How Internal Medicine Clerkship Directors Are Using Entrustable Professional Activities: A National Survey Study.

BACKGROUND: In the present assessment environment in undergraduate medical education at U.S. medical schools, the prevalence and implementation of Entrustable Professional Activities (EPAs) in internal medicine (IM) clerkships are not well understood. OBJECTIVE: To describe the prevalence and approach to EPA use in U.S. IM clerkships. DESIGN: Cross-sectional, nationally representative survey of core IM clerkship directors. PARTICIPANTS: One-hundred forty IM clerkship directors at Liaison Committee on Medical Education-accredited U.S./U.S. territory-based allopathic medical schools with membership in the Clerkship Directors in Internal Medicine (CDIM) as of December 2022. MAIN MEASURES: Use of EPAs in IM core clerkships, including use for grading, types of EPAs, use of supportive measures for assessment, and current validity frameworks. KEY RESULTS: The survey response was 80% (112/140); two additional respondents completed the section on EPA use (n = 114). Approximately half of respondents (47%) reported their IM clerkship used EPAs. Among schools accredited after 1977, a higher percentage was associated with having incorporated EPAs (p = 0.03). The Association of American Medical Colleges Core EPAs for Entering Residency (CEPAER) was the most common framework used by Clerkship Directors (CDs) for developing EPAs (55%). Most CDs (56%) used EPAs for both formative and summative assessments, and approximately half of CDs (48%) used EPAs for a portion of the final grade determination. CDs who used EPAs were no more likely to report efforts to ensure the validity of assessment, the use of faculty development, or that written assessments were a valid measure of students' performance compared to those who did not use EPAs. CONCLUSIONS: Although EPAs have experienced substantial uptake in the IM clerkship and contribute to formative and summative assessment of learners, their use does not appear to be associated with enhanced efforts to obtain validity information.

Sexually Transmitted Infections in People with Human Immunodeficiency Virus.

Sexually transmitted infections (STIs) are more commonly seen in patients with human immunodeficiency virus (PWH). Routine sexual history taking and appropriate multisite screening practices support prompt identification and treatment of patients, which in turn reduces morbidity and spread of STIs including HIV. Nucleic acid amplification testing has high accuracy for diagnosing many of the major STIs. Diagnosis of syphilis remains complex, requiring 2 stage serologic testing, along with provider awareness of the myriad symptoms that can be attributable to this disease. Prevention through mechanisms such as vaccines and postexposure prophylaxis hold promise to reduce the burden of STIs in PWH.

Teaching Sideways: Implementing a Peer-Led Medical Student Orientation Bootcamp and Survival Guide for Internal Medicine Clerkship.

