Eddy A. Bresnitz

Investigation of bioterrorism-related anthrax, United States, 2001: epidemiologic findings.

In October 2001, the first inhalational anthrax case in the United States since 1976 was identified in a media company worker in Florida. A national investigation was initiated to identify additional cases and determine possible exposures to Bacillus anthracis. Surveillance was enhanced through health-care facilities, laboratories, and other means to identify cases, which were defined as clinically compatible illness with laboratory-confirmed B. anthracis infection. From October 4 to November 20, 2001, 22 cases of anthrax (11 inhalational, 11 cutaneous) were identified; 5 of the inhalational cases were fatal. Twenty (91%) case-patients were either mail handlers or were exposed to worksites where contaminated mail was processed or received. B. anthracis isolates from four powder-containing envelopes, 17 specimens from patients, and 106 environmental samples were indistinguishable by molecular subtyping. Illness and death occurred not only at targeted worksites, but also along the path of mail and in other settings. Continued vigilance for cases is needed among health-care providers and members of the public health and law enforcement communities.

Sample size nomograms for interpreting negative clinical studies.

In recent years there has been increasing attention to the appropriate interpretation of a clinical study. One special concern has been the difficulty inherent in interpreting studies that were not statistically significant: Was the sample size sufficient to detect a clinically important effect if, in fact, it existed? This concern is further complicated because readers may have differing opinions of what size effect is clinically important. A pair of sample size nomograms has been developed, using common levels of statistical significance, to assist in this interpretation. The nomograms are intended to provide the clinician with a handy and easy-to-use reference for ascertaining whether an apparently negative study has a sample size adequate to detect reliably any difference between treatment groups that the clinician believes is clinically important. Examples are provided to show these principles and the use of the nomograms in interpreting negative studies.

The Critical Role of Pathology in the Investigation of Bioterrorism-Related Cutaneous Anthrax

Cutaneous anthrax is a rare zoonotic disease in the United States. The clinical diagnosis traditionally has been established by conventional microbiological methods, such as culture and gram staining. However, these methods often yield negative results when patients have received antibiotics. During the bioterrorism event of 2001, we applied two novel immunohistochemical assays that can detect Bacillus anthracis antigens in skin biopsy samples even after prolonged antibiotic treatment. These assays provided a highly sensitive and specific method for the diagnosis of cutaneous anthrax, and were critical in the early and rapid diagnosis of 8 of 11 cases of cutaneous anthrax during the outbreak investigation. Skin biopsies were obtained from 10 of these 11 cases, and histopathological findings included various degrees of ulceration, hemorrhage, edema, coagulative necrosis, perivascular inflammation, and vasculitis. Serology was also an important investigation tool, but the results required several weeks because of the need to test paired serum specimens. Other tests, including culture, special stains, and polymerase chain reaction assay, were less valuable in the diagnosis and epidemiological investigation of these cutaneous anthrax cases. This report underscores the critical role of pathology in investigating potential bioterrorism events and in guiding epidemiological studies, a role that was clearly demonstrated in 2001 when B. anthracis spores were intentionally released through the United States postal system.

Job and industry classifications associated with sarcoidosis in a case-control etiologic study of sarcoidosis (ACCESS)

Objectives: Objective: To determine whether specific occupations and industries may be associated with sarcoidosis. Methods: A Case Control Etiologic Study of Sarcoidosis (ACCESS) obtained occupational and environmental histories on 706 newly diagnosed sarcoidosis cases and matched controls. We used Standard Industrial Classification (SIC) and Standard Occupational Classification (SOC) to assess occupational contributions to sarcoidosis risk. Results: Univariable analysis identified elevated risk of sarcoidosis for workers with industrial organic dust exposures, especially in Caucasian workers. Workers for suppliers of building materials, hardware, and gardening materials were at an increased risk of sarcoidosis as were educators. Work providing childcare was negatively associated with sarcoidosis risk. Jobs with metal dust or metal fume exposures were negatively associated with sarcoidosis risk, especially in Caucasian workers. Conclusions: In this study, we found that exposures in particular occupational settings may contribute to sarcoidosis risk.

Epidemiologic investigations of bioterrorism-related anthrax, New Jersey, 2001.

At least four Bacillus anthracis–containing envelopes destined for New York City and Washington, D.C., were processed at the Trenton Processing and Distribution Center (PDC) on September 18 and October 9, 2001. When cutaneous anthrax was confirmed in a Trenton postal worker, the PDC was closed. Four cutaneous and two inhalational anthrax cases were identified. Five patients were hospitalized; none died. Four were PDC employees; the others handled or received mail processed there. Onset dates occurred in two clusters following envelope processing at the PDC. The attack rate among the 170 employees present when the B. anthracis–containing letters were sorted on October 9 was 1.2%. Of 137 PDC environmental samples, 57 (42%) were positive. Five (10%) of 50 local post offices each yielded one positive sample. Cutaneous or inhalational anthrax developed in four postal employees at a facility where B. anthracis–containing letters were processed. Cross-contaminated mail or equipment was the likely source of infection in two other case-patients with cutaneous anthrax.

