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PubMed2006

The weapon potential of human pathogenic fungi.

With the exception of Coccidioides spp., human pathogenic fungi are not found among lists of microbes with potential for biological warfare and bioterrorism against humans. However, many human pathogenic fungi are easily obtainable from the environment, are highly dispersible and can cause significant disease after inhalation with relatively low inocula. When the biological and pathogenic attributes of certain human pathogenic fungi are considered using a formula for calculating the relative weapon potential of a microbe it is as apparent that some organisms such as Coccidioides spp. are comparable to other microbes for which there is significant concern. Our analysis suggests that the current indifference to fungi as potential biological weapons against human populations is probably a perception engendered by their non-communicability, lack of history of use or development as biological weapons, and a relatively low incidence of symptomatic disease following natural infection. Awareness of the weapon potential of human pathogenic fungi is an important consideration for greater preparedness against the threat posed by biowarfare and bioterrorism.

Biological Warfare↗
PubMed2003

Protective immunity evoked against anthrax lethal toxin after a single intramuscular administration of an adenovirus-based vaccine encoding humanized protective antigen.

Because of the need to develop a vaccine to rapidly protect the civilian population in response to a bioterrorism attack with Bacillus anthracis, we designed AdsechPA, a replication-deficient human serotype 5 adenovirus encoding B. anthracis protective antigen (PA) with codons optimized for expression in mammalian cells. With a single intramuscular administration to mice of 10(9) particle units of AdsechPA, a dose that can be scaled to human use, anti-PA antibodies were evoked more rapidly and at a higher level than with a single administration of the new U.S. military recombinant PA/Alhydrogel vaccine. Importantly, AdsechPA afforded approximately 2.7-fold more protection than the recombinant PA vaccine against B. anthracis lethal toxin challenge 4 weeks after a single vaccination. Even at 11 days postvaccination, AdsechPA provided some survival benefit, whereas the rPA/Alhydrogel vaccine provided none. In the context that equivalent human doses of Ad vectors have already been demonstrated to be safe in humans, a single administration of AdsechPA may provide the means to rapidly protect the civilian population against B. anthracis in response to a bioterrorism attack.

Adenoviridae↗
PubMed2004

Diagnosing smallpox: would you know it if you saw it?

The intentional release of anthrax in the United States in 2001 and other recent acts of terrorism have highlighted the possibility of intentional release of smallpox by terrorists. Little is known about physicians' ability to diagnose smallpox, especially in the critical first days, when the potential for rapid control of transmission is greatest. During December 2002 and January 2003, primary care and emergency physicians at a large urban academic medical center were surveyed regarding the diagnosis and management of patients who present with vesicular rash illness. In addition to demographic and training-related questions, the questionnaire included items about perceived comfort in diagnosing and evaluating rashes, knowledge of the key differential diagnostic characteristics of chickenpox and smallpox, and the diagnostic interpretation of color photographs of patients with smallpox or chickenpox. Responses were summarized as a perceived comfort score, a differential diagnosis score, and a picture score. Of 266 eligible physicians, 178 (67%) responded. Of these, 95% thought clinicians need more education about bioterrorism; only 17% reported comfort in diagnosing smallpox. Although most physicians recognized pictures of smallpox and chickenpox, only 36% correctly answered 3 of 4 questions regarding differential diagnosis, an important aspect of identifying cases early. Those who were comfortable diagnosing rash illnesses had higher differential diagnosis scores. Strategies for bioterrorism-related training could take advantage of physicians' awareness of their own knowledge deficits.

Attitude of Health Personnel↗
PubMed2004

Risk of occupationally acquired illnesses from biological threat agents in unvaccinated laboratory workers.