OBJECTIVES: Transitioning from classroom learning to clerkships presents a challenge for medical students because there is often sparse preparation material on how to effectively contribute to the medical team as a clerkship student. Although some medical schools have implemented transition-to-clerkship sessions, they often are led by faculty and lack the practical and contemporary guidance from students who have recently completed clerkships themselves. METHODS: Using a sideways mentorship approach, we implemented a 1-hour near-peer Internal Medicine (IM) clerkship orientation bootcamp at our medical school and wrote an accompanying survival guide to teach students how to function as part of a medical team and to increase the transparency of student expectations and evaluations during the clerkship. The 1-hour session covered the following core topics: clerkship logistics, how to gather/present clinical information, a resident/student question-and-answer panel, and how to contribute to the medical team. A postclerkship medical student and second-year IM resident conducted the bootcamp for four student cohorts (105 students total) during the January to December 2022 clerkship year before the IM rotation of each cohort. After the bootcamp, students received a copy of the survival guide to solidify concepts covered in the session. RESULTS: A preclerkship survey included questions to assess student confidence in 10 core IM clerkship domains pre- and postbootcamp. Both pre- and postclerkship surveys asked students to provide feedback on bootcamp strengths and weaknesses. Wilcoxon signed rank tests revealed a significant increase in postbootcamp student confidence rating for all 10 clerkship domains in the early clerkship cohort and in the late clerkship cohort for all of the domains, except finding clinical reference resources (P = 0.15). The bootcamp had the largest effect size (r) on student confidence in both early and late clerkship cohorts for the following clerkship domains: familiarity with IM clerkship evaluation (early: r = 0.61, P < 0.001; late: r = 0.56, P = 0.002), identification of ways to contribute to the medical team (early: r = 0.58, P < 0.001; late: r = 0.63, P < 0.001), and prerounding/chart checking (early r = 0.52, P < 0.001; late: r = 0.55, P = 0.001). The percentage of students rating the helpfulness of both the bootcamp and survival guide as a 3 to 5 on a 5-point Likert scale in the postclerkship survey was highest for the following domains: being familiar with the structure of a subjective, objective, assessment, and plan presentation (88% and 97%), prerounding/chart checking (82% and 95%), writing progress notes (82% and 92%), and identifying ways to contribute to the medical team (82% and 95%). Students commented that the main strengths of the bootcamp included its specific tips on synthesizing and presenting clinical information and its transparency about student expectations and experiences. CONCLUSIONS: A structured student-led bootcamp can increase clerkship preparation in core domains. The bootcamp is now part of mandatory clerkship didactics at our medical school, given its success during the 2022 clerkship year, and its content is continuing to be expanded upon by postclerkship students and residents. In addition, the format of the bootcamp also is being adapted to other clerkships, including surgery and obstetrics/gynecology.

Comparison of traditional instruction versus nontraditional learning to improve trainee knowledge of urine culture practices in catheterized patients.

We surveyed trainees about their urine culture practices and assessed the impact of an educational intervention delivered electronically and in-person. Trainee scores improved across all levels of training and across all questions on the post-intervention survey, but there was no difference in scores by mode of education (P=0.91).

WBAs in UME-How Many Are Needed? A Reliability Analysis of 5 AAMC Core EPAs Implemented in the Internal Medicine Clerkship.

BACKGROUND: Reliable assessments of clinical skills are important for undergraduate medical education, trustworthy handoffs to graduate medical programs, and safe, effective patient care. Entrustable professional activities (EPAs) for entering residency have been developed; research is needed to assess reliability of such assessments in authentic clinical workspaces. DESIGN: A student-driven mobile assessment platform was developed and used for clinical supervisors to record ad hoc entrustment decisions using the modified Ottawa scale on 5 core EPAs in an 8-week internal medicine (IM) clerkship. After a 12-month period, generalizability (G) theory analysis was performed to estimate the reliability of entrustment scores and determine the proportion of variance attributable to the student and the other facets, including particular EPA, evaluator type (attending versus resident), or case complexity. Decision (D) theory analysis determined the expected reliability based on the number of hypothetical observations. A g-coefficient of 0.7 was used as a generally agreed upon minimum reliability threshold. KEY RESULTS: A total of 1368 ratings over the 5 EPAs were completed on 94 students. Variance attributed to person (true variance) was high for all EPAs; EPA-5 had the lowest person variance (9.8% across cases and four blocks). Across cases, reliability ranged from 0.02 to 0.60. Applying this to the Decision study, the estimated number of observations needed to reach a reliability index of 0.7 ranged between 9 and 11 for all EPAs except EPA5 which was sensitive to case complexity. CONCLUSIONS: Work place-based clinical skills in IM clerkship students were assessed and logged using a convenient mobile platform. Our analysis suggests that 9-11 observations are needed for these EPA workplace-based assessments (WBAs) to achieve a reliability index of 0.7. Note writing was very sensitive to case complexity. Further reliability analyses of core EPAs are needed before US medical schools consider wider adoption into summative entrustment processes and GME handoffs.

Lower Gastrointestinal Syphilis: Case Series and Literature Review.

