Christiana Iyasere

High-level HIV-1 viremia suppresses viral antigen-specific CD4+ T cell proliferation

In chronic viral infections of humans and experimental animals, virus-specific CD4+ T cell function is believed to be critical for induction and maintenance of host immunity that mediates effective restriction of viral replication. Because in vitro proliferation of HIV-specific memory CD4+ T cells is only rarely demonstrable in HIV-infected individuals, it is presumed that HIV-specific CD4+ T cells are killed upon encountering the virus, and maintenance of CD4+ T cell responses in some patients causes the restriction of virus replication. In this study, proliferative responses were absent in patients with poorly restricted virus replication although HIV-specific CD4+ T cells capable of producing IFN-γ were detected. In a separate cohort, interruption of antiretroviral therapy resulted in the rapid and complete abrogation of virus-specific proliferation although HIV-1-specific CD4+ T cells were present. HIV-specific proliferation returned when therapy was resumed and virus replication was controlled. Further, HIV-specific CD4+ T cells of viremic patients could be induced to proliferate in response to HIV antigens when costimulation was provided by anti-CD28 antibody in vitro. Thus, HIV-1-specific CD4+ T cells persist but remain poorly responsive (produce IFN-γ but do not proliferate) in viremic patients. Unrestricted virus replication causes diminished proliferation of virus-specific CD4+ T cells. Suppression of proliferation of HIV-specific CD4+ T cells in the context of high levels of antigen may be a mechanism by which HIV or other persistently replicating viruses limit the precursor frequency of virus-specific CD4+ T cells and disrupt the development of effective virus-specific immune responses.

Diminished Proliferation of Human Immunodeficiency Virus-Specific CD4+ T Cells Is Associated with Diminished Interleukin-2 (IL-2) Production and Is Recovered by Exogenous IL-2

ABSTRACT Virus-specific CD4+ T-cell function is thought to play a central role in induction and maintenance of effective CD8+ T-cell responses in experimental animals or humans. However, the reasons that diminished proliferation of human immunodeficiency virus (HIV)-specific CD4+ T cells is observed in the majority of infected patients and the role of these diminished responses in the loss of control of replication during the chronic phase of HIV infection remain incompletely understood. In a cohort of 15 patients that were selected for particularly strong HIV-specific CD4+ T-cell responses, the effects of viremia on these responses were explored. Restriction of HIV replication was not observed during one to eight interruptions of antiretroviral therapy in the majority of patients (12 of 15). In each case, proliferative responses to HIV antigens were rapidly inhibited during viremia. The frequencies of cells that produce IFN-γ in response to Gag, Pol, and Nef peptide pools were maintained during an interruption of therapy. In a subset of patients with elevated frequencies of interleukin-2 (IL-2)-producing cells, IL-2 production in response to HIV antigens was diminished during viremia. Addition of exogenous IL-2 was sufficient to rescue in vitro proliferation of DR0101 class II Gag or Pol tetramer+ or total-Gag-specific CD4+ T cells. These observations suggest that, during viremia, diminished in vitro proliferation of HIV-specific CD4+ T cells is likely related to diminished IL-2 production. These results also suggest that relatively high frequencies of HIV-specific CD4+ T cells persist in the peripheral blood during viremia, are not replicatively senescent, and proliferate when IL-2 is provided exogenously.

Diminished Production of Monocyte Proinflammatory Cytokines during Human Immunodeficiency Virus Viremia Is Mediated by Type I Interferons

ABSTRACT The effect of human immunodeficiency virus (HIV) infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated levels of spontaneous production of some or all of the monocyte proinflammatory cytokines measured (interleukin-1β [IL-1β], IL-6, and tumor necrosis factor alpha [TNF-α]) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was diminished in the context of viremia during an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culture with autologous CD4+ T cells or monocytes from an on-therapy time point or lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated type I interferon-stimulated gene transcripts. The addition of exogenous alpha 2A interferon diminished the spontaneous production of IL-1β, IL-6, and TNF-α but did not affect responses to LPS, recapitulating the changes observed for HIV-viremic patients. These results suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons. This effect on monocytes during viremia may play a role in diminished innate or adaptive immune system functions in HIV-infected patients. In addition, the restoration of these functions may also play a role in some immune reconstitution syndromes observed during initiation of therapy.

Beyond Continuing Medical Education: Clinical Coaching as a Tool for Ongoing Professional Development.

