compared with patients who continued on their previous methotrexate dose,” Josef S. Smolen, MD, of the Medical University of Vienna, and his colleagues wrote in the Lancet.

The phase 3, double-blind, placebo-controlled trial randomized 648 RA patients with active disease despite methotrexate therapy from 138 sites in 24 countries.

Higher proportions of patients receiving upadacitinib 15 mg and 30 mg versus continued methotrexate achieved the primary endpoints of the proportion of patients achieving a 20% improvement in American College of Rheumatology (ACR 20) criteria at 14 weeks and the proportion achieving low disease activity defined as a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) of 3.2 or lower.

An ACR 20 response was achieved by 89 (41%) of 216 patients (95% confidence interval, 35%-48%) in the continued methotrexate group, 147 (68%) of 217 patients (95% CI, 62%-74%) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (95% CI, 65%-77%) receiving upadacitinib 30 mg (P less than .0001 for both doses vs. continued methotrexate).

A DAS28-CRP score of 3.2 or lower was met by 42 (19%) of 216 (95% CI, 14%-25%) receiving methotrexate, 97 (45%) of 217 (95% CI, 38%-51%) receiving upadacitinib 15 mg, and 114 (53%) of 215 (95% CI, 46%-60%) receiving upadacitinib 30 mg (P less than .0001 for both doses vs. continued methotrexate).

The investigators noted that responses were observed with both 15-mg and 30-mg doses of upadacitinib, although numerically higher responses were seen with the 30-mg dose.

“Whether the 15-mg or the 30-mg dose is the more appropriate one for patients who switch from methotrexate to upadacitinib will have to be established in conjunction with data from the other phase 3 upadacitinib trials,” they wrote.

Treatment-emergent adverse events were reported at similar frequencies across the arms (n = 102 with methotrexate; n = 103 with upadacitinib 15 mg; n = 105 with upadacitinib 30 mg).

Serious adverse events were reported in 11 (5%) of 217 patients in the upadacitinib 15 mg arm, 6 (3%) of 216 patients in the continued methotrexate arm, and 6 (3%) of 215 patients in the upadacitinib 30 mg arm.

“This favorable benefit-risk profile of upadacitinib monotherapy has the potential to provide a treatment option for patients who are intolerant to methotrexate or who prefer a treatment without the need for concomitant [conventional synthetic] DMARDs,” the authors wrote.

The study was funded by AbbVie. Dr. Smolen and most authors reported financial ties to AbbVie and other companies marketing rheumatoid arthritis treatments. Five authors are employees of AbbVie.

SOURCE: Smolen JS et al. Lancet. 2019;393[10188]:2303-11. doi: 10.1016/S0140-6736(19)30419-2

Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.

In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.

“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.

Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.

“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.

Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.

Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).

One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.

Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.

The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.

Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.

Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.

“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.

In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).

Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.

Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.

“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.

They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.

They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”

The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.

SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.

Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.

In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.

“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.

Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.

“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.

Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.

Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).

One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.

Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.

The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.

Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.

Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.

“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.

In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).

Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.

Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.

“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.

They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.

They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”

The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.

SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.

Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.

In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.

“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.

Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.

“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.

Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.

Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).

One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.

Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.

The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.

Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.

Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.

“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.

In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).

Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.

Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.

“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.

They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.

They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”

The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.

SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.