BACKGROUND: Syphilis infections are increasing globally. Lower gastrointestinal syphilis (LGIS) is a rare manifestation of early syphilis transmitted through anal sexual contact. Misdiagnosis of LGIS as inflammatory bowel disease may result from clinician underawareness. METHODS: We searched the literature for articles describing cases of LGIS, and identified additional cases diagnosed within our institution. Data were extracted from the articles and medical records and analyzed to provide a summative account. RESULTS: Fifty-four cases of LGIS were identified in 39 articles published between 1958 and 2020. Eight additional cases were diagnosed at our institution between 2011 and 2020, totaling 62 cases. All cases were described in men and transwomen aged 15-73 years. Fifty (93%) individuals reported having sex with men. In 26 cases (52%), the individuals were human immunodeficiency virus (HIV) coinfected. LGIS presented most commonly with hematochezia (67%) and anal pain (46%). The most common physical examination findings were rectal mass (38%), lymphadenopathy (31%), and rash (26%). Nontreponemal titers ranged from 1:2 to 1:1024. Of the 52 cases in which endoscopy was reported, 22 (42%) showed anorectal mass and 18 (35%) showed anorectal ulcer. In 44 cases (75%), histopathology revealed a chronic inflammatory infiltrate with a prominent lymphocyte component (45%) and/or plasma cells (36%). Seventy-eight percent of specimens to which a tissue stain was applied were positive for spirochetes. CONCLUSIONS: LGIS should be suspected in men and transwomen presenting with a lower gastrointestinal symptom or mucosal abnormality. A sexual history must be elicited and guide testing. Misdiagnosis can delay treatment and threatens patient and public health.

Coronavirus Disease 2019 in a Patient With a Systemic Autoinflammatory Syndrome due to an NLRC4 Inflammasomopathy.

The effect of autoinflammatory diseases on severe acute respiratory syndrome coronavirus 2 infection remains unknown. We report a case of coronavirus disease 2019 (COVID-19) in a patient with autoinflammation with infantile enterocolitis with inflammatory flares due to a mutation in the inflammasome component NLRC4. This case highlights the role of immunosuppression in patients with autoinflammation with COVID-19.

A Woman With Dyspnea, Weight Loss, and Splenic Lesions.

CASE PRESENTATION: The patient is a 37-year-old hospital employee and current smoker with a 10 pack-year smoking history, who presented with dyspnea, chest pain, and weight loss. She was in her usual state of health until 4 months prior to admission when she developed intermittent left-sided chest pain, cough productive of scant yellow sputum, fevers, and anorexia. Initial chest radiograph was normal and her outpatient physician prescribed azithromycin, which she took without improvement. One month prior to admission, a follow-up chest radiograph revealed a left-sided upper lobe consolidation; she received a course of levofloxacin without improvement. At follow-up, given her occupation, 13.6-kg unintentional weight loss, and persistent pulmonary symptoms and infiltrate despite treatment for pneumonia, her provider referred her for admission with particular concern for exclusion of active TB. As a hospital employee with clinical exposure, she underwent annual TB screening, which was always negative. She had no known exposure to patients with TB. Her most recent travel was to the Midwestern United States, without significant outdoors exposure. Review of systems was positive for wheezing, anorexia, and arthralgias of both knees and the left ankle and wrist. There was no hemoptysis, leg swelling, visual changes, palpitations, or muscle weakness.

Development of a Novel Competency-Based Evaluation System for HIV Primary Care Training: the HIV Entrustable Professional Activities.