Problem For most physicians, the period of official apprenticeship ends with the completion of residency or fellowship, yet the acquisition of expertise requires ongoing opportunities to practice a given skill and obtain structured feedback on one’s performance. Approach In July 2013, the authors developed a clinical coaching pilot program to provide early-career hospitalists with feedback from a senior clinical advisor (SCA) at Massachusetts General Hospital. A Hospital Medicine Unit–wide retreat was held to help design the SCA role and obtain faculty buy-in. Twelve SCAs were recruited from hospitalists with more than five years of experience; each served as a clinical coach to 28 early-career hospitalists during the pilot. Clinical narratives and programmatic surveys were collected from SCAs and early-career hospitalists. Outcomes Of 25 responding early-career hospitalists, 23 (92%) rated the SCA role as useful to very useful, 20 (80%) reported interactions with the SCA led to at least one change in their diagnostic approach, and 13 (52%) reported calling fewer subspecialty consults as a result of guidance from the SCA. In response to questions about professional development, 18 (72%) felt more comfortable as an independent physician following their interactions with the SCA, and 19 (76%) thought the interactions improved the quality of care they delivered. Next Steps To better understand the impact and generalizability of clinical coaching, a larger, longitudinal study is required to look at patient and provider outcomes in detail. Further refinement of the SCA role to meet faculty needs is needed and could include faculty development.

Case records of the Massachusetts General Hospital. Case 38-2014. An 87-year-old man with sore throat, hoarseness, fatigue, and dyspnea.

Dr. Leigh H. Simmons: An 87-year-old man with multiple chronic medical problems was seen in an outpatient clinic of this hospital because of sore throat and fatigue. The patient had been in his usual health until several weeks before presentation, when hoarseness, sore throat, and increasing fatigue developed. At the urging of his family, he was seen by his physician in an outpatient clinic of this hospital. He reported hoarseness, increasing facial puffiness, and periorbital swelling, with no chest pain, dyspnea, or new joint pains or muscle aches. The patient had hypertension, hyperlipidemia, and chronic kidney disease. Two months earlier, the creatinine level was 2.22 mg per deciliter (196 μmol per liter; reference range, 0.60 to 1.50 mg per deciliter [53 to 133 μmol per liter]), which was stable, as compared with values obtained the previous year. He also had hypothyroidism, with a normal thyrotropin level 8 months earlier (3.38 μU per milliliter [reference range, 0.40 to 5.00]), as well as gastroesophageal reflux disease, esophageal motility disorder, an abdominal aortic aneurysm, chronic back pain, depression related to the death of his wife several years before, and recurrent urinary tract infections. In the past, he had had pneumonia and had undergone angioplasty of the right renal artery (10 years earlier), a cholecystectomy, a lobectomy of the right middle lobe due to a spiculated nodule that was found to be benign, photoselective vaporization of the prostate due to obstructive benign prostatic hypertrophy (2 months before this presentation), and wrist surgery. Medications included atenolol, vitamin D3, a fluticasone propionate and salmeterol inhaler, aspirin, citalopram, a fluticasone nasal spray, atorvastatin, omeprazole, and levothyroxine. Lisinopril had caused a cough, and zolpidem tartrate had caused nightmares. The patient was retired and lived alone. He could independently perform activities of daily living, and he managed his own medications. His three children lived nearby and were in frequent contact with him, but he came to most medical appointments unaccompanied. He was under the regular care of an internist, a nephrologist, a cardiologist, and a urologist. Immunizations were up to date. He had stopped smoking many years earlier and did not drink alcohol. His father had died of liver cancer, and a son had sarcoidosis; his two other children were healthy. On examination, the patient was pleasant, smiling, and in no distress; he spoke From the Departments of Medicine (C.A.I.), Internal Medicine (L.H.S.), Radi‐ ology (F.J.F.), and Pathology (A.S.D.), Massachusetts General Hospital, and the Departments of Medicine (C.A.I.), Inter‐ nal Medicine (L.H.S.), Radiology (F.J.F.), and Pathology (A.S.D.), Harvard Medical School — both in Boston.

