Biomedical subjects
Publications and source records attributed to H Masur.
Despite advances in prophylaxis and the reduction of mortality and morbidity resulting from highly active antiretroviral therapy, neumocystis pneumonia remains a common problem in HIV-infected patients. There are many possible causes for the continued prevalence of this condition. This article examines the characteristics, and some of the complex causes of P. carinii pneumonia in AIDS patients.
The CD4+ T-cell pool in HIV-infected patients is in a constant state of flux as CD4+ T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4+ T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA+ T-cell population relative to the CD4/CD45RO+ population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4+ T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace.
OBJECTIVE: The development of practice guidelines for evaluating adult patients who develop new fever in the intensive care unit (ICU) for the purpose of guiding clinical practice. PARTICIPANTS: A task force of 13 experts in disciplines related to critical care medicine, infectious diseases, and surgery was convened from the membership of the Society of Critical Care Medicine and the Infectious Disease Society of America. EVIDENCE: The task force members provided personal experience and determined the published literature (articles retrieved with use of MEDLINE or textbooks) from which consensus would be sought. The published literature was reviewed and classified into one of four categories, according to study design and scientific value. CONSENSUS PROCESS: The task force met several times in person and twice monthly by teleconference over a 1-year period to identify the pertinent literature and arrive at consensus recommendations. Consideration was given to the relationship between the weight of scientific evidence and the experts' opinions. Draft documents were composed and debated by the task force until consensus was reached by nominal group process. CONCLUSIONS: The panel concluded that because fever can have many infectious and noninfectious etiologies, a new fever in an adult patient in the ICU should trigger a careful clinical assessment rather than automatic orders for laboratory and radiological tests. A cost-conscious approach to obtaining diagnostic studies should be undertaken if they are indicated after a clinical evaluation. The goal of such an approach is to determine, in a directed manner, whether infection is present so that additional testing can be avoided and therapeutic options can be identified.
OBJECTIVE: To develop practice parameters for the evaluation of adult patients who develop a new fever in the intensive care unit (ICU) for the purpose of guiding clinical practice. PARTICIPANTS: A task force of 13 experts in disciplines related to critical care medicine, infectious diseases, and surgery was convened from the membership of the Society of Critical Care Medicine, and the Infectious Disease Society of America. EVIDENCE: The task force members provided the personal experience and determined the published literature (MEDLINE articles, textbooks, etc.) from which consensus would be sought. Published literature was reviewed and classified into one of four categories, according to study design and scientific value. CONSENSUS PROCESS: The task force met several times in person and twice monthly by teleconference over a 1-yr period of time to identify the pertinent literature and arrive at consensus recommendations. Consideration was given to the relationship between the weight of scientific evidence and the experts' opinions. Draft documents were composed and debated by the task force until consensus was reached by nominal group process. CONCLUSIONS: The panel concluded that, because fever can have many infectious and noninfectious etiologies, a new fever in a patient in the ICU should trigger a careful clinical assessment rather than automatic orders for laboratory and radiologic tests. A cost-conscious approach to obtaining cultures and imaging studies should be undertaken if it is indicated after a clinical evaluation. The goal of such an approach is to determine, in a directed manner, whether or not infection is present, so additional testing can be avoided and therapeutic options can be made.
The duration of the postexcitatory inhibition after transcranial magnetic stimulation was investigated in 16 patients with drug-induced parkinsonism and in 20 healthy control individuals. In the patients, the chlorpromazine-equivalent of the neuroleptic medication was determined, and the severity of the drug-induced parkinsonism was measured using the Simpson-Angus Scale score. Group comparison (U-test) revealed a significant shorter postexcitatory inhibition in patients than in control individuals. Regression analyses showed a negative correlation between the Simpson-Angus scale score and the duration of the postexcitatory inhibition. The correlation only reached significance for a group of patients who received at least one butyrophenone derivate. No clear-cut relation was found between the chlorpromazine equivalent and the postexcitatory inhibition. These results indicate that drug-induced parkinsonism shares features of genuine Parkinson's disease. Furthermore, it seems possible to assess the extrapyramidal side effect of butyrophenone derivates, but not for other neuroleptic drugs, by means of the method described.