Many vaccines for bioterrorism agents are investigational and therefore not available (outside of research protocol use) to all at-risk laboratory workers who have begun working with these agents as a result of increased interest in biodefense research. Illness surveillance data archived from the U.S. offensive biological warfare program (from 1943 to 1969) were reviewed to assess the impact of safety measures on disease prevention (including biosafety cabinets [BSCs]) before and after vaccine availability. Most laboratory-acquired infections from agents with higher infective doses (e.g., anthrax, glanders, and plague) were prevented with personal protective measures and safety training alone. Safety measures (including BSCs) without vaccination failed to sufficiently prevent illness from agents with lower infective doses in this high-risk research setting. Infections continued with tularemia (average 15/year), Venezuelan equine encephalitis (1.9/year), and Q fever (3.4/year) but decreased dramatically once vaccinations became available (average of 1, 0.6, and 0 infections per year, respectively). While laboratory-acquired infections are not expected to occur frequently in the current lower-risk biodefense research setting because of further improvements in biosafety equipment and changes in biosafety policies, the data help to define the inherent risks of working with the specific agents of bioterrorism. The data support the idea that research with these agents should be restricted to laboratories with experience in handling highly hazardous agents and where appropriate safety training and precautions can be implemented.

Biological Warfare↗
PubMed2005

Emerging and reemerging infectious diseases: the perpetual challenge.

Public health officials once suggested that it might someday be possible to "close the book" on the study and treatment of infectious diseases. However, it is now clear that endemic diseases as well as newly emerging ones (e.g., severe acute respiratory syndrome [SARS]), reemerging ones (e.g., West Nile virus), and even deliberately disseminated infectious diseases (e.g., anthrax from bioterrorism) continue to pose a substantial threat throughout the world. Over the past several decades, the global effort to identify and characterize infectious agents, decipher the underlying pathways by which they cause disease, and develop preventive measures and treatments for many of the world's most dangerous pathogens has helped control many endemic diseases. But despite considerable progress, infectious diseases continue to present significant challenges as new microbial threats emerge and reemerge. HIV/AIDS, malaria, tuberculosis, influenza, SARS, West Nile virus, Marburg virus, and bioterrorism are examples of some of the emerging and reemerging threats. In responding to these ongoing challenges, a new paradigm in countermeasure development is needed. In the past, U.S. government-sponsored biomedical researchers have focused on basic research and concept development, leaving product development to the pharmaceutical industry. Increasingly, however, the government has become involved in more targeted countermeasure development efforts. In this regard, partnerships between government, industry, and academia are necessary as we struggle to maintain and update our armamentarium in the struggle to outwit the microbes that pose a never-ending threat to mankind.

Biomedical Research↗
PubMed2005

Recognizing biothreat diseases: realistic training using standardized patients and patient simulators.

The UofL Center for the Deterrence of Biowarfare and Bioterrorism's (CDBB's) training involving standardized patients, who can make convincingly accurate representations of clinical signs and symptoms, and patient simulators has proven to be an effective means of enhancing bioterrorism preparedness. In addition to providing ready access to formative measures of preparedness, both of these teaching and learning tools also offer the option of summative evaluation of skills and knowledge acquired during training sessions. The use of moulage allows for very realistic representations of cutaneous anthrax and smallpox as well as other conditions such as recluse spider bites and chickenpox with which these biothreat infections can be confused. Exercises and drills expose deficiencies and permit essential reinforcement of skills developed in training. Unannounced exercises are especially useful in assessing public health preparedness.

Biological Warfare↗
PubMed2005

Worldwide disaster medical response: an historical perspective.

OBJECTIVE: Disaster medicine and disaster medical response is a complex and evolving field that has existed for millennia. The objective of this article is to provide a brief review of significant milestones in the history of disaster medicine with emphasis on applicability to present and future structures for disaster medical response. RESULTS: Disaster medical response is an historically necessary function in any society. These range from response to natural disasters, to the ravages of warfare, and most recently, to medical response after terrorist acts. Our current disaster response systems are largely predicated on military models derived over the last 200 yrs. Their hallmark is a structured and graded response system based on numbers of casualties. In general, all of these assume that there is an identifiable "ground zero" and then proceed with echelons of casualty retrieval and care that proceeds rearward to a hospital(s). In a civil response setting, most civilian models of disaster medical response similarly follow this military model. This historical approach may not be applicable to some threats such as bioterrorism. A "new" model of disaster medical response for this type of threat is still evolving. Using history to guide our future education and planning efforts is discussed. CONCLUSION: We can learn much from an historical perspective that is still applicable to many current disaster medical threats. However, a new response model may be needed to address the threats of bioterrorism.

