Paul D. Stolley

The Guillain–Barré Syndrome and the 1992–1993 and 1993–1994 Influenza Vaccines

BACKGROUND The number of reports of influenza-vaccine-associated Guillain-Barré syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992-1993 to 74 in 1993-1994, arousing concern about a possible increase in vaccine-associated risk. METHODS Patients given a diagnosis of the Guillain-Barré syndrome in the 1992-1993 and 1993-1994 influenza-vaccination seasons were identified in the hospital-discharge data bases of four states. Vaccination histories were obtained by telephone interviews during 1995-1996 and were confirmed by the vaccine providers. Disease with an onset within six weeks after vaccination was defined as vaccine-associated. Vaccine coverage in the population was measured through a random-digit-dialing telephone survey. RESULTS We interviewed 180 of 273 adults with the Guillain-Barré syndrome; 15 declined to participate, and the remaining 78 could not be contacted. The vaccine providers confirmed influenza vaccination in the six weeks before the onset of Guillain-Barré syndrome for 19 patients. The relative risk of the Guillain-Barré syndrome associated with vaccination, adjusted for age, sex, and vaccine season, was 1.7 (95 percent confidence interval, 1.0 to 2.8; P=0.04). The adjusted relative risks were 2.0 for the 1992-1993 season (95 percent confidence interval, 1.0 to 4.3) and 1.5 for the 1993-1994 season (95 percent confidence interval, 0.8 to 2.9). In 9 of the 19 vaccine-associated cases, the onset was in the second week after vaccination, all between day 9 and day 12. CONCLUSIONS There was no increase in the risk of vaccine-associated Guillain-Barré syndrome from 1992-1993 to 1993-1994. For the two seasons combined, the adjusted relative risk of 1.7 suggests slightly more than one additional case of Guillain-Barré syndrome per million persons vaccinated against influenza.

Dental and Cardiac Risk Factors for Infective Endocarditis: A Population-Based, Case-Control Study