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Prostaglandin E analogs have been shown to be effective in the treatment of refractory trigeminal neuralgia in patients with multiple sclerosis. Prostaglandin E inhibits the functions of T lymphocytes which are involved in the pathophysiology of cluster headache. Therefore, a double-blind, placebo-controlled, crossover study on the efficacy of misoprostol in chronic refractory cluster headache was performed. Eight patients were treated with 600 micrograms misoprostol and with placebo for a 2-week period. No differences in attack frequency, intensity, global impression, and side effects could be detected, suggesting that prostaglandin E analogs are not effective in the treatment of chronic cluster headache.
Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.
The safety and efficacy were assessed of 5-day cycles of subcutaneous (sc) interleukin-2 (IL-2) every 8 weeks in human immunodeficiency virus type 1-infected outpatients with >200 CD4 cells/mm3. Immunologic, virologic, and toxicity parameters were measured in 18 patients receiving standard antiretrovirals plus 5-day courses of sc IL-2 (3-18 MIU/day) every 2 months. Systemic toxicities established the maximally tolerated dose (MTD) of IL-2 as 15 MIU/day. CD4 cell responses appeared to correlate directly with baseline CD4 cell counts, with several patients experiencing a dramatic rise after 3 cycles. Virus load increased only transiently in the peri-injection period. It was concluded that serial cycles of outpatient sc IL-2 can be administered safely, with an MTD of 15 MIU/day. Patients with higher baseline counts appear to have a greater CD4 cell response to sc IL-2 therapy.
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The use of antiretroviral agents and drugs for the treatment and prophylaxis of opportunistic infections has lengthened the survival of persons with AIDS. In the era of multidrug therapy, drug interactions are important considerations in designing effective and tolerable regimens. Clarithromycin has had a significant impact on the treatment of disseminated Mycobacterium avium complex infection, and zidovudine is the best-studied and one of the most widely used antiretroviral agents in this population. We conducted a study to determine the maximally tolerated dose of clarithromycin and the pharmacokinetics of clarithromycin and zidovudine individually and in combination. Mixing studies were conducted to simulate potential interaction in the gastric environment. The simultaneous administration of zidovudine and clarithromycin had little impact on the pharmacokinetics of clarithromycin or of its major metabolite. However, coadministration of zidovudine and clarithromycin at three doses (500 mg orally [p.o.] twice daily [b.i.d.], 1,000 mg p.o. b.i.d., and 2,000 mg p.o. b.i.d.) reduced the maximum concentration of zidovudine by 41% (P < 0.005) and the area under the concentration-time curve from 0 to 4 h for zidovudine by 25% (P < 0.05) and increased the time to maximum concentration of zidovudine by 84% (P < 0.05), compared with zidovudine administered alone. Mixing studies did not detect the formation of insoluble complexes due to chelation, suggesting that the decrease in zidovudine concentrations results from some other mechanism. Simultaneous administration of zidovudine and clarithromycin appears to decrease the levels of zidovudine in serum, and it may be advisable that these drugs not be given at the same time. Drug interactions should be carefully evaluated in persons with advanced human immunodeficiency virus infection who are receiving multiple pharmacologic agents.
This study assessed the presence of cytomegalovirus (CMV) in bronchoalveolar lavage (BAL) in three subpopulations of HIV-infected patients and correlated its presence with clinical status during 3 mo of follow-up. Nineteen asymptomatic volunteers, six patients with CMV retinitis, and 46 patients with acute pulmonary symptoms underwent BAL and were assessed for CMV by cytopathology, conventional shell vial cultures, and antigen detection. Transbronchial biopsies were also obtained when possible and evaluated for histopathologic changes of CMV. All patients were followed for approximately 3 mo. Cytomegalovirus was detected in BAL in nine of 19 (47%) asymptomatic volunteers, in all six patients with CMV retinitis, and in 33 of 46 (72%) patients with pulmonary symptoms. Only one symptomatic patient with a positive CMV BAL culture developed clinically significant CMV pulmonary disease; this patient developed disseminated CMV and died. The only other death occurred in a patient with CMV retinitis who developed staphylococcal bacteremia. None of the asymptomatic volunteers or patients with CMV retinitis developed evidence of CMV pneumonia or any other organ disease with CMV. Cytomegalovirus is frequently detected in BAL from HIV-infected patients regardless of their pulmonary symptoms and its presence does not clinically predict significant pulmonary morbidity or mortality in 3 mo of follow-up.