Disaster Planning↗
PubMed2006

Morphologic, immunologic, and molecular methods to detect bacillus anthracis in formalin-fixed tissues.

Due to the importance of Bacillus anthracis as a cause of naturally occurring infection among humans and as an agent of bioterrorism, there is a vital need for rapid and specific assays, including immunohistochemistry (IHC) and polymerase chain reaction (PCR) assays, to detect the bacterium in formalin-fixed tissues. Colorimetric IHC assays were developed using a multistep indirect immunoalkaline phosphatase method with anti-B. anthracis cell wall (EAII-6G6-2-3) and anti-B. anthracis capsule (FDF-1B9) mAbs to detect B. anthracis antigens in formalin-fixed, paraffin-embedded bacterial cultures and tissues. B. anthracis antigens were localized, using both antibodies, in samples from B. anthracis-infected animals and humans. The colorimetric IHC assay with both antibodies was expedient in diagnosing the presence of B. anthracis in formalin-fixed, paraffin-embedded tissue from bioterrorism-associated cases of inhalational and cutaneous anthrax and from a case of naturally occurring cutaneous anthrax. Using the same antibodies, confocal microscopy demonstrated the structure of replicating B. anthracis in tissues. B. anthracis-specific primers were successfully used with PCR to amplify and detect B. anthracis sequences derived from formalin-fixed tissues of anthrax cases. In this study, morphologic, immunologic, and molecular assays were used to study and diagnose 22 veterinary and human anthrax cases.

Animals↗
PubMed2003

Surveillance of infectious disease occurrences in the community: an analysis of symptom presentation in the emergency department.

OBJECTIVES: To determine the effectiveness of a simulated emergency department (ED)-based surveillance system to detect infectious disease (ID) occurrences in the community. METHODS: Medical records of patients presenting to an urban ED between January 1, 1999, and December 31, 2000, were retrospectively reviewed for ICD-9 codes related to ID symptomatology. ICD-9 codes, categorized into viral, gastrointestinal, skin, fever, central nervous system (CNS), or pulmonary symptom clusters, were correlated with reportable infectious diseases identified by the local health department (HD). These reportable infectious diseases are designated class A diseases (CADs) by the Ohio Department of Health. Cross-correlation functions (CCFs) tested the temporal relationship between ED symptom presentation and HD identification of CADs. The 95% confidence interval for lack of trend correlation was 0.0 +/- 0.074; thus CCFs > 0.074 were considered significant for trend correlation. Further cross-correlation analysis was performed after chronic and non-community-acquirable infectious diseases were removed from the HD database as a model for bioterrorism surveillance. RESULTS: Fifteen thousand five hundred sixty-nine ED patients and 6,489 HD patients were identified. Six thousand two hundred eight occurrences of true CADs were identified. Only 87 (1.33%) HD cases were processed on weekends. During the study period, increased ED symptom presentation preceded increased HD identification of respective CADs by 24 hours for all symptom clusters combined (CCF = 0.112), gastrointestinal symptoms (CCF = 0.084), pulmonary symptoms (CCF = 0.110), and CNS symptoms (CCF = 0.125). The bioterrorism surveillance model revealed increased ED symptom presentation continued to precede increased HD identification of the respective CADs by 24 hours for all symptom clusters combined (CCF = 0.080), pulmonary symptoms (CCF = 0.100), and CNS symptoms (CCF = 0.120). CONCLUSIONS: Surveillance of ED symptom presentation has the potential to identify clinically important ID occurrences in the community 24 hours prior to HD identification. Lack of weekend HD data collection suggests that the ED is a more appropriate setting for real-time ID surveillance.

Central Nervous System Diseases↗
PubMed2003

Rickettsialpox in New York City: a persistent urban zoonosis.

