Stephen J. Gluckman

First Human Trial of a DNA-Based Vaccine for Treatment of Human Immunodeficiency Virus Type 1 Infection: Safety and Host Response

A DNA-based vaccine containing human immunodeficiency virus type 1 (HIV-1) env and rev genes was tested for safety and host immune response in 15 asymptomatic HIV-infected patients who were not using antiviral drugs and who had CD4+ lymphocyte counts of > or = 500 per microliter of blood. Successive groups received three doses of vaccine (30, 100, or 300 microg) at 10-week intervals in a dose-escalation trial. Vaccine administration induced no local or systemic reactions, and no laboratory abnormalities were detected. Specifically, no patient developed anti-DNA antibody or muscle enzyme elevations. No consistent change occurred in CD4 or CD8 lymphocyte counts or in plasma HIV concentration. Antibody against gp120 increased in individual patients in the 100- and 300-/microg groups. Some increases were noted in cytotoxic T lymphocyte activity against gp160-bearing targets and in lymphocyte proliferative activity. The safety and potential immunogenicity of an HIV-directed DNA-based vaccine was demonstrated, a finding that should encourage further studies.

A randomized clinical trial of granulocyte transfusions for infection in acute leukemia.

In a prospective, controlled, randomized study to evaluate the efficacy of filtration-leukapheresis granulocytes in granulocytopenic, febrile patients with leukemia, 19 patients received antibiotics alone, and 12 received antibiotics plus daily granulocyte transfusions from ABO-matched donors. In skin-chamber studies the granulocytes appeared at sites of inflammation for at least six hours after transfusion. Infected subjects survived longer if they received granulocytes. Differences between control and transfused patients were greatest in patients with persistent bone-marrow failure, the 21-day survival being 20 per cent in controls, and 75 per cent in transfused patients. Granulocytes appeared to have no effect on the outcome of febrile episodes in which infection was not documented, the 21-day survival being 79 per cent for controls and 88 per cent for transfused patients. The transfusion of granulocytes thus appears to offer a survival advantage to infected, persistently granulocytopenic patients.

Kikuchi-Fujimoto disease: A benign cause of fever and lymphadenopathy

PURPOSE To describe 6 cases of Kikuchi-Fujimoto disease and to review the literature. PATIENTS AND METHODS Review of 6 patients with biopsy-proven Kikuchi-Fujimoto disease detected at a university hospital over a 5-year period. RESULTS Six patients presented with localized, mild lymph node enlargement. In 3 cases, dramatic fever, chills, weight loss and systemic complaints were present. These features prompted prolonged antibiotic therapy and extensive evaluations of fever of unknown origin before the diagnosis was made by biopsy of the minimally enlarged lymph nodes. The 3 remaining patients were otherwise asymptomatic and well. All 6 subjects recovered without specific therapy. CONCLUSIONS Kikuchi-Fujimoto disease is a recently described cause of benign, self-limited lymphadenopathy that is easily confused histologically and clinically with lymphoma and systemic lupus erythematosis. Clinicians and pathologists must be aware of this condition. Although it is an uncommon cause of fever of unknown origin, early recognition of KFD will minimize potentially harmful and unnecessary evaluations and treatments.

Early Versus Delayed Antiretroviral Therapy and Cerebrospinal Fluid Fungal Clearance in Adults With HIV and Cryptococcal Meningitis

BACKGROUND The burden of Cryptococcus neoformans in cerebrospinal fluid (CSF) predicts clinical outcomes in human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) and is lower in patients on antiretroviral therapy (ART). This study tested the hypothesis that initiation of ART during initial treatment of HIV/CM would improve CSF clearance of C. neoformans. METHODS A randomized treatment-strategy trial was conducted in Botswana. HIV-infected, ART-naive adults aged≥21 years initiating amphotericin B treatment for CM were randomized to ART initiation within 7 (intervention) vs after 28 days (control) of randomization, and the primary outcome of the rate of CSF clearance of C. neoformans over the subsequent 4 weeks was compared. Adverse events, including CM immune reconstitution inflammatory syndrome (CM-IRIS), and immunologic and virologic responses were compared over 24 weeks. RESULTS Among 27 subjects enrolled (13 intervention and 14 control), [corrected] the median times to ART initiation were 7 (interquartile range [IQR], 5–10) and 32days (IQR, 28–36), respectively. The estimated rate of CSF clearance did not differ significantly by treatment strategy (-0.32 log10 colony-forming units [CFU]/mL/day±0.20 intervention and -0.52 log10 CFUs/mL/day (±0.48) control, P=.4). Two of 13 (15%) and 5 of 14 (36%) subjects died in the intervention and control arms, respectively (P=0.39). Seven of 13 subjects (54%) in the intervention arm vs 0 of 14 in the control arm experienced CM-IRIS (P=.002). CONCLUSIONS Early ART was not associated with improved CSF fungal clearance, but resulted in a high risk of CM-IRIS. Further research on optimal incorporation of ART into CM care is needed. CLINICAL TRIALS REGISTRATION NCT00976040.