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Cytomegalovirus (CMV) retinitis, a common complication of the acquired immunodeficiency syndrome (AIDS), is increasing in frequency as patients infected with the human immunodeficiency virus (HIV) live longer. In recent years, the lifetime risk for CMV disease in HIV-infected persons has increased from 24.9% to 44.9%. Cytomegalovirus retinitis is usually diagnosed clinically: Almost all patients are CMV seropositive and have CD4+ counts less than 50 cells/mm3. Specific diagnostic tests that use antigen detection or quantitation of circulating nucleic acid to detect CMV are being developed, but they have not been validated for routine clinical use. Such tests would help predict disease, diagnose acute retinitis, and monitor therapy. Therapy with systemic agents, including intravenous ganciclovir, intravenous foscarnet, and intravenous cidofovir, is effective. However, it is cumbersome, costly, and associated with considerable toxicity, therapy encouraging investigation of other therapeutic approaches. Intravitreous injections with antiviral agents are effective, but the short half-life of available agents makes these injections inconvenient. Intraocular implants that slowly release ganciclovir have been effective for both acute therapy and long-term maintenance, but they need to be directly compared with intravenous and oral regimens to determine which regimen will optimally maximize convenience, preserve vision, and improve survival. Cytomegalovirus retinitis could be prevented by improved antiretroviral therapies or by immune-based therapies that would prolong the time during which patients remain immunocompetent. Once patients become immunologically susceptible to CMV end-organ disease (when their CD4+ counts decrease to < 50 cells/ mm3), specific chemotherapy with oral ganciclovir is promising, but the cost, inconvenience, toxicity, and conflicting reports of efficacy associated with this strategy mean that it needs careful assessment before it can be considered standard treatment. Management of CMV retinitis is on the verge of major changes. In the next few years, improvements in diagnostic, therapeutic, and preventive tools should reduce morbidity and mortality from this disease.
The patient population at risk for opportunistic pulmonary infections has increased during the last decade. The spectrum of organisms causing opportunistic infections has also grown. With an ever broader list of potential diagnosis, a specific diagnosis of the cause of pulmonary disease becomes more important. Recent microbiologic advances have helped to facilitate the laboratory diagnosis of some of these agents. Immunoassays are available for the detection of antigen in nasopharyngeal secretions (respiratory syncytial virus, influenza) in serum (Cryptococcus species), and in urine (Legionella or Histoplasma species). Rapid-culture techniques are available for the culture and detection of various viruses, including cytomegalovirus. Molecular probes can now assist in the rapid identification of Mycobacterium tuberculosis and some fungi. In the near future, polymerase chain reaction-based techniques may assist in the detection of Pneumocystis carinii and Legionella, Chlamydia, Mycoplasma, and Mycobacteria species. An expeditious evaluation of pulmonary disease requires an understanding of the differential diagnosis of likely causes of pulmonary disease in specific immunosuppressed patient populations, an understanding of the most appropriate specimens to process for these diagnoses, and an understanding of the limitations (sensitivity and specificity) of these diagnostic tests. An understanding of the most appropriate specimens and tests in a given institution should allow for early, relatively specific treatment of many potentially life-threatening infections.
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PURPOSE: To assess the efficacy of informed consent in subjects differing in disease severity, ranging from those with immediately life-threatening disease to healthy volunteers. SUBJECTS AND METHODS: A total of 127 subjects, enrolled in four types of clinical research protocols, were tested. Subjects completed questionnaires before entry into the protocol, within 24 hours of signing the primary protocol's consent document, and 4 to 6 weeks after entry. RESULTS: Healthy volunteers retained the most information about risks and side effects, and severely ill Phase I subjects retained the least (P <0.0001). Phase I and II subjects had the best long-term retention of information about procedures, whereas Phase III subjects and healthy volunteers retained the least (P <0.001). Information about the scientific purpose and confidentiality of data were retained best by symptom-free, Phase III subjects (P <0.05). Phase I subjects entered the study primarily for treatment purposes, and the consent document was rated less useful by subjects with more advanced disease (P <0.05). CONCLUSIONS: Subjects with differing disease processes and illness severities focused on and retained different aspects of experimental protocols for dissimilar reasons. During the informed consent process, research staff should inquire of potential subjects' personal goals for participating in experimental protocols and develop means for ensuring subjects' understanding of the inherent risks and alternative interventions available.