Infective endocarditis is uncommon but potentially fatal. Administration of antibiotic prophylaxis is conventional [1], but data supporting its effectiveness derive solely from anecdotal reports, studies of bacteremia after dental and other procedures, and animal models. The low incidence of disease [2] has made randomized human trials of antibiotic effectiveness impractical. Even if effective, antibiotic prophylaxis should be reserved for patients at increased risk, such as those with cardiac abnormalities who are undergoing dental procedures. However, controlled human studies of risk factors are lacking. Previous case series indicate that approximately 15% of patients with infective endocarditis caused by mouth organisms had undergone a recent dental procedure [3], but the comparable percentage from a general population is unknown. The single hospital-based casecontrol study did not find an elevated risk associated with dental therapy, except for a borderline increase with dental scaling [4]. We are unaware of controlled human studies that quantify the risk for infective endocarditis associated with cardiac valve abnormalities other than mitral valve prolapse. We therefore conducted a population-based casecontrol study to evaluate and quantify risk factors for infective endocarditis, especially those considered by the American Heart Association (AHA) to be indications for antibiotic prophylaxis [1]. Methods Participants From August 1988 to November 1990, we maintained surveillance for infective endocarditis in 54 hospitals of the Delaware Valley Case-Control Network, a population-based network of hospitals in the eight counties that constitute the Philadelphia Metropolitan Statistical Area and the county of New Castle, Delaware. Patients with a putative diagnosis of infective endocarditis were identified by hospital personnel and were reported to study nurses, who also actively sought cases. To assess the completeness of ascertainment, five high-yield hospitals and three low-yield hospitals were asked to list all patients discharged with a diagnosis of endocarditis over 3 months. These lists were compared with those obtained from our surveillance; charts were reviewed when differences were identified. We obtained informed consent from physicians and case-patients, then used structured forms to abstract medical records, including echocardiographic reports and hospital laboratory information on the infecting organism. We deleted information on purported risk factors for infective endocarditis and submitted these records for review by three of the authors, who are consultants in infectious diseases recognized for their expertise in infective endocarditis [5, 6]. These experts used their own global clinical judgment to classify potential cases as definite, probable, or possible cases or probable noncases. Agreement of two of the three reviewers was required to make the determination of a case or a noncase [6]. One control from the community was selected for each case-patient by using a modification of the Waksberg random-digit dialing method [7]. Controls and case-patients were matched for age (in 5-year strata), sex, and neighborhood of residence (by using area code, telephone exchange, and the first subsequent digit of the case-patients telephone number). We excluded from these analyses patients with infective endocarditis who were younger than 18 years of age, intravenous drug users, and patients who developed endocarditis in the hospital. This study received separate institutional review board approval at the University of Pennsylvania and all 54 participating hospitals. Data Collection Information was obtained from case-patients by conducting a structured telephone interview after hospital discharge. The date of hospital admission served as the study date for case-patients; for controls, the date of the telephone interview was used. Telephone interviewers collected information on demographic characteristics; diagnostic and therapeutic medical and dental procedures in the year before the study date; potential host risk factors, including preexisting cardiac lesions, preexisting local infection, risk factors for oral or dental disease, diabetes mellitus, immune deficiencies, family history of endocarditis, alcoholism, malignant conditions, and autoimmune disease; previous antibiotic use; and other recent illnesses. For each host risk factor, we requested the date of diagnosis, diagnostic method (for example, echocardiography for mitral valve prolapse), and the name of the practitioner who made the diagnosis. For each medical and dental procedure, we sought information about the procedure, the month and year in which it was performed, and the practitioner. We requested medical and dental records describing procedures and validating individual diagnoses. Study Variables Case-patients were considered infected with dental flora if the organism found was viridans streptococci; nutritionally variant streptococci; Actinobacillus species; Cardiobacterium hominis; anaerobes; -hemolytic streptococci (not group D); unspecified streptococci; or Haemophilus, Eikenella, Kingella, or Neisseria species. Because this study focused on indications for antibiotic prophylaxis, we examined host characteristics reported by patients as the primary risk factor variables, reflecting the information that would be available to a practitioner about to perform a procedure for which prophylaxis might be indicated. A variable called any valvular heart abnormality was defined as the presence of any of the following self-reported, preexisting conditions: mitral valve prolapse, congenital heart disease, history of rheumatic fever with heart involvement, prosthetic heart valve, previous episode of endocarditis, or other valvular heart disease. Dental visit information was obtained solely from dental records. Dental hygiene care was defined as preventive oral health services and therapeutic services, including coronal scaling and polishing. Consistent with AHA guidelines, invasive dental procedures were defined to include dental hygiene care, extractions, periodontal treatment (including scaling and root planing), endodontic treatment, mouth or gingival surgery, and treatment of tooth abscess. Noninvasive dental procedures were simple restorations, prosthetic and restorative dentistry, fluoride treatment, and other procedures (prosthetic services, including adjustments and suture removal). Unless otherwise specified, dental treatment refers to all dental treatment and is not limited to invasive procedures. Initial analyses focused on dental procedures performed at any time in the 3 months before the study date. Analyses were then narrowed to 2 months and 1 month before the study date. Time frames are approximate because the onset of infective endocarditis is often difficult to determine with certainty. We therefore chose the date of hospital admission as the study date, collected procedural data based on month rather than on a specific date, and calculated time frames under the assumption that procedures were performed on the 15th of the month. Statistical Analysis Frequencies and cross-tabulations between casecontrol status and potential risk factors were obtained. Conditional logistic regression was used to determine the independent effects of the various potential risk factors and the possibility of any interactions among factors [8]. Variables were included in multiple regression models if they were significant (P < 0.2) in unadjusted (matched) analyses (such as kidney disease and diabetes), if their inclusion had a substantial effect (>15% change) on coefficients for variables already in the model (such as insurance status) [9], or if they were strongly suspected a priori of being confounders (such as ethnicity). For analyses specific to participants with known cardiac valvular abnormalities, odds ratios and CIs were calculated from a model that included main effects for cardiac valvular abnormalities and dental treatment and the interaction between those variables. The odds ratio for various dental therapy variables among participants with cardiac valvular abnormalities was estimated by combining coefficients for the dental therapy variable and the interaction term. The CI for this combination of coefficients was estimated by using the appropriate variance and covariance terms [8]. With the interaction terms, participants with and those without valvular abnormalities were included in these analyses. Exact odds ratios and CIs, stratified on the matching variables, were calculated when data were too sparse for conditional logistic regression [10]. We used SAS statistical software (SAS Institute Inc, Cary, North Carolina) for data management and to obtain frequencies and cross-tabulations. We used EGRET (Epidemiological Graphics, Estimation and Testing software, version 0.25.1, Cytel Software Corp., Cambridge, Massachusetts) for conditional logistic regressions and exact analyses. All CIs are 95%, and all P values are two-sided. The sample size for the study was chosen so that by assuming an level of 0.05 (two-sided) and a power of 80%, we would be able to detect associations with an odds ratio of 2.0 or more for risk factors with a prevalence between 0.1 and 0.8. Results Participants We identified and recruited 416 potential case-patients (Figure 1). Our assessment process confirmed that more than 90% of true cases of infective endocarditis had been identified. The expert panel judged 379 patients to have definite, probable, or possible infective endocarditis; 37 (9%) were judged to be probable noncases and were excluded. Agreement among judgments was high, ranging from 92% to 96% [6]. Figure 1. Enrollment of case-patients. Of these 379 patients, 287 had community-acquired infective endocarditis not associated with intravenous drug use (248 on native valves and 39 on prosthetic valves), 27 had nosocomial infective endocarditis (18 on nativ