The Use of HAART Is Associated With Decreased Risk of Death During Initial Treatment of Cryptococcal Meningitis in Adults in Botswana

Objective:The objective of this study was to evaluate outcomes among adults with a first episode of cryptococcal meningitis (CM), comparing those on highly active antiretroviral therapy (HAART) with those not on HAART. Methods:We conducted a prospective cohort study among HIV-infected adults (aged 18 years and older) with a first episode of CM at the Princess Marina Hospital, in Gaborone, Botswana. The proportions surviving to discharge were compared. Logistic regression was used to evaluate the relationship between HAART use and risk of death in the hospital, adjusting for potential confounders. Results:Ninety-two patients [median CD4 41 cells/mm3 (interquartile range 22-85)] were included, 26 of whom were on HAART at the time that they developed CM. The in-hospital mortality was lower among those on HAART {2 of 26 (8%) vs 14 of 66 (21%); odds ratio = 0.36 [95% confidence interval (CI) 0.09 to 1.49]}, and this result was statistically significant after adjustment for male sex and tuberculosis [adjusted odds ratio = 0.19 (95% CI 0.04 to 1.00)]. Conclusions:HAART use at the time of a first admission with CM is associated with decreased risk of death during the acute phase of disease. Reasons for this association should be explored.

Eosinophilic Meningitis Due to Angiostrongylus cantonensis in a Returned Traveler: Case Report and Review of the Literature

Angiostrongylus cantonensis, the rat lungworm, is the principal cause of eosinophilic meningitis worldwide, and the increase in world travel and shipborne dispersal of infected rat vectors has extended this parasite to regions outside of its traditional geographic boundaries. We report a case of eosinophilic meningitis due to A. cantonensis in a patient who recently returned from a trip in the Pacific.

Blood and Body Fluid Exposures Among US Medical Students in Botswana

IntroductionMedical students from resource-rich countries who rotate in resource-limited settings have little pre-departure experience performing procedures, and lack familiarity with local equipment. The risk of blood and body fluid exposures during such rotations is significant.Aim1) Determine whether a simulation-based intervention reduced exposures among US medical students on a rotation in Botswana; 2) determine whether exposures were underreported; 3) describe exposures and provision of human immunodeficiency virus (HIV) post-exposure prophylaxis (PEP).SettingUniversity of Pennsylvania medical students who traveled to Botswana for a clinical rotation from July 2007 to February 2010 were eligible to participate.Program DescriptionTwenty-two students participated in the simulation-based intervention.Program EvaluationTo evaluate the intervention, we used a pre/post quasi-experimental design and administered a retrospective survey. The response rate was 81.7% (67/82). Needlesticks were eliminated [8/48 (16.7%) to 0/19 (0.0%), p = 0.07]. Splashes were unchanged (6/48 [12.5%) to 3/19 (15.8%), p=>0.99]. Three students did not report their exposure. Fifteen exposures were reported to an attending, who counseled the student regarding HIV PEP. Three students did not take PEP because the exposure was low-risk.DiscussionOur intervention was associated with a decrease in needlestick exposures. Medical schools should consider training to reduce exposures abroad.

The Perceived Benefits of a Medical School Course in Wilderness Medicine

Founded in 1983, the Wilderness Medical Society has since grown in numbers and stature. Its specific purpose has been ‘‘to encourage, foster, support, and conduct activities or programs concerned with life sciences which may improve the scientific knowledge of the membership and the general public in matters related to wilderness environments and human activities in these environments.’’1 It was natural that this society and its goals would attract the interest of medical students and medical residency programs. A number of formal courses have been established in medical schools to expose students to the many disciplines of wilderness medicine. The Wilderness Medical Society sponsors it own course for thirdand fourth-year medical students, and courses also are taught at the University of Massachusetts Medical School; Stanford University; the University of South Carolina; University of California, San Francisco, Fresno; and the University of New Mexico. The University of Pennsylvania School of Medicine established a wilderness medicine ‘‘minicourse’’ in 1995. During the course, approximately 16 medical students live in a wilderness setting in central New Jersey for 2 weeks in January. Their days and evening are devoted to didactic lectures, demonstrations, and practical applications in the various areas of wilderness medicine. (An overview of the curriculum is listed in the Appendix.) This course is an intensive couple of weeks and requires much more preparation and organization by the students and the faculty than do standard courses. Furthermore, it does not appear to have the obvious direct clinical applications for hospital or office care of the more traditional courses offered at the University of Pennsylvania School of Medicine and most other medical schools. Rather, the Wilderness Medicine course at the University of Pennsylvania is designed to teach students to deal with emergency medical scenarios in remote, outdoor settings. Therefore, we were curious to see how often and in what