BACKGROUND: There is an anticipated shortage of primary care providers trained to care for patients with HIV. The Yale School of Medicine developed and implemented a novel HIV training track within our Primary Care Internal Medicine Residency Program. A set of 12 Entrustable Professional Activities (EPAs) were developed to guide curriculum development and resident assessment. AIM: To describe the process of implementing a novel EPA-based curriculum for the HIV Primary Care Training Track including EPA-based trainee evaluation tools. PARTICIPANTS/SETTINGS: Two to three residents were enrolled annually from 2012 to 2017 (total n = 11). Training sites included the outpatient academic center HIV clinic and inpatient HIV ward. PROGRAM DESCRIPTION: An expert panel developed 12 HIV-specific EPAs. These were mapped to curricular and reporting internal medicine milestones. Curricular activities and evaluation tools were developed to guide EPA progress. PROGRAM EVALUATION: Graduating residents were ready for unsupervised practice in 91% of EPAs at the end of the 3-year program. DISCUSSION: Development of HIV-specific training EPAs was effective for driving curricular development and resident evaluation, and served as an effective method to communicate expectations to resident participants. These HIV-specific EPAs could serve as a useful template to enhance HIV education in academic settings.

Views of institutional leaders on maintaining humanism in today's practice.

OBJECTIVE: To explore leadership perspectives on how to maintain high quality efficient care that is also person-centered and humanistic. METHODS: The authors interviewed and collected narrative transcripts from a convenience sample of 32 institutional healthcare leaders at seven U.S. medical schools. The institutional leaders were asked to identify factors that either promoted or inhibited humanistic practice. A subset of authors used the constant comparative method to perform qualitative analysis of the interview transcripts. They reached thematic saturation by consensus on the major themes and illustrative examples after six conference calls. RESULTS: Institutional healthcare leaders supported vision statements, policies, organized educational and faculty development programs, role modeling including their own, and recognition of informal acts of kindness to promote and maintain humanistic patient-care. These measures were described individually rather than as components of a coordinated plan. Few healthcare leaders mentioned plans for organizational or systems changes to promote humanistic clinician-patient relationships. CONCLUSIONS: Institutional leaders assisted clinicians in dealing with stressful practices in beneficial ways but fell short of envisaging systems approaches that improve practice organization to encourage humanistic care. PRACTICE IMPLICATIONS: To preserve humanistic care requires system changes as well as programs to enhance skills and foster humanistic values and attitudes.

Specialty and Lifestyle Preference Changes during Medical School.

PURPOSE: Medical student specialty choices have significant downstream effects on the availability of physicians and, ultimately, the effectiveness of health systems. This study investigated how medical student specialty preferences change over time in relation to their demographics and lifestyle preferences. METHOD: Students from ten medical schools were surveyed at matriculation (2012) and graduation (2016). The two surveys included questions about specialty and lifestyle preferences, demographics, educational background, and indebtedness. Student data from 2012 to 2016 were paired together and grouped into those whose specialty preferences remained constant or switched. RESULTS: Response rates in 2012 and 2016 were 65% (997/1530) and 50% (788/1575), respectively. Fourth-year students ranked "enjoying the type of work I am doing" as less important to a good physician lifestyle than did first-year students (from 59.6 to 39.7%). The lifestyle factors "having control of work schedule" and "having enough time off work" were ranked as more important to fourth-year students than first-year students (from 15.6 to 18.2% and 14.8 to 31.9%, respectively). The paired dataset included 19% of eligible students (237/1226). Demographic and lifestyle factors were not significantly associated with specialty preference switching. Additionally, no significant association existed between changing lifestyle preferences and switching specialty preference (p = 0.85). CONCLUSIONS: During the course of medical school, lifestyle preferences became more focused on day-to-day factors and less on deeper motivational factors. Neither demographics nor lifestyle preferences appear to relate to a student's decision to switch specialty preference during medical school. These findings represent an important step in uncovering causes of specialty preference trends.

The Changing Face of HIV Care: Expanding HIV Training in an Internal Medicine Residency Program.

