Antibody-mediated bacterial adhesion to cytomegalovirus-induced Fc receptors. Potential relationship to secondary infections complicating herpesvirus infections.

Cytomegalovirus (CMV) and other viruses within the herpes group have recently been shown to induce Fc receptors in infected monolayers. We have examined the possibility that such receptors might facilitate the adherence of antibody-coated bacteria to CMV-infected cells. To do this, we infected confluent human embryonic lung (HEL) cell monolayers with CMV (strain AD 169) and then used a double radiolabel assay to measure adherence of Escherichia coli 06 to both infected and control monolayers. We examined infected monolayers 48 h after viral seeding, at which time 30-60% of the cells exhibited characteristic cytopathic changes. We compared the adherence of untreated E. coli 06 with the adherence of E. coli 06 that had been preincubated for 1 h at 37 degrees C with either nonimmune or anti-E. coli 06 antiserum. Pretreatment of the E. coli 06 with specific antiserum significantly enhanced its adherence to CMV-infected, but not to control, monolayers (P less than 0.01 by the Mann-Whitney U test). We did not see such enhancement when we used anti-E. coli 06 antiserum to treat a nontypable E. coli. The augmented adherence of antibody-coated E. coli 06 to CMV-infected monolayers was abrogated by pretreating the monolayers with nonimmune serum or purified Fc fragments, but not by pretreating with IgA, IgM, or 1 mM trypan blue. Preincubating HEL cell monolayers with 100 U/ml human leukocyte interferon for 72 h at 37 degrees C did not affect the adherence of antibody-coated E. coli 06 to the monolayers. To determine if antibody-coated bacteria that adhered to the surface of CMV-infected monolayers might themselves act as receptors for microorganisms with Fc binding potential, we compared the adherence of Cowan strain Staphylococcus aureus to CMV-infected and control monolayers that had been preincubated with antibody-coated E. coli 06. The S. aureus adhered significantly better to the former monolayers (P less than 0.001). These results illustrate a previously unrecognized mechanism by which certain herpesviruses might enhance the adherence of secondary pathogens to nonphagocytic cell populations. Such a mechanism, if active in vivo, might facilitate the colonization of mucosal surfaces by these pathogenic microorganisms, and in this way might contribute to both the reported predisposition of CMV-infected patients to secondary infections and to the high prevalence of S. aureus in the vaginal flora of women with histories of genital herpes.

Concepts of fever.

If asked to define fever, most physicians would offer a thermal definition, such as "fever is a temperature greater than...." In offering their definition, many would ignore the importance of the anatomic site at which temperature measurements are taken, as well as the diurnal oscillations that characterize body temperature. If queried about the history of clinical thermometry, few physicians could identify the source or explain the pertinacity of the belief that 98.6 degrees F (37.0 degrees C) has special meaning vis-à-vis normal body temperature. Fewer still could cite the origin of the thermometer or trace the evolution of modern concepts of clinical thermometry. Although many would have some knowledge of the fundamentals of thermoregulation and the role played by exogenous and endogenous pyrogens in the induction of fever, few would have more than a superficial knowledge of the broad biological activities of pyrogenic cytokines or know of the existence of an equally complex and important system of endogenous cryogens. A distinct minority would appreciate the obvious paradoxes inherent in an enlarging body of data concerned with the question of fever's adaptive value. The present review considers many of these issues in the light of current data.

Antipyretic therapy: physiologic rationale, diagnostic implications, and clinical consequences.

Various treatments have been used to suppress fever since antiquity. Surprisingly, few studies have been performed to ascertain the physiologic consequences of antipyresis and validate the rationale behind such therapy. More importantly, it has not been established conclusively that the benefits of antipyretic therapy outweigh its risks. The present review considers these issues in light of currently available data and formulates guidelines for antipyretic therapy based on these data.

Effects of anatomic site, oral stimulation, and body position on estimates of body temperature.