The Johns Hopkins AIDS Service

The Johns Hopkins AIDS Service; The Johns Hopkins University Division of Infectious Diseases. Baltimore: Johns Hopkins Univ; 1998. Free. http://www.hopkins-aids.edu. Information phone 410-955-3150. Field of medicine: Infectious disease. Format: World Wide Web site. System requirements: Optimized for Microsoft Internet Explorer 3.01 and Netscape Navigator 3.0 or above. Audience: Infectious disease specialists, practitioners caring for patients with HIV infection, medical students, internal medicine house officers, and patients. Purpose: To provide comprehensive information on HIV for treatment and educational purposes. Content: The site includes Medical Management of HIV Infection by John Bartlett, MD, a comprehensive management manual describing the standards of care of the Johns Hopkins AIDS Service. It also includes the Hopkins HIV Report, a bimonthly newsletter of recent developments and practical reviews. Also accessible are treatment guidelines; epidemiology data; Case Rounds, illustrated with high-resolution images of patient test results; descriptions of ongoing clinical studies at The Johns Hopkins Hospital; and self-assessment tests of knowledge about HIV. Visiting patients may post their questions to a forum, to be answered online by Johns Hopkins AIDS Service clinicians. Usability: The interface is clean and attractive, with easy-to-find controls and simple, small graphics for quick navigation. The opening screen clearly displays the eight major topic areas; visitors may also consult a site map and perform a full-text search of a single resource (such as the textbook) or the entire site. The sites designers have effectively adapted printed information to the online environment; content is presented in manageable pieces and is enhanced with appropriate graphics. The Case Rounds graphics, for example, are displayed in a small format that users can enlarge for closer inspection. Highlights: Centralized, online access to the textbook and newsletter make this authoritative, up-to-date site an invaluable resource for practitioners. Physicians may also gain insights into diagnosis and therapy by reading Case Rounds and by browsing through patient questions and the accompanying answers. The site includes topics less commonly covered elsewhere; for example, it provides an extensive review of outcomes research related to HIV infection and a section on managed care with a useful glossary of terms. Limitations: The search engine does not answer specific clinical questions quickly enough for office use. A clinician looking up the side effects of a therapeutic agent might have to scan a dozen or more documents returned by the search engine to find the desired information. A searchable index would complement the full-text search by augmenting the speed of use and overall usefulness of the site. Related sites: HIV InSite (http://hivinsite.ucsf.edu/) offers similar clinician information supplemented with considerable patient-oriented information and sections on prevention, social issues, and clinical trials throughout the United States. The JAMA HIV/AIDS Information Center (http://www.ama-assn.org/special/hiv/hivhome.htm) is one of several JAMA disease- and condition-specific Web offerings that combine breaking news, literature reviews, treatment guidelines, health policy material, and information on disease prevention. Reviewers: Stephen J. Gluckman, MD, University of Pennsylvania, Philadelphia, Pennsylvania; and Chris Dwyer, BA, American College of Physicians-American Society of Internal Medicine, Philadelphia, Pennsylvania.

Acute Respiratory Infections in a Recently Arrived Traveler to Your Part of the World

Many acute infectious pulmonary diseases have incubation periods that are long enough for travelers to have symptoms after returning home to a health-care system that is not familiar with “foreign” infections. Respiratory infections have a relatively limited repertoire of clinical manifestations, so that there is often nothing characteristic enough about a specific infection to make the diagnosis obvious. Thus, the pathway to the diagnosis of infections that are not endemic in a region relies heavily on taking a thorough history of both itinerary and of specific exposures. One important caveat is that on occasion, the history of a recent trip creates an element of “tunnel vision” in the evaluating health-care provider. It is tempting to relate a persons problem to that recent trip; however, when evaluating recent returnees, it is always important to remember that the travel may have nothing to do with the patients presentation. Recent travel may add diagnostic considerations to the list of possibilities, but an astute clinician must not disregard the possibility that the patients illness has nothing to do with the recent trip.