Rickettsialpox, a spotted fever rickettsiosis, was first identified in New York City (NYC) in 1946. During the next five years, approximately 540 additional cases were identified in NYC. However, during the subsequent five decades, rickettsialpox received relatively little attention from clinicians and public health professionals, and reporting of the disease diminished markedly. During February 2001 through August 2002, 34 cases of rickettsialpox in NYC were confirmed at CDC from cutaneous biopsy specimens tested by using immunohistochemical (IHC) staining, PCR analysis, and isolation of Rickettsia akari in cell culture, as well as an indirect immunofluorescence assay of serum specimens. Samples were collected from patients with febrile illnesses accompanied by an eschar, a papulovesicular rash, or both. Patients originated predominantly from two boroughs (Manhattan and the Bronx). Only 8 (24%) of the cases were identified prior to the reports of bioterrorism-associated anthrax in the United States during October 2001, and lesions of several patients evaluated during and subsequent to this episode were suspected initially to be cutaneous anthrax. IHC staining of biopsy specimens of eschars and papular lesions were positive for spotted fever group rickettsiae for 32 patients. Of the eleven patients for whom paired serum samples were obtained, all demonstrated fourfold or greater increases in antibody titers reactive with R. akari. The 17-kDa protein gene sequence of R. akari was amplified from eschars of five patients. Four isolates of R. akari were obtained from cutaneous lesions. Possible factors responsible for the increase in clinical samples evaluated for rickettsialpox during this interval include renewed clinical interest in the disease, improved diagnostic methods, epizootiological influences, and factors associated with the recent specter of bioterrorism.

Animals↗
PubMed2006

[Synptons of outpatients as data for syndromic surveillance].

OBJECTIVE: To review complaints (such as fever, respiratory symptoms, diarrhea, vomiting, and rashes) in the medical records of outpatients as potential sources of data for syndromic surveillance, and to examine the possibility of practical application from a statistical view point. MATERIALS AND METHODS: Using data obtained from a certain internal and pediatric clinic, we count the number of patients each day who suffered from one of the above five symptoms from January 1st, 2003 to June 30th, 2005. In order to detect outbreaks prospectively after January 1st, 2005, we at first estimate the baseline using the data from January 1st, 2003 to the day before any given day. We then predict the number of patients there ought to be in any given day and judge whether or not an outbreak has occurred. So as to evaluate the system, we check the sensitivity and specificity in its ability to detect outbreaks other than those seen in previous patterns. RESULTS: The total number of cases in which each of the above symptoms occurred were respectively: 11,896 cases of fever, 16,273 cases of respiratory symptoms, 3,672 cases of diarrhea, 3,485 cases of vomiting, and 542 cases of rash. We found prolonged outbreaks of fever and respiratory symptoms in February and March and shorter outbreaks of vomiting and diarrhea in January. The sensitivity and specificity of this system' s ability to detect outbreaks was very high and thus we can confirm that it showed satisfactory performance. DISCUSSION: We found large-scale outbreaks of influenza late in the 2004/2005 season, and small outbreaks of GI that seemed to be particularly related to the Noro virus. In both cases, these outbreaks seemed to be natural phenomena, not artificial, human induced phenomena such as outbreaks caused by bioterrorism attacks. However, since this system was able to detect these outbreaks, we would also be able to use it to detect an outbreak caused by a bioterrorism attack if the size of the outbreak was similar to these cases. CONCLUSION: In order to use this system to detect outbreaks in the community on a smaller level we would have to increase the number of medical institutions cooperating in this study. Moreover, we would need to find a way to handle the different electronic medical record systems and different writing styles used by different medical institutions in order to move toward the practical use of Syndromic Surveillance.

Child↗
PubMed2005

Effective antimicrobial regimens for use in humans for therapy of Bacillus anthracis infections and postexposure prophylaxis.