BACKGROUND: A prior investigation characterized the range of body temperature in healthy young adults and established the importance of diurnal variations in defining the febrile state. METHODS: Sequential rectal, oral, and tympanic membrane temperature measurements were performed on 22 healthy subjects to determine the quantitative effects of anatomic site, oral stimulation, and body position on estimates of body temperature. RESULTS: Mean rectal temperatures exceeded concurrent oral readings by 0.4 degrees C +/- 0.4 degrees C (0.8 degrees F +/- 0.7 degrees F), which, in turn, exceeded concurrent tympanic membrane readings (obtained with a digital thermometer [IVAC Corp, San Diego, Calif]) by 0.4 degrees C +/- 1.1 degrees C (0.7 degrees F +/- 2.0 degrees F). Tympanic membrane readings were significantly more variable (both intrasubject and intersubject) than rectal or oral readings, especially when cerumen was present in the external ear canal being examined (P<.05). Mastication and smoking both caused significant increases in oral temperature that persisted for greater than 20 minutes. Drinking ice water caused a significant but more transient decrease in oral temperature. Of these activities, only mastication appeared to influence tympanic membrane readings. Body position exerted a modest effect on rectal temperature readings, but did not significantly affect oral or tympanic membrane readings. CONCLUSIONS: These findings indicate that, in addition to diurnal fluctuations in body temperature, the effects of anatomic site, oral stimulation, and body position should be considered in establishing criteria for the febrile state.

Pharyngeal colonization by gram-negative bacilli in aspiration-prone persons.

We compared the prevalence of Gram-negative bacilli in the pharyngeal flora of two groups of patients with a known predilection for Gram-negative bacillary pneumonia (chronic alcoholics and diabetics), two other groups of aspiration-prone persons with no known predilection for Gram-negative bacillary pneumonia (epileptics and narcotic addicts), and normal control subjects. Quantitative cultures of saline gargles showed pharyngeal Gram-negative bacilli to be significantly (P less than .05) more prevalent among alcoholics (35%) and diabetics (36%) but not epileptics (17%) or addicts (20%) than controls (18%). Counts of greater than or equal to 100 Gram-negative bacilli per milliliter were also significantly more common in alcoholics (14%) and diabetics (24%) than controls (5%, P less than .05). Enterobacter sp, Klebsiella pneumoniae, and Escherichia coli were the most common Gram-negative bacilli isolated. Increased colonization by Gram-negative bacilli might be a factor contributing to the propensity of alcoholics and diabetics for Gram-negative pneumonia.

Effects of IFN-beta on human cerebral blood flow distribution.

The effect of interferon-beta1b (IFN-beta) on human cerebral blood flow distribution was examined in five multiple sclerosis patients using functional brain single-photon emission tomography (SPECT). Of nine regions of interest studied, only the basal ganglia exhibited a significant change (increase) in relative photon emission intensity (i.e., relative blood flow) when comparing SPECT scans obtained 6 h after s.c. IFN-beta injection with scans obtained at the same time of day (noon) 30 h after IFN-beta injection (IFN-beta-free day). The increase in relative blood flow to the basal ganglia following IFN-beta injection correlated positively with changes in mean arterial pressure (MAP). Additional studies will be required to determine the relevance of these observations for IFN-beta-induced central nervous system side effects.

Microbial oncogenesis.

For more than a century, medical investigators have sought to incriminate microorganisms in the cause of cancer. The first scientific evidence of such a relationship came in 1911, with the first successful induction of a tumor using a cell-free extract. Since that time, considerable data have accrued linking retroviruses, herpes viruses, the hepatitis B virus, papovaviruses, and adenoviruses to various malignant neoplasms. There is also increasing evidence that certain bacteria and parasites participate as cofactors in the development of some cancers. Although proof of cause-and-effect relationships has been difficult to obtain, there can be little doubt that microorganisms occasionally play pivotal roles in the origin of some cancers. Whether attempted intervention against these cancers is best directed against the oncogenic microorganisms themselves or against other environmental cofactors is not yet clear. Nevertheless, the successful application of tumor vaccines in the prevention of Marek's disease in chickens and in modifying the outcome of oncogenic herpesvirus infections in nonhuman primates offers hope of at least limited application of microbial vaccines in the prevention of human cancer.

Clinical uses of microorganisms and their products.

