key: cord-0008168-lcvvtt0m
authors: Weber, Stephen G; Bottei, Ed; Cook, Richard; O'Connor, Michael
title: SARS, emerging infections, and bioterrorism preparedness
date: 2004-07-30
journal: Lancet Infect Dis
DOI: 10.1016/s1473-3099(04)01098-9
sha: 1a80dc0003f1cfb59d3ade7fce22dfcdbf80af70
doc_id: 8168
cord_uid: lcvvtt0m

nan

Infectious Diseases Vol 4 August 2004 http://infection.thelancet.com

The response to the 2002-03 outbreak of severe acute respiratory syndrome (SARS), although effective, was hindered by initial confusion about the identity of the causative pathogen, 1 uncertainty about the epidemiology of transmission and spread, 2 and difficulties with the flow of information owing to political rivalries. 3 Recurrence of the SARS epidemic in Toronto highlighted the potential difficulties of containing similar outbreaks of unfamiliar and highly contagious organisms. 4 Naturally occurring diseases such as SARS offer valuable lessons in preparation for a deliberate release of biological agents by terrorists. But there is a darker side to the relation between naturally emerging infections and bioterrorism. Whereas clinicians and policy makers view diseases like SARS as public-health threats, terrorists could see them as weapons of opportunity.

SARS-associated coronavirus has several features that could be uniquely attractive to those seeking a biological weapon (table) . The SARS pathogen is highly contagious. Of the healthcare workers who had unprotected exposure to the initial SARS cases in Asia, more than 50% became ill. 5 If SARS was released within a susceptible population, it could proliferate extensively before containment measures were implemented. A well-defined geographical distribution of cases was integral to the identification of suspect SARS cases in the 2002-03 outbreak. Wider distribution could delay identification, making it difficult to control the spread of infection.

Lethality also makes SARS coronavirus a viable bioterrorism agent. The mortality rate from SARS during the 2002-03 epidemic exceeded 40% in elderly and debilitated people. 6 SARS also killed people who were young and otherwise healthy. The demographic profile of healthcare workers who died of SARS is comparable to that of military personnel. Therefore, SARS coronavirus has the potential to be employed as a weapon targeted at military units. Moreover the prolonged convalescence of those who survive SARS infection would further strain the resources of the nation or military units attacked. 7 Unlike smallpox, access to SARS coronavirus is not heavily restricted; it is conceivable that the virus could be obtained from the wild. Many deaths from SARS during the 2002-03 epidemic were in parts of the world where security of the remains is not guaranteed. As a result, several nations have access to specimens from which large quantities of SARS coronavirus could be cultivated. Furthermore, the virus could be obtained from the animal species that seem to be its natural reservoirs.

The most alarming feature of SARS coronavirus as a potential bioweapon is perhaps the difficulty in detecting an attack. No clinical, radiographic, or laboratory feature easily distinguishes SARS from other respiratory infections. So an attack coinciding with the influenza season may not be detected until after widespread transmission has taken place. Detection of the epidemic of 2002-03 was helped by a limited geographical distribution, which was the result of the outward spread of the virus from a single focus. By contrast, a deliberate attack would likely be designed to spread the virus and would result in proliferation of new cases over a wide area. As such, the opportunity to contain the epidemic and to follow a forensic trail to identify those responsible would likely be lost.

The resources devoted to understanding SARS and preventing another natural epidemic have been generous and seemingly effective. Preventing a deliberate epidemic will be more difficult. In addition to developing improved treatments and containment strategies for SARS, the factors that make SARS coronavirus a potential bioweapon must be addressed.

Access to specimens from which SARS coronavirus and other emerging pathogens can be isolated and made into weapons should be limited. Proper documentation and a secure chain of custody, lacking from most healthcare settings and absent from many preparedness plans, must be strengthened and applied to clinical samples, sick patients, and the remains of those who have died. Such measures will complement efforts to reduce the likelihood of laboratory accidents involving SARS coronavirus. 8 It may also be time to reconsider current standards for sharing technical information about emerging pathogens. Although dissemination of the genetic sequence of SARS coronavirus could advance research on countermeasures, it could also help those who intend harm. Greater accountability for access to such information is needed. The scientific and clinical communities should direct the structure and application of such regulations.