Case 38-2014

Dr. Leigh H. Simmons: An 87-year-old man with multiple chronic medical problems was seen in an outpatient clinic of this hospital because of sore throat and fatigue. The patient had been in his usual health until several weeks before presentation, when hoarseness, sore throat, and increasing fatigue developed. At the urging of his family, he was seen by his physician in an outpatient clinic of this hospital. He reported hoarseness, increasing facial puffiness, and periorbital swelling, with no chest pain, dyspnea, or new joint pains or muscle aches. The patient had hypertension, hyperlipidemia, and chronic kidney disease. Two months earlier, the creatinine level was 2.22 mg per deciliter (196 μmol per liter; reference range, 0.60 to 1.50 mg per deciliter [53 to 133 μmol per liter]), which was stable, as compared with values obtained the previous year. He also had hypothyroidism, with a normal thyrotropin level 8 months earlier (3.38 μU per milliliter [reference range, 0.40 to 5.00]), as well as gastroesophageal reflux disease, esophageal motility disorder, an abdominal aortic aneurysm, chronic back pain, depression related to the death of his wife several years before, and recurrent urinary tract infections. In the past, he had had pneumonia and had undergone angioplasty of the right renal artery (10 years earlier), a cholecystectomy, a lobectomy of the right middle lobe due to a spiculated nodule that was found to be benign, photoselective vaporization of the prostate due to obstructive benign prostatic hypertrophy (2 months before this presentation), and wrist surgery. Medications included atenolol, vitamin D3, a fluticasone propionate and salmeterol inhaler, aspirin, citalopram, a fluticasone nasal spray, atorvastatin, omeprazole, and levothyroxine. Lisinopril had caused a cough, and zolpidem tartrate had caused nightmares. The patient was retired and lived alone. He could independently perform activities of daily living, and he managed his own medications. His three children lived nearby and were in frequent contact with him, but he came to most medical appointments unaccompanied. He was under the regular care of an internist, a nephrologist, a cardiologist, and a urologist. Immunizations were up to date. He had stopped smoking many years earlier and did not drink alcohol. His father had died of liver cancer, and a son had sarcoidosis; his two other children were healthy. On examination, the patient was pleasant, smiling, and in no distress; he spoke From the Departments of Medicine (C.A.I.), Internal Medicine (L.H.S.), Radi‐ ology (F.J.F.), and Pathology (A.S.D.), Massachusetts General Hospital, and the Departments of Medicine (C.A.I.), Inter‐ nal Medicine (L.H.S.), Radiology (F.J.F.), and Pathology (A.S.D.), Harvard Medical School — both in Boston.

Effect of Increased Inpatient Attending Physician Supervision on Medical Errors, Patient Safety, and Resident Education: A Randomized Clinical Trial

Importance While the relationship between resident work hours and patient safety has been extensively studied, little research has evaluated the role of attending physician supervision on patient safety. Objective To determine the effect of increased attending physician supervision on an inpatient resident general medical service on patient safety and educational outcomes. Design, Setting, and Participants This 9-month randomized clinical trial performed on an inpatient general medical service of a large academic medical center used a crossover design. Participants were clinical teaching attending physicians and residents in an internal medicine residency program. Interventions Twenty-two faculty provided either (1) increased direct supervision in which attending physicians joined work rounds on previously admitted patients or (2) standard supervision in which attending physicians were available but did not join work rounds. Each faculty member participated in both arms in random order. Main Outcomes and Measures The primary safety outcome was rate of medical errors. Resident education was evaluated via a time-motion study to assess resident participation on rounds and via surveys to measure resident and attending physician educational ratings. Results Of the 22 attending physicians, 8 (36%) were women, with 15 (68%) having more than 5 years of experience. A total of 1259 patients (5772 patient-days) were included in the analysis. The medical error rate was not significantly different between standard vs increased supervision (107.6; 95% CI, 85.8-133.7 vs 91.1; 95% CI, 76.9-104.0 per 1000 patient-days; P = .21). Time-motion analysis of 161 work rounds found no difference in mean length of time spent discussing established patients in the 2 models (202; 95% CI, 192-212 vs 202; 95% CI, 189-215 minutes; P = .99). Interns spoke less when an attending physician joined rounds (64; 95% CI, 60-68 vs 55; 95% CI, 49-60 minutes; P = .008). In surveys, interns reported feeling less efficient (41 [55%] vs 68 [73%]; P = .02) and less autonomous (53 [72%] vs 86 [91%]; P = .001) with an attending physician present and residents felt less autonomous (11 [58%] vs 30 [97%]; P < .001). Conversely, attending physicians rated the quality of care higher when they participated on work rounds (20 [100%] vs 16 [80%]; P = .04). Conclusions and Relevance Increased direct attending physician supervision did not significantly reduce the medical error rate. In designing morning work rounds, residency programs should reconsider their balance of patient safety, learning needs, and resident autonomy. Trial Registration ClinicalTrials.gov Identifier: NCT03318198

Brief Report: Meeting the Needs of Medically Hospitalized Adults with Autism: A Provider and Patient Toolkit

In an effort to meet the needs of adults with autism spectrum disorder (ASD) while hospitalized, a team of experts and providers from Massachusetts General Hospital (MGH), MGH for Children as well as parents of individuals with ASD was sparked in 2013. This became a multidisciplinary collaborative, the MGH Autism Care Collaborative, to improve adult care for inpatients with ASD. The collaborative was created with three goals in mind: (1) to educate internal medicine adult inpatient providers and staff on the unique needs of adults with ASD when hospitalized; (2) to create ASD specific resources for internal medicine adult inpatient providers; (3) to optimize patient care from admission to discharge among adults with ASD admitted to internal medicine services.