Relationship of environmental exposures to the clinical phenotype of sarcoidosis

STUDY OBJECTIVES Sarcoidosis is a granulomatous disorder with heterogeneous clinical manifestations, which are potentially reflective of a syndrome with different etiologies leading to similar histologic findings. We examined the relationship between environmental and occupational exposures, and the clinical phenotype of sarcoidosis. DESIGN We performed a cross-sectional study of incident sarcoidosis cases that had been identified by A Case Control Etiologic Study of Sarcoidosis. Subjects were categorized into the following two groups: (1) pulmonary-only disease; and (2) systemic disease (with or without pulmonary involvement). Logistic regression was used to examine the associations of candidate exposures with clinical phenotype. SETTING Ten academic medical centers across the United States. PATIENTS The current study included 718 subjects in whom sarcoidosis had been diagnosed within 6 months of study enrollment. Patients met the following criteria prior to enrollment: (1) tissue confirmation of noncaseating granulomas on tissue biopsy on one or more organs within 6 months of study enrollment with negative stains for acid-fast bacilli and fungus; (2) clinical signs or symptoms that were consistent with sarcoidosis; (3) no other obvious explanation for the granulomatous disease; and (4) age > 18 years. MEASUREMENTS AND RESULTS Several exposures were associated with significantly less likelihood of having extrapulmonary disease in multivariate analysis, including agricultural organic dusts and wood burning. The effects of many of these exposures were significantly different in patients of different self-defined race. CONCLUSIONS The differentiation of sarcoidosis subjects on the basis of clinical phenotypes suggests that these subgroups may have unique environmental exposure associations. Self-defined race may play a role in the determination of the effect of certain exposures on disease phenotypes.

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-β1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-β1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-β1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-β1 variants or haplotypes. The −509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the −509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the −509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the −509C and codon 10T, implicated in lower levels of TGF-β1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-β1, although future studies will be needed to correlate TGF-β1 protein levels with known TGF-β1 genotypes and assess whether there is a shared mechanisms for TGF-β1 in these two granulomatous diseases.

A preventable outbreak of pneumococcal pneumonia among unvaccinated nursing home residents in New Jersey during 2001.

OBJECTIVE To characterize risk factors for invasive pneumococcal infection in a nursing home outbreak. DESIGN Outbreak investigation, case-control study. SETTING A 114-bed nursing home in New Jersey. PARTICIPANTS Case-patients were nursing home residents hospitalized with febrile respiratory illness and radiographic findings consistent with pneumonia, and either sputum specimens positive for diplococci or blood cultures positive for Streptococcus pneumoniae, with illness onset during April 3-24, 2001. Control-patients were selected randomly from remaining residents without respiratory symptoms. METHODS Chart reviews were performed for case-patients and control-patients. Serotyping and susceptibility testing were performed on S. pneumoniae isolates. Long-term-care facilities (LTCFs) were surveyed to assess compliance with a state regulation mandating pneumococcal vaccination of residents 65 years and older. RESULTS Nine case-patients were identified, with a median age of 86 years (range, 78 to 100 years). The median age of control-patients was 86 years (range, 58 to 95 years). No case-patients versus 9 (50%) control-patients received pneumococcal vaccine before the outbreak (OR, 0; CI95, 0-0.7). Recent antibiotic use, pneumonia history, and physical functioning were not associated with illness. Illness attack rate was 16% among all unvaccinated residents versus 0 among vaccinated residents. S. pneumoniae serotype 14, included in pneumococcal vaccine, was isolated from blood cultures of 7 case-patients. Of 361 LTCFs (42%) that replied to the survey, 28 (8%) were not complying with state immunization regulations. CONCLUSIONS This outbreak occurred in an LTCF with low vaccine coverage. Implementing standing order programs, enforcing regulations, documenting vaccinations, and providing education might increase coverage among nursing home residents.

Possible Risk Factors for Sarcoidosis

Descriptions of sarcoidosis first appeared in the medical literature approximately 100 years ago.’ During the last 30 years, there have been many epidemiological studies of sarcoidosis that have demonstrated relatively few risk factors for this disease. Accepted facts include a higher incidence of sarcoidosis in the young adult, black population in the United States;*.-’ a clustering of disease in families; and an increased incidence in females. The etiology of the disease, however, remains unknown: Several groups of investigators have used the case-control method to either generate hypotheses or to test a specific hypothesis of an association between sarcoidosis and a suspected risk factor. In 1961, Comstock et aLS reported the results of a case-control study that was done to investigate potential etiologic factors for sarcoidosis. Although the study produced no definitive leads, the authors concluded that the case-control research design was a valid method to generate hypotheses concerning the etiology of sarcoidosis. Interestingly, Comstock et al..’ in the study cited above, observed that patients with sarcoidosis smoked less than matched controls. The observation persisted when

Surveillance for Anthrax Cases Associated with Contaminated Letters, New Jersey, Delaware, and Pennsylvania, 2001

In October 2001, two inhalational anthrax and four cutaneous anthrax cases, resulting from the processing of Bacillus anthracis–containing envelopes at a New Jersey mail facility, were identified. Subsequently, we initiated stimulated passive hospital-based and enhanced passive surveillance for anthrax-compatible syndromes. From October 24 to December 17, 2001, hospitals reported 240,160 visits and 7,109 intensive-care unit admissions in the surveillance area (population 6.7 million persons). Following a change to reporting criteria on November 8, the average of possible inhalational anthrax reports decreased 83% from 18 to 3 per day; the proportion of reports requiring follow-up increased from 37% (105/286) to 41% (47/116). Clinical follow-up was conducted on 214 of 464 possible inhalational anthrax patients and 98 possible cutaneous anthrax patients; 49 had additional laboratory testing. No additional cases were identified. To verify the limited scope of the outbreak, surveillance was essential, though labor-intensive. The flexibility of the system allowed interim evaluation, thus improving surveillance efficiency.