PROBLEM: People with HIV/AIDS are living longer and are at an increased risk of comorbidities. A qualified physician workforce is needed to care for this growing population. APPROACH: In 2012, a novel three-year HIV training track (HIV TT) was implemented as part of the Yale Primary Care Residency Program. To prepare for the implementation of this program, a needs assessment was performed, a web-based curriculum and 12 HIV-specific entrustable professional activities (EPAs) were created, and adequate clinical training opportunities in HIV and primary care were established. Program evaluation included process, learner, and outcome evaluations from 2012 to 2017. OUTCOMES: Since its inception, the HIV TT has enrolled a total of 11 residents (6-7 at a time), with 5 graduating to date. Residents delivered high-quality HIV and primary care for a diverse panel of patients; improved their knowledge and performance in HIV care, including according to the HIV-specific EPAs; and were highly satisfied with the program. All faculty remained with the program, and patients indicated satisfaction. NEXT STEPS: Next steps include enhanced coordination of residents' schedules, improved EPA documentation, evaluation of residents' HIV and non-HIV competence beyond residency, and monitoring graduates' career trajectories. Expanding HIV training within internal medicine residency programs is feasible and effective and has the potential to alleviate the shortage of physicians trained to provide HIV care and primary care in a single setting.

Healthcare at the Crossroads: The Need to Shape an Organizational Culture of Humanistic Teaching and Practice.

BACKGROUND: Changes in the organization of medical practice have impeded humanistic practice and resulted in widespread physician burnout and dissatisfaction. OBJECTIVE: To identify organizational factors that promote or inhibit humanistic practice of medicine by faculty physicians. DESIGN: From January 1, 2015, through December 31, 2016, faculty from eight US medical schools were asked to write reflectively on two open-ended questions regarding institutional-level motivators and impediments to humanistic practice and teaching within their organizations. PARTICIPANTS: Sixty eight of the 92 (74%) study participants who received the survey provided written responses. All subjects who were sent the survey had participated in a year-long small-group faculty development program to enhance humanistic practice and teaching. As humanistic leaders, subjects should have insights into motivating and inhibiting factors. APPROACH: Participants' responses were analyzed using the constant comparative method. KEY RESULTS: Motivators included an organizational culture that enhances humanism, which we judged to be the overarching theme. Related themes included leadership supportive of humanistic practice, responsibility to role model humanism, organized activities that promote humanism, and practice structures that facilitate humanism. Impediments included top down organizational culture that inhibits humanism, along with related themes of non-supportive leadership, time and bureaucratic pressures, and non-facilitative practice structures. CONCLUSIONS: While healthcare has evolved rapidly, efforts to counteract the negative effects of changes in organizational and practice environments have largely focused on cultivating humanistic attributes in individuals. Our findings suggest that change at the organizational level is at least equally important. Physicians in our study described the characteristics of an organizational culture that supports and embraces humanism. We offer suggestions for organizational change that keep humanistic and compassionate patient care as its central focus.

A Multi-Institutional Longitudinal Faculty Development Program in Humanism Supports the Professional Development of Faculty Teachers.

The authors describe the first 11 academic years (2005-2006 through 2016-2017) of a longitudinal, small-group faculty development program for strengthening humanistic teaching and role modeling at 30 U.S. and Canadian medical schools that continues today. During the yearlong program, small groups of participating faculty met twice monthly with a local facilitator for exercises in humanistic teaching, role modeling, and related topics that combined narrative reflection with skills training using experiential learning techniques. The program focused on the professional development of its participants. Thirty schools participated; 993 faculty, including some residents, completed the program.In evaluations, participating faculty at 13 of the schools scored significantly more positively as rated by learners on all dimensions of medical humanism than did matched controls. Qualitative analyses from several cohorts suggest many participants had progressed to more advanced stages of professional identity formation after completing the program. Strong engagement and attendance by faculty participants as well as the multimodal evaluation suggest that the program may serve as a model for others. Recently, most schools adopting the program have offered the curriculum annually to two or more groups of faculty participants to create sufficient numbers of trained faculty to positively influence humanistic teaching at the institution.The authors discuss the program's learning theory, outline its curriculum, reflect on the program's accomplishments and plans for the future, and state how faculty trained in such programs could lead institutional initiatives and foster positive change in humanistic professional development at all levels of medical education.

How physicians draw satisfaction and overcome barriers in their practices: "It sustains me".