Expanded options for treatments directed against pathogens that can be used for bioterrorism are urgently needed. Treatment regimens directed against such pathogens can be identified only by using data derived from in vitro and animal studies. It is crucial that these studies reliably predict the efficacy of proposed treatments in humans. The objective of this study was to identify a levofloxacin treatment regimen that will serve as an effective therapy for Bacillus anthracis infections and postexposure prophylaxis. An in vitro hollow-fiber infection model that replicates the pharmacokinetic profile of levofloxacin observed in humans (half-life [t(1/2)], 7.5 h) or in animals, such as the mouse or the rhesus monkey (t(1/2), approximately 2 h), was used to evaluate a proposed indication for levofloxacin (500 mg once daily) for the treatment of Bacillus anthracis infections. The results obtained with the in vitro model served as the basis for the doses and the dose schedules that were evaluated in the mouse inhalational anthrax model. The effects of levofloxacin and ciprofloxacin treatment were compared to those of no treatment (untreated controls). The main outcome measure in the in vitro hollow-fiber infection model was a persistent reduction of culture density (> or = 4 log10 reduction) and prevention of the emergence of levofloxacin-resistant organisms. In the mouse inhalational anthrax model the main outcome measure was survival. The results indicated that levofloxacin given once daily with simulated human pharmacokinetics effectively sterilized Bacillus anthracis cultures. By using a simulated animal pharmacokinetic profile, a once-daily dosing regimen that provided a human-equivalent exposure failed to sterilize the cultures. Dosing regimens that "partially humanized" levofloxacin exposures within the constraints of animal pharmacokinetics reproduced the antimicrobial efficacy seen with human pharmacokinetics. In a mouse inhalational anthrax model, once-daily dosing was significantly inferior (survival end point) to regimens of dosing every 12 h or every 6 h with identical total daily levofloxacin doses. These results demonstrate the predictive value of the in vitro hollow-fiber infection model with respect to the success or the failure of treatment regimens in animals. Furthermore, the model permits the evaluation of treatment regimens that "humanize" antibiotic exposures in animal models, enhancing the confidence with which animal models may be used to reliably predict the efficacies of proposed antibiotic treatments in humans in situations (e.g., the release of pathogens as agents of bioterrorism or emerging infectious diseases) where human trials cannot be performed. A treatment regimen effective in rhesus monkeys was identified.

Animals↗
PubMedDate not supplied

Smallpox-related knowledge and beliefs among recent college graduates.

UNLABELLED: Recent world events have increased concern and preparations for possible bioterror events. Despite worldwide efforts to limit access to bio-weapons, smallpox is still considered a potential bioterror threat. Americans' understanding of smallpox could prevent panic and enhance the willingness of citizens to receive vaccinations. OBJECTIVE: The authors' purpose in this study was to describe graduating college students' levels of smallpox-related knowledge. METHOD SUMMARY: Participants at a graduation ceremony--mostly female, with a mean age of 28.4+/-8.1 years--were handed a 35-item questionnaire that assessed smallpox knowledge and whether respondents would submit to vaccination under hypothetical circumstances. RESULTS: The convenience sample was ignorant of numerous facts about smallpox and unaware of government efforts to prepare for an attack, answering an average of 3.8 out of 10 items correctly. CONCLUSION: These findings raise concern because, in a smallpox event, prompt responses to directives of public health officials will be necessary to maximize the effectiveness of response plans.

Adolescent↗
PubMed2002

Sequencing of 16S rRNA gene: a rapid tool for identification of Bacillus anthracis.

In a bioterrorism event, a tool is needed to rapidly differentiate Bacillus anthracis from other closely related spore-forming Bacillus species. During the recent outbreak of bioterrorism-associated anthrax, we sequenced the 16S rRNA generom these species to evaluate the potential of 16S rRNA gene sequencing as a diagnostic tool. We found eight distinct 16S types among all 107 16S rRNA gene seqs fuences that differed from each other at 1 to 8 positions (0.06% to 0.5%). All 86 B. anthracis had an identical 16S gene sequence, designated type 6; 16S type 10 was seen in all B. thuringiensis strains; six other 16S types were found among the 10 B. cereus strains. This report describes the first demonstration of an exclusive association of a distinct 16S sequence with B. anthracis. Consequently, we were able to rapidly identify suspected isolates and to detect the B. anthracis 16S rRNA gene directly from culture-negative clinical specimens from seven patients with laboratory-confirmed anthrax.

