Summary: Clued In: Review and Analysis of Carbones Book

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This action might not be possible to undo. Are you sure you want to continue? Upload Sign In Join. They observed an increase in FRAP and a correlated increase in plasma urate levels, leading them to speculate that fructose-mediated urate production might account for their observations. A recent animal study indicated that AP are potentially important in counteracting dietary prooxidants. Pigs were fed a prooxidant diet, high in PUFA linseed oil with or without concurrent fresh apples for 22 d and then tested for several markers of oxidative damage.

Apple feeding significantly reduced the concentration of the oxidative marker MDA in urine to levels lower than those in healthy control animals. Apple intake also reduced DNA damage in mononuclear blood cells, an effect the investigators proposed was likely mediated by antioxidant mechanisms. Feeding trials are important in illustrating in vivo effects of AP and there are convincing data that AP intake is associated with improved antioxidant capacity in plasma and other tissues. However, it is still not fully understood which components mediate the observed effects.

Whereas it has been argued that the low bioavailability of most flavonoids results in plasma concentrations that are well below the levels needed to exert antioxidant effects 41 , others attribute the antioxidant capacity of fruit, including AP, to the flavonoid content, particularly the high procyanidin levels. Several studies, summarized below, have attempted to elucidate specific antioxidant components in AP using in vitro assays.

An extensive analysis of phytochemical metabolites in apple was reported by Cefarelli et al. All of the isolated compounds, including newly characterized triterpenes, had antioxidant activity at various levels. The authors provided a detailed analysis of the association between compound structure and related antioxidant potential using TBARS, autooxidation of methyl linoleate, and scavenging of radicals including 2,2-diphenylpicrylhydrazyl hydrate, H 2 O 2 , and NO.

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Others have worked to characterize the effects of individual compounds known to be present in AP. Individual phytochemicals, including rutin, chlorogenic acid, and caffeic acid, were all effective, with some reconstituted mixtures being more effective than the original, in terms of antioxidant capacity and reducing DNA damage The most effective compounds on all antioxidative parameters included quercetin and phloretin.

In a follow-up study, the above investigators developed reconstituted mixtures including 5 major apple-derived compounds to determine the relative antioxidant contribution of selected polyphenolics The range of the isolated compounds with demonstrated activity was comparable to levels observed in human plasma in feeding trials. It has been suggested that the aglycone form of flavonoids i. This is of importance, because many flavonoids and dihydrocalchones are present in intact plant foods as glycosides with saccharide residues, but during processing and storage hydrolysis occurs, leading to the aglycone form.

However, the authors suggest that more work remains to fully understand the effects of hydrolysis on antioxidant capacity in AP. A variety of in vitro systems have been used to test AP extracts for potential antioxidant capacity and the results of these studies have been variable. It has been proposed that assessment of total oxidant scavenging activity might overcome the inconsistencies observed in other assays. Lichtenthaler et al. Commercial apple juice in Germany was tested among other fruit juices. The results showed that apple juice was a fairly effective antioxidant compared to other juices against some ROS peroxyl and hydroxyl radicals but less effective against peroxynitrite.

The authors are among the few to address the potential importance of pH in flavonoid-mediated activity. Studies aimed at ranking in vitro antioxidant capacity of AP have been inconsistent as have those of other fruits and vegetables; some investigations rank antioxidant capacity as relatively poor, whereas others report good antioxidant activity compared to other fruits There is also inconsistency in the correlation between in vitro outcomes and in vivo antioxidant activity mediated by AP. The variability might be attributed in part to the many types of apples and apple components studied in addition to varied reaction conditions, including pH, concentration, types of ROS, and other study conditions.

It has been proposed that an integrated approach incorporating antioxidant capacity values from several different assays in a validated statistical model might provide a more accurate assessment of the relative antioxidant capacity of foods Several ranking studies have been completed and the pros and cons of chemical methods used to assess in vitro antioxidant activity of fruits and vegetables have been debated and will not be reviewed here. Further investigation of the in vivo effects of AP as well as other sources of antioxidants relative to antioxidant status is relevant and warranted.

Elevated lipids and aberrations in lipid metabolism are well-established risk factors for many types of cardiovascular disease. Research in animals allows for detailed analyses of the effect of AP on lipid parameters beyond simply measuring lipid levels in plasma. A recent study in hamsters evaluated the effects of adding daily apples and apple juice pressed from fresh apples to an atherogenic diet on lipids, oxidative markers, and early aortic lesions The calculated intake of phenols was comparable to dietary intake in humans mg in apple group; mg in apple juice group.

Ogino et al. The authors concluded that the high procyanidin content and metabolites in the apple extract might directly interfere with cholesterol absorption in addition to modulating lipids and lipid-related processes. In vitro work in cultured human intestinal cells suggested that AP may directly alter lipid absorption and metabolism It was found that the accumulation of esterified cholesterol decreased and the secretion of apo-B B and B containing lipoproteins was reduced.

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Similar results were found in cells exposed to an enriched extract of procyanidins flavanols, catechin, and epicatechin. If these findings are applicable to the in vivo situation, altered intestinal lipid secretion might account for the lipid-lowering effect of AP observed in some studies and suggest one possible mechanism for reduced risk of cardiovascular disease.

The prevalence of pulmonary disorders, particularly asthma, has been increasing over the past several decades worldwide It is speculated that environmental and lifestyle factors, such as reduced intake of dietary antioxidants, are contributing to the rise It is thought that lungs are particularly susceptible to oxidative damage due to high and continual exposure to oxygen. Oxidant stress also activates inflammatory mediators that induce asthma in experimental models and appears to be important in the etiology of asthma in humans AP might be protective because of their antioxidant potential and phytochemical content.