OBJECTIVE: Major reorganizations of medical practice today challenge physicians' ability to deliver compassionate care. We sought to understand how physicians who completed an intensive faculty development program in medical humanism sustain their humanistic practices. METHODS: Program completers from 8 U.S. medical schools wrote reflections in answer to two open-ended questions addressing their personal motivations and the barriers that impeded their humanistic practice and teaching. Reflections were qualitatively analyzed using the constant comparative method. RESULTS: Sixty-eight physicians (74% response rate) submitted reflections. Motivating factors included: 1) identification with humanistic values; 2) providing care that they or their family would want; 3) connecting to patients; 4) passing on values through role modelling; 5) being in the moment. Inhibiting factors included: 1) time, 2) stress, 3) culture, and 4) episodic burnout. CONCLUSIONS: Determination to live by one's values, embedded within a strong professional identity, allowed study participants to alleviate, but not resolve, the barriers. Collaborative action to address organizational impediments was endorsed but found to be lacking. PRACTICE IMPLICATIONS: Fostering fully mature professional development among physicians will require new skills and opportunities that reinforce time-honored values while simultaneously partnering with others to nurture, sustain and improve patient care by addressing system issues.

Sexually Transmitted Infections in the Context of HIV Disease: Clinical Implications.

Universal screening and frequent retesting are required to reduce the burden of sexually transmitted infections in the HIV-infected population. Dual treatment is available for gonorrhea, expedited partner therapy is effective and legal in most states, sexually transmitted infection rates are high in the context of preexposure prophylaxis, and there is a continuing rise in rates of syphilis, particularly early neurosyphilis. This article summarizes a presentation by Dana W. Dunne, MD, FACP, at the IAS-USA continuing education program, Improving the Management of HIV Disease, held in New York, New York, in March 2016.

Lifestyle factors and primary care specialty selection: comparing 2012-2013 graduating and matriculating medical students' thoughts on specialty lifestyle.

PURPOSE: To compare how first-year (MS1) and fourth-year students (MS4) ascribe importance to lifestyle domains and specialty characteristics in specialty selection, and compare students' ratings with their primary care (PC) interest. METHOD: In March 2013, MS4s from 11 U.S. MD-granting medical schools were surveyed. Using a five-point Likert-type scale (1 = not important at all; 5 = extremely important), respondents rated the importance of 5 lifestyle domains and 21 specialty selection characteristics. One-way analysis of variance was used to assess differences by PC interest among MS4s. Using logistic regression, ratings from MS4s were compared with prior analyses of ratings by MS1s who matriculated to the same 11 schools in 2012. RESULTS: The response rate was 57% (965/1,701). MS4s, as compared with MS1s, rated as more important to good lifestyle: time off (4.3 versus 4.0), schedule control (4.2 versus 3.9), and financial compensation (3.4 versus 3.2). More MS4s than MS1s selected "time-off" (262/906 [30%] versus 136/969 [14%]) and "control of work schedule" (169/906 [19%] versus 146/969 [15%]) as the most important lifestyle domains. In both classes, PC interest was associated with higher ratings of working with the underserved and lower ratings of prestige and salary. CONCLUSIONS: In the 2012-2013 academic year, matriculating students and graduating students had similar perceptions of lifestyle and specialty characteristics associated with PC interest. Graduating students placed more importance on schedule control and time off than matriculating students. Specialties should consider addressing a perceived lack of schedule control or inadequate time off to attract students.

Primary care, the ROAD less traveled: what first-year medical students want in a specialty.