Anthrax↗
PubMed2004

Clostridium botulinum and the clinical laboratorian: a detailed review of botulism, including biological warfare ramifications of botulinum toxin.

OBJECTIVE: This review article is designed to thoroughly familiarize all health care professionals with the history, classification, epidemiology, clinical characteristics, differential diagnosis, diagnostic evaluation (including laboratory-based testing), treatment, and prognosis of botulism. It is especially targeted toward clinical laboratorians and includes a detailed enumeration of the important clinical laboratory contributions to the diagnosis, treatment, and monitoring of patients with botulism. Finally, the bioterrorism potential for botulism is discussed, with an emphasis on the clinical laboratory ramifications of this possibility. DATA SOURCES: Included medical periodicals and textbooks accessioned from computerized and manual medical literature searches. More than 1000 medical works published from the 1800s through 2003 were retrieved and reviewed in this process. DATA SYNTHESIS: Pertinent data are presented in textual and tabular formats, the latter including 6 tables presenting detailed information regarding the clinical parameters, differential diagnosis, diagnostic studies, laboratory testing, and therapeutic approaches to botulism. CONCLUSIONS: Because botulism is such a rare disease, a keen awareness of its manifestations and prompt diagnosis are absolutely crucial for its successful treatment. The bioterrorism potential of botulism adds further urgency to the need for all health care professionals to be familiar with this disease, its proper evaluation, and timely treatment; the need for such urgency clearly includes the clinical laboratory.

Biological Warfare↗
PubMed2001

Applying molecular biological techniques to detecting biological agents.

Recent efforts in the civilian and military health care and public health communities are directed at strengthening surveillance systems and our national laboratory capabilities for early detection of infectious disease outbreaks. These new systems will address proper specimen collection, transport, nucleic acid processing, molecular assay diagnostic reagent and equipment development, and standardization for sensitive and rapid detection of bioagents in blood and other clinical samples. A greater understanding of the genetic diversity and virulence factors for each organism that could be used for bioterrorism would aid design of rapid molecular detection strategies. Combinations of appropriate diagnostic technologies (culture, immunoassay, and molecular assay) can provide rapid diagnostic response capabilities to microbial threats with antimicrobial resistant organisms, new emerging infectious disease agents, and possible agents of bioterrorism.

Animals↗
PubMed2002

Symptoms associated with anthrax exposure: suspected "aborted" anthrax.

Anthrax is a naturally occurring organism with a low incidence of infection. There are no known cases of human-to-human transmission. Bioterrorism-related anthrax in the United States has been seen in three high-risk groups: (1) postal workers, (2) politicians and their staffs, and (3) the press. It appears as though the bioterrorism-related anthrax cases of fall 2001 have been transmitted through the US Postal Service. The authors present a case in which a person at high risk for anthrax exposure was inadequately treated and had symptoms that do not fall into any specific category of disease. It emphasizes the need for someone who has been started on prophylaxis for anthrax to complete a full 60-day course of treatment. It also shows the effectiveness of antibiotic therapy, even in those with high exposure to weaponized anthrax. Further, we would like to suggest that there may exist a new clinical entity of "aborted anthrax infection."

Adult↗
PubMed2004

Mass sociogenic illness--real and imaginary.

Mass sociogenic illness is the occurrence of a group of nonspecific physical symptoms for which no organic cause can be determined and is often transmitted by 'line of sight'. The fear of bioterrorism can also lead to panic and produce cases of mass sociogenic illness, in which people develop symptoms in response to an imaginary threat. Poison centers are faced with resolving the dilemma of sociogenic vs poison related symptoms. We report 2 situations of mass sociogenic illnesses involving school age children where multiple victims exhibited similar symptoms prompted by the presence or suggestion of fumes. Symptoms resolved spontaneously. When clusters of unexplained illness occur, a sociogenic etiology should be considered in the differential diagnosis. As fears about bioterrorism increase, the frequency of such incidents and the anxiety generated may increase.

Child↗