Effectiveness of hysterectomy

Objective To measure the effectiveness of hysterectomy in relieving adverse symptoms and to identify factors associated with lack of symptom relief. Methods In a 2-year prospective study, data were collected before and at 3, 6, 12, 18, and 24 months after hysterectomy in 1299 women who had hysterectomies for benign conditions at 28 hospitals across Maryland. Effectiveness was measured in terms of relief of symptoms such as problematic vaginal bleeding, pelvic pain, and urinary incontinence. Psychologic function and quality of life before and after surgery also were assessed. Results Symptom severity, depression, and anxiety levels decreased significantly after hysterectomy and quality of life improved, particularly in the area of social function. However, 8% of women had at least as many symptoms at problematic-severe levels 1 and 2 years after hysterectomy as before. In multiple logistic regression, several presurgical patient characteristics predicted lack of symptom relief, including therapy for emotional or psychologic problems, depression, and household income of

Risk of Localized and Widespread Endometrial Cancer in Relation to Recent and Discontinued Use of Conjugated Estrogens

35,000 or less. Bilateral oophorectomy predicted lack of symptom relief at 24 months but not at 12 months after hysterectomy. Conclusion Significant improvements were seen after hysterectomy for all three aspects of health status (symptoms, psychologic function, and quality of life), which persisted or continued to improve throughout the 2 years of follow-up. However, hysterectomy did not relieve symptoms for some women, particularly those who had low incomes or were in therapy at the time of hysterectomy.

Risk Factors for Infective Endocarditis Oral Hygiene and Nondental Exposures

In a case-control study of the risk of adenocarcinoma of the endometrium in relation to conjugated-estrogen use, we found that 31 per cent of 425 women with endometrial cancer and 15 per cent of 792 controls reported having used conjugated estrogens; the rate-ratio estimate was 3.5 with a 95 per cent confidence interval of 2.6 to 4.7. For use that lasted at least one year, the rate-ratio estimate for Stage I or II cancer was 5.2 (95 per cent confidence interval, 3.7 to 7.2), and for Stages III and IV combined it was 3.1 (1.5 to 6.4). Among women who had used estrogen for at least one year and then discontinued it, the risk of endometrial cancer remained significantly elevated even after estrogen-free intervals of over 10 years. The findings suggest that long-term use of conjugated estrogen increases the risk of both localized and widespread endometrial cancer. The data also suggest that women who have taken conjugated estrogen for one or more years remain at increased risk for at least 10 years after they discontinue use. Such women should be considered for long-term gynecologic surveillance.

Risk of Myocardial Infarction in Relation to Current and Discontinued Use of Oral Contraceptives