PURPOSE: Medical students are increasingly choosing non-primary-care specialties. Students consider lifestyle in selecting their specialty, but how entering medical students perceive lifestyle is unknown. This study investigates how first-year students value or rate lifestyle domains and specialty-selection characteristics and whether their ratings vary by interest in primary care (PC). METHOD: During the 2012-2013 academic year, the authors conducted a cross-sectional survey of first-year medical students from 11 MD-granting medical schools. Using a five-point Likert-type scale (1 = not important at all; 5 = extremely important), respondents rated the importance of 5 domains of good lifestyle and 21 characteristics related to specialty selection. The authors classified students into five groups by PC interest and assessed differences by PC interest using one-way analysis of variance. RESULTS: Of 1,704 participants, 1,020 responded (60%). The option "type of work I am doing" was the highest-rated lifestyle domain (mean 4.8, standard deviation [SD] 0.6). "Being satisfied with the job" was the highest-rated specialty-selection characteristic (mean 4.7, SD 0.5). "Availability of practice locations in rural areas" was rated lowest (mean 2.0, SD 1.1). As PC interest decreased, the importance of "opportunities to work with underserved populations" also decreased, but importance of "average salary earned" increased (effect sizes of 0.98 and 0.94, respectively). CONCLUSIONS: First-year students valued enjoying work. The importance of financial compensation was inversely associated with interest in PC. Examining the determinants of enjoyable work may inform interventions to help students attain professional fulfillment in PC.

MyD88 deficiency markedly worsens tissue inflammation and bacterial clearance in mice infected with Treponema pallidum, the agent of syphilis.

Research on syphilis, a sexually transmitted infection caused by the non-cultivatable spirochete Treponema pallidum, has been hampered by the lack of an inbred animal model. We hypothesized that Toll-like receptor (TLR)-dependent responses are essential for clearance of T. pallidum and, consequently, compared infection in wild-type (WT) mice and animals lacking MyD88, the adaptor molecule required for signaling by most TLRs. MyD88-deficient mice had significantly higher pathogen burdens and more extensive inflammation than control animals. Whereas tissue infiltrates in WT mice consisted of mixed mononuclear and plasma cells, infiltrates in MyD88-deficient animals were predominantly neutrophilic. Although both WT and MyD88-deficient mice produced antibodies that promoted uptake of treponemes by WT macrophages, MyD88-deficient macrophages were deficient in opsonophagocytosis of treponemes. Our results demonstrate that TLR-mediated responses are major contributors to the resistance of mice to syphilitic disease and that MyD88 signaling and FcR-mediated opsonophagocytosis are linked to the macrophage-mediated clearance of treponemes.

Increased TLR4 expression and downstream cytokine production in immunosuppressed adults compared to non-immunosuppressed adults.

BACKGROUND: An increasing number of patients have medical conditions with altered host immunity or that require immunosuppressive medications. While immunosuppression is associated with increased risk of infection, the precise effect of immunosuppression on innate immunity is not well understood. We studied monocyte Toll-like receptor (TLR) expression and cytokine production in 137 patients with autoimmune diseases who were maintained on immunosuppressive medications and 419 non-immunosuppressed individuals. METHODOLOGY/PRINCIPAL FINDINGS: Human peripheral blood monocytes were assessed for surface expression of TLRs 1, 2, and 4. After incubation with TLR agonists, in vitro production of the cytokines IL-8, TNFalpha, and MIF were measured by ELISA as a measure of TLR signaling efficiency and downstream effector responsiveness. Immunosuppressed patients had significantly higher TLR4 surface expression when compared to non-immunosuppressed adults (TLR4 %-positive 70.12+/-2.28 vs. 61.72+/-2.05, p = 0.0008). IL-8 and TNF-alpha baseline levels did not differ, but were significantly higher in the autoimmune disease group following TLR stimulation. By contrast, baseline MIF levels were elevated in monocytes from immunosuppressed individuals. By multivariable analyses, IL-8 and TNFalpha, but not MIF levels, were associated with the diagnosis of an underlying autoimmune disease. However, only MIF levels were significantly associated with the use of immunosuppressive medications. CONCLUSIONS/SIGNIFICANCE: Our results reveal that an enhanced innate immune response is a feature of patients with autoimmune diseases treated with immunosuppressive agents. The increased risk for infection evident in this patient group may reflect a dysregulation rather than a simple suppression of innate immunity.