Although antibiotics and conventional vaccines are the two most familiar examples of man's exploitation of microorganisms as clinical allies, microorganisms and their products are assuming an increasingly prominent role in the diagnosis, treatment and prevention of human diseases. This report attempts to give a brief overview of the status of the use of microorganisms in clinical medicine and to identify potentially fertile areas for future progress in their clinical application, concentrating on areas other than the already extensively reviewed ones of antibiotics and classic immunization.

Pseudocholelithiasis in an elderly man with calcified hydatid cysts.

A 69 year old man with intrabiliary rupture of a calcified echinococcal cyst mimicking acute cholelithiasis is discussed. This case is of interest because the correct diagnosis was not recognized preoperatively despite the fact that certain aspects of the illness were classic features of this complication of hydatid disease. Although this is a common complication of hydatid disease, which is well recognized in other countries, only seven cases have been reported in the American literature. Treatment of our patient included successful use of a Roux-en-Y drainage procedure which, to the best of our knowledge, has not previously been employed in treating this disease.

Infections of hairy cell leukemia. Clinical evidence of a pronounced defect in cell-mediated immunity.

We compared infection rates in 12 patients with hairy cell leukemia (a malignant neoplasm for which the cell of origin remains controversial) with rates in 15 patients with chronic lymphocytic leukemia (a known B-lymphocyte neoplasm) recently treated at four Dallas hospitals. We found a significantly higher over-all rate of infections in the patients with hairy cell leukemia (P = 0.004 BY Gehan's variation on the generalized Wilcoxon test). This increased rate was primarily due to a significantly higher rate of infections normally controlled by the cell-mediated immune system (P = 0.005). Despite these findings, five of six patients with hairy cell leukemia who were skin-tested exhibited intact delayed type hypersensitivity, and each of the three patients examined serologically produced antibodies normally in response to recent infections. A review of the case records of 173 previously described patients with hairy cell leukemia, demonstrated a similar predilection of patients with this disease for infections normally controlled by cell-mediated immunity. In this regard, they were similar to previously described patients with Hodgkin's disease. Both over-all infection rates and rates of fatal infection were highest in patients with hairy cell leukemia who received chemotherapy as their sole form of treatment and lowest in those who underwent splenectomy as their only form of antitumor therapy.

Effects of physiologic variations in temperature on the rate of antibiotic-induced bacterial killing.

The effects of physiologic temperature variations on antibiotic-induced killing of Escherichia coli, Pseudomonas aeruginosa, Streptococcus faecalis, and Streptococcus pneumoniae were studied. At concentrations less than or equal to four times the minimal bactericidal concentration, the activity of each of the antibiotics (gentamicin sulfate, sodium ampicillin, and chloramphenicol) against the test bacteria was influenced by changes in temperature. Only with S. pneumoniae did such influence appear to result directly from temperature-induced changes in the multiplication rate of the bacteria. Repeated subculturing of bacteria at 41 degrees C to induce temperature adaptation had a variable effect on the rate of bacterial killing by appropriate antibiotics. The magnitude of the effect of temperature on antibiotic-induced rates of bacterial killing varies with the antibiotic class, the species of bacteria, and the temperature to which bacteria have been adapted.

Failure of the urinalysis and quantitative urine culture in diagnosing symptomatic urinary tract infections in patients with long-term urinary catheters.

Since urine culture and urinalysis are both of uncertain reliability in diagnosing symptomatic urinary tract infections in patients with chronic urinary catheters, we performed sequential quantitative cultures and urinalyses on 177 urine specimens from 14 patients with long-term urinary catheters during a 12-month period. We found high concentrations of greater than or equal to 2 species of aerobic bacteria or fungi in most specimens examined. Pyuria was common even during asymptomatic periods; hematuria was less common. During symptomatic urinary tract infections, neither urinalyses nor quantitative urine cultures exhibited changes specific for such infections. Thus neither urinalysis nor urine culture appears to be a reliable test for symptomatic urinary tract infections in patients with chronic urinary catheters.

The pharmacologic consequences of fever.

Despite its potential importance to the management of patients with febrile illnesses, the effect of fever on pharmacokinetics and pharmacodynamics has received little attention in the clinical literature. This article considers literature published in this potentially important area.

Effect of antipyretic therapy on the duration of illness in experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections.