Current systems intended to detect the onset of naturally emerging infections may be of limited use for detecting the deliberate spread of SARS coronavirus and similar agents, and must be strengthened-for example, automated detectors of airborne pathogens may not identify human carriers intentionally infected with SARS coronavirus. Likewise, syndromic surveillance could miss the clues that an attack with SARS coronavirus is underway, especially if surveillance is limited in scope or not deployed near the location of the attack. 9 Notably, the US anthrax attack was not recognised through elaborate sensors or surveillance networks but through the meticulous attention of a single clinician. Wide distribution of a validated, rapid diagnostic assay for the detection of SARS coronavirus in patients with a suspicious clinical syndrome will be a critical aid to detecting an attack. 

Studies on ancient DNA indicate that Yersinia pestis was the cause of Black Death. Like others, 1-3 we disagree with this conclusion. There are many problems with palaeogenetic research that make interpretation of the available, but scarce, DNA data difficult. 2, 4, 5 To address the contribution of Y pestis in the pandemics of the past millennium, we looked for parts of the yersinial proteome (via F1 antigen test) rather than the genome (via PCR) in old specimens.

Suzanne Chanteau and coworkers have developed a specific and sensitive method of detecting the Y pestis-specific fraction 1-capsular antigen in a variety of fresh sample materials. [6] [7] [8] Their plague test uses a hand-held immunochromatographic dipstick assay and is a milestone in diagnostic epidemiology. 6 We tested for Y pestis in 17th century skeletal remains by PCR, Southern blotting, and radioactive hybridisation techniques-molecular genetic techniques that provide specificity and sensitivity-and compared these results with those obtained with the dipstick assay.

The samples used were from a charnel house from the municipal church of St Germanus, Stuttgart, Germany. They are thought to be from people who died from the plague and those who were not affected by it. 9 ,10 This region experienced several plague epidemics in 1348-49, 1502, 1574, 1626, 1634-39, 1650, and 1676-78. 11 The 17th century epidemics correlate with distinct layers in the chamber, easily identifiable by their "disinfection" with lime [CaO/Ca(OH) 2 /CaCO 3 ].

Samples were removed from 24 skeletons: 12 from people who died from Black Death (exposed to lime) and 12 from controls (not exposed to lime). DNA extraction and purification was done on these samples. 12 Pooled extracts were used for PCR amplification of Y pestis DNA, with specific primers recognising a 93 bp fragment of the caf1 gene (pFra/pMT1) that encodes the Y pestis capsular F1 antigen. Y pestisspecific amplicons were detected after Southern blotting and filter hybridisation to radioactively labelled Y pestis oligoprobes (figure).

The dipstick assay was better than the molecular genetic approach. Whereas only two of 12 samples from people thought to have died from the plague were positively identified by the genetic assay (specimen numbers five and seven), ten of these were positive in the dipstick assay (including specimen numbers five and seven, figure) . The 12 control samples were negative with both methods of assay. In summary, PCR was successful in only two cases, suggesting that in 83% of samples the PCR reactions started from less template molecules than is needed for positive identification. 5, 6 This finding is probably the result of several factors: PCR inhibition by co-extracted soil components or degraded collagen, the minute amounts of nucleic acids and high degree of fragmentation of the old DNA in the samples (our attempts to amplify larger caf1 PCR products failed), chemical modification of the nucleic acids, and severe DNA denaturation by alkaline treatment with lime. 5, 10, 13 The poor state of sample preservation is confirmed by the high degree of racemisation of aspartic acid (D/L ratio higher than 0·08) 14 and depleted aminoacid content (14% compared with modern bone). Nevertheless, the amount of F1 antigen in our positive samples was about 1·0 ng/mL. So the 0·5 ng/mL detection threshold of the dipstick is sufficient for a Plague diagnosis in ancient specimens. Samples from people who died from Black Death were examined by PCR and Southern hybridisation as well as the dipstick assay. Location of PCR primers (arrows) and caf1 segment targeted by the Southern probe (grey) are shown. +=positive result. iC=internal control of the dipsticks. F1 antigen detection was done according to standard protocols. 6, 12 

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Politics hindering SARS work

Update: severe acute respiratory syndrome-Toronto, Canada

Outbreak of severe acute respiratory syndromeworldwide

Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong

SARS attacks, China shudders

Dangerous pathogens in the laboratory: from smallpox to today's SARS setbacks and tomorrow's polio-free world

Accuracy of a local surveillance system for early detection of emerging infectious disease