Background—The risks of infective endocarditis (IE) associated with various conditions and procedures are poorly defined. Methods and Results—This was a population-based case-control study conducted in 54 Philadelphia, Pa–area hospitals from 1988 to 1990. Community-acquired IE cases unassociated with intravenous drug use were compared with matched community residents. Subjects were interviewed for risk factors. Diagnoses were confirmed by expert review of medical record abstracts with risk factor data removed. Cases were more likely than controls to suffer from prior severe kidney disease (adjusted OR [95% CI]=16.9 [1.5 to 193], P =0.02) and diabetes mellitus (adjusted OR [95% CI]=2.7 [1.4 to 5.2], P =0.004). Cases infected with skin flora had received intravenous fluids more often (adjusted OR [95% CI]=6.7 [1.1 to 41], P =0.04) and had more often had a previous skin infection (adjusted OR [95% CI]=3.5 [0.7 to 17], P =0.11). No association was seen with pulmonary, gastrointestinal, cardiac, or genitourinary procedures or with surgery. Edentulous patients had a lower risk of IE from dental flora than patients who had teeth but did not floss. Daily flossing was associated with a borderline decreased IE risk. Conclusions—Within the limits of the available sample size, the data showed that IE patients differ from people without IE with regard to certain important risk factors but not regarding recent procedures.

Sample size calculations for clinical pharmacology studies.

In a hospital-based case-control study, we evaluated the rate of myocardial infarction in relation to discontinued as well as current use of oral contraceptives. We compared 556 women with infarction, 25 to 49 years old, with 2036 age-matched control subjects. For current users, the rate-ratio estimate was 3.5 (95 per cent confidence limits, 2.2 to 5.5). For past users 40 to 49 years of age, the magnitude of the rate ratio was related to the duration of use: for total durations of past use of less than five years, five to nine years, and 10 or more years, respectively, the rate-ratio estimates (with 95 per cent confidence limits) were 1.0 (0.8 and 1.4), 1.6 (1.1 and 2.5), and 2.5 (1.5 and 4.1). This trend was statistically significant (P less than 0.01). The findings suggest that an effect on the risk of myocardial infarction persists after the discontinuation of long-term use of oral contraceptives.

Risk Factors for Dehydration Among Elderly Nursing Home Residents

Clinical Pharmacology and Therapeutics (1986) 39, 489–490; doi:10.1038/clpt.1986.85

The Relationship between Physician Characteristics and Prescribing Appropriateness

Dehydration is the most common fluid and electrolyte disorder among the elderly, yet risk factors are not known. This study identifies risk factors for dehydration in acutely ill nursing home residents. All 339 elderly residents of two nursing homes who developed an acute illness requiring hospitalization during 1984 were included in the study. The 173 patients having a serum Na < 150 mg/dL and blood urea nitrogen to creatinine ratio (BUN:Cre) < 20 were designated controls; 91 patients having a serum Na > 150 mg/dL or a serum BUN:Cre > 25 were designated cases. Odds ratios (OR) and confidence intervals were calculated for age, sex, chronic conditions, acute illnesses, medications, functional status measures, and season. Acutely ill dehydrated patients were female (OR, 3.3); over 85 years old (OR, 2.2); had more than four chronic conditions (OR, 4.0); took more than four medications (OR, 2.8); and were bedridden (OR, 2.9). Among the most severely dehydrated (serum Na > 150 mg/dL and BUN:Cre > 25), the odds ratios for the above factors were strengthened and other factors, such as inability to feed oneself and type of acute diagnosis, emerged as risk factors. Among the variables unrelated to functional status, laxatives (OR, 3.2) and chronic infections (OR, 1.8) were risk factors. We conclude that a group at high risk for dehydration can be defined and that they are better characterized by the number of chronic diseases and debilitated functional status than by acute disease processes.

Chromosome aberrations in individuals occupationally exposed to ethylene oxide, and in a large control population☆

Primary care physicians in private practice were surveyed in depth to enable evaluation of various structural and sociologic variables as predictors of differential prescribing practices. “Appropriateness” or quality of prescribing behavior was determined by expert judges. While it is often suggested that longer professional experience leads to provision of higher quality medical care, this investigation found more appropriate prescribers to be younger, more recent graduates who have taken additional courses and postgraduate training, but who have had fewer years of experience in practice, maintain larger, hurried practices with more ancillary assistants, and spend less time with each patient. Better prescribes are also found to be more cosmopolitan, modern, and concerned with both psychosocial and quality dimensions of medical care. They frequently consult with (and refer more of their patients to) other physicians and rely most heavily upon journal articles for drug information. Good prescribers are more satisfied with their prior training in therapeutics and more concerned about the current general level of prescribing quality; they seek data on contraindications and are more dissatisfied with existing sources of prescribing information. Finally, the better prcscriber is critical of the pharmaceutical industry and supports an expanded role for the Federal Government in regulating drug quality and costs.