STUDY OBJECTIVES: To determine whether antipyretic therapy prolongs the course of experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections. DESIGN: Retrospective observational study. SETTING: University Center for Vaccine Development. SUBJECTS: Fifty-four volunteers with experimentally induced influenza A, 45 with S. sonnei, and 21 with R. rickettsii infections participated. INTERVENTIONS: Subjects from the six influenza A studies were challenged intranasally. If they met certain criteria, they were offered aspirin or acetaminophen for symptomatic relief. Subjects from the three Shigella studies were challenged with the bacteria and then given trimethoprimsulfamethoxazole. Acetaminophen also could be administered. In the one R. rickettsii trial, subjects were inoculated intradermally and treated with tetracycline. Again, acetaminophen was administered for symptomatic relief. MEASUREMENTS AND MAIN RESULTS: Data, excerpted from subjects' study records, were evaluated using Wilcoxon tests, Spearman's correlation coefficients, and multiple regression analysis. Two-tailed hypotheses with a p value of 0.05 were used for all of the analyses. There was a striking correlation between antipyretic therapy and duration of illness in subjects infected with influenza A and S. sonnei, but not R. rickettsii. CONCLUSIONS: Multivariate analysis suggested that antipyretic therapy prolonged illness in subjects infected with influenza A, but its use was the result of prolonged illness in those infected with S. sonnei. The precise nature of these relationships requires a prospective, randomized, placebo-controlled trial.

A resource-allocation model to enhance productivity of academic physicians.

The authors describe a resource-allocation model developed in the Medical Care Clinical Center at the Baltimore Veterans Affairs Medical Center (a part of the VA Maryland Health Care System) and implemented in 1989. This model is a computer-based system that tracks the workload of each of the clinical center's specialty sections (e.g., cardiology) and calculates each section's workload as a percentage of the total clinical center workload. As the basis of this calculation, six activities of each section are tracked by the model (e.g., inpatient attending physicians' rotations; inpatient consultations; etc.) to determine what percentage of each activity of the entire clinical center was provided by each section. Each of these percentages is then recalculated according to a weighted average based on the relative value of the activity to the department; these averages are revised periodically as needed. The model provides an incentive for the specialty sections to increase productivity by generating competition among sections for physician salary support. Communication among all concerned at the clinical center and its associated medical school and teaching hospital has been the key to success in implementing the model, which is periodically reviewed and has been revised several times after meetings with section chiefs and division heads. The authors are confident that the use of the model has been at least partly responsible for increased productivity of clinical center physicians, especially in the areas of visits per physician and funded VA research dollars per physician. Perhaps equally important is the future potential of the model. Because of its simplicity and because it is generally seen to be fair and effective, it will continue to be used to reward activities most important to the clinical center, especially now that the center operates under a fully capitated system, and in this way wil help ensure the financial viability of the center.

The salary responsibility program for full-time faculty members in an academic clinical department.

The authors report a system developed in the Department of Medicine of the University of Maryland School of Medicine to encourage members of the full-time faculty to assume greater responsibility for their compensation. A member of the department's administrative staff individually interviews each faculty member and fills out, with the member, a "scorecard" that contains the number of hours per month and per year that the member reports were spent on his or her duties--such as teaching, attending, and consulting--that are assigned by the department or its divisions. This report also contains the record of unassigned time devoted to research (for investigators) or to personal practice (for clinicians). Assigned duties includes the time spent by clinicians performing procedures such as bronchoscopy cardiac catheterization, and endoscopy. The department pays for the otherwise unsupported costs of salary and benefits associated with assigned duties, and the faculty member is responsible for part of his or her compensation for time spent in research or practice. The program was developed and the data collected during the summer and fall of 1995. The salary reductions were applied on July 1, 1996. During the 1996-97 academic year the department projects a savings of $110,362 from compensation withheld from faculty members unable to fulfill their salary responsibilities and not paid to members who left the department, in part because of expected reductions in their incomes. The program has stimulated other faculty members to develop salary support with even greater vigor than that might otherwise have shown.

Drug fever: mechanisms, maxims and misconceptions.

Although drug fever is a clinical entity that has received considerable attention in textbooks and review articles, only recently have such writings been subjected to critical analysis. In the present review, mechanisms responsible for drug fever are examined. In addition, published characterizations of the syndrome are compared with the results of a recently published systematic analysis of 148 cases of drug fever. This comparison identified a number of important areas in which descriptions of the clinical entity in textbooks and review articles are at odds with the clinical profile exhibited by actual cases of drug fever.

The enterococci: evidence of species-specific clinical and microbiologic heterogeneity.

Investigations of the clinical role of enterococci have been limited largely to enterococcal bacteremia and endocarditis and have not distinguished between the various species of enterococci. To characterize the full spectrum of enterococcal disease and to determine whether clinically important differences exist among infections and/or instances of colonization (infections/colonizations) by the various enterococcal species, cases of enterococcal infection/colonization diagnosed at the Dallas Veterans Administration Medical Center (DVAMC) in 1986 were reviewed. During this period, 220 Enterococcus faecalis, 21 Enterococcus faecium, 12 Enterococcus avium, and no Enterococcus durans isolates were identified in clinical specimens (other than stool) submitted to the DVAMC microbiology laboratory. Clinical characteristics of cases of infection/colonization by the three species of enterococci were similar and did not vary significantly when blood stream invasion occurred. Nevertheless, mortality data and therapeutic response rates suggested differences in virulence of the three enterococcal species. Enterococcal infections/colonizations (including bacteremia) frequently were polymicrobial. Although Enterobacteriaceae were the most common copathogens identified overall, Staphylococcus aureus was the most common copathogen in bloodstream infections. E. avium was more resistant than E. faecalis or E. faecium to penicillin G and ampicillin and less resistant to most other antimicrobial agents. The results of this investigation suggest that enterococci are a heterogeneous group of bacteria that should not be treated as a single entity in clinical investigations.

The relationship between age and fever magnitude.

BACKGROUND: Infections are an important cause of morbidity and mortality in older people; however, they are often difficult to diagnose because the signs and symptoms of infection in older people are frequently atypical. Fever, one of the most important signs of infection, is a case in point. Preliminary evidence suggests that the febrile response in older persons is blunted, leading to the clinical maxim, "the older, the colder." The objective of this study was to assess the effect of age on the febrile response to moderate-to-severe pneumonia in hospitalized patients adjusted for the effect of anatomic site at which the temperature was measured. METHODS: This is a retrospective cohort study of 320 hospitalized patients with moderate-to-severe pneumonia. The study was designed to assess the effect of age on the febrile response to moderate-to-severe pneumonia in hospitalized patients, adjusting for the effect of the anatomic location of the temperature measurement. The highest temperature of each day and the anatomic sites at which temperatures were taken (axillary, oral, rectal, or other) on days 1 and 2 of infection and at hospital discharge. Baseline demographic information, including age, were obtained for each patient. RESULTS: There were 320 patients (median age, 64 years; range, 18-97 years). Using a linear regression model, significant inverse correlations were found between age and the temperature for patients on the first and second days of hospitalization (P < 0.001). For each decade increase in age, the average temperature on the first 3 days of infection was lower by 0.15 degrees C. Temperature at discharge, a surrogate for baseline temperature, also decreased at an equal rate with age. CONCLUSION: In this study, the febrile response to infections was reduced with increasing age and baseline temperatures were generally lower in older patients.

Polymicrobial sepsis: an analysis of 184 cases using log linear models.

Polymicrobial sepsis is a common and frequently fatal clinical condition that has received relatively little attention in published reports. Retrospectively, we reviewed the case records of 184 patients with polymicrobial sepsis seen at three Dallas hospitals between 1972 and 1977. Analysis of clinical data using log linear models enabled us to identify significant positive correlations (p < 0.05) between mortality resulting from polymicrobial sepsis and underlying disease category, failure to manifest fever, a pulmonary portal of entry, hypotension, and hospital-associated sepsis. No significant correlation with outcome could be demonstrated for age, hospital service, species of infecting microorganisms, number of microorganisms isolated from blood, WBC count, or antimicrobial therapy. In spite of indirect evidence for synergistic relationships between microorganisms responsible for polymicrobial sepsis in man, we could not resolve whether antimicrobial regimens that are effective against all of the microorganisms participating in polymicrobial infections are required to insure a favorable outcome.