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Early research described an inverse association between AP consumption and asthma and chronic obstructive pulmonary disease, including bronchitis and emphysema, as well as a general benefit to ventilatory function in healthy individuals as reviewed in 1. Recent data support these findings, particularly those related to asthma. A new report using data from the French branch of the European Prospective Investigation into Cancer and Nutrition trial provided evidence of a link between apple intake and reduced asthma prevalence in a sample of 68, adult women, mostly teachers, enrolled in a national health insurance plan Validated FFQ including food items and photographic prompts were used to determine dietary intake and categorize food into quartiles.

Diagnosed asthma, on the basis of self-reported data using validated questionnaires, was present in 3.

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Women in the highest quartile of apple intake compared to the lowest quartile had a significantly lower incidence of asthma. Although this effect was less robust after adjustment for intake of other fruits and vegetables, the association remained. Other reports have indicated that apple intake is associated with reduced risk of asthma and related symptoms. Investigators in the laboratory of Shaheen et al. The goal of the follow-up study was to determine if flavonoid content of apples accounted for the observed improvement in outcomes related to asthma.

More than adult participants in a case-control study of dietary antioxidants and asthma in the UK completed FFQ for assessment of daily intake of 3 major classes of flavonoids, including flavonols, flavones, and catechins. There was no statistical association between reduced asthma or asthma severity and any of the flavonoids examined, inferring that compounds other than those studied must be attributed to the observed reduction in risk of asthma.

Several investigators have proposed that unknown compounds beyond those currently examined and characterized in AP might account for improved health and be linked to reduced risk of disease. In a separate study, Shaheen et al. An intriguing report published in involved studying the association between maternal diet and the presence of asthma and respiratory symptoms in offspring 5 y later A self-administered FFQ was used to assess maternal diet at 32 wk of gestation.

The association persisted even after correction for other factors, including childhood diet and lifestyle variables. Among the various foods studied, apples were the only individual fruit associated with the protective association. Although data relating AP intake to reduced risk of asthma are provocative, there are some inconsistent reports. One study published by a different group in did not find an association between fruit intake reported in a semiquantitative FFQ and several endpoints related to diagnosed asthma in Dutch children A case-control study from the UK also did not show a protective effect of apples on risk of developing asthma In this study, adults with diagnosed asthma were compared to controls using dietary assessment by a 6-d food diary and h recall.

Although apples and citrus were collectively associated with reduced risk of diagnosed asthma, adjustment for citrus eliminated the significance of the effect of apples. There is growing evidence that dietary variables may be related to cognitive decline in normal aging and also influence the risk and course of neurodegenerative diseases of aging. A series of recent studies from the laboratory of Shea et al. This group developed a standardized mouse model of neurodegeneration in which aged mice exhibit impaired cognitive performance and increased oxidative parameters in brain tissue when subjected to a prooxidant diet deficient in vitamin E and folate; high in iron.

However, when these mice received apple juice concentrate diluted in drinking water 0. Additional work from this laboratory using mice with genetically induced oxidative stress an ApoE-deficient strain showed that 1 mo of apple juice concentrate intake reduced the accumulation of ROS in brain tissue and attenuated cognitive impairment 60 , Further examination demonstrated that apple juice intake reduced a compensatory increase in the endogenous antioxidant glutathione, suggesting that the antioxidant activity of apple juice accounts in part for the observed protective effects in animals subject to dietary and genetic oxidative stress and a potential neuroprotective effect of AP under these conditions Investigations with this model have provided important clues that mechanisms of neuroprotection may extend beyond antioxidant effects.

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In particular, apple juice concentrate prevents the characteristic decline in acetylcholine associated with aging and oxidative stress Because cholinergic depletion is associated with impaired memory and reduced cognitive performance, and acetylcholine reduction in particular is associated with Alzheimer's disease, there is potential importance in the ability of apple juice to maintain levels of this neurotransmitter. Shea et al. A research group in Italy studied the effects of 10 wk of fresh apple intake in aged rats They found that apple consumption reduced anxious behavior in rats in elevated maze tests and restored synaptic function long-term potentiation to the level of younger animals.

In addition, apple intake was associated with reduction in SOD elevation in the hippocampus of aged rats, suggesting that apples provide antioxidant protection that mitigates the predicted compensatory elevation of enzymes associated with aging. These data support the potential of antioxidant activity to improve markers related to behavioral changes associated with the aging process. The incidence of diabetes, chiefly type 2 diabetes, has increased dramatically and is the subject of intensive study around the world.

New data have suggested a possible link between AP consumption and reduced risk of diabetes. In a large ongoing trial, the Women's Health Study, semiquantitative FFQ were analyzed to determine if dietary flavonoid intake was associated with risk of diabetes and related markers of insulin resistance and inflammation Apples were identified as the only flavonoid-rich food that might be protective. Inflammatory markers and insulin resistance were not affected by any dietary components.

The authors of this study also searched for an association between total flavonol and flavone intake and a limited number of subtypes of these flavonoids 5 total and reduced risk. The protective effect of AP was not associated with any of these, leading the authors to speculate that other unrecognized compounds, including catechins, may have accounted for the link. It is not known whether this is important under physiologic conditions, but it is an interesting mechanism by which AP might be related to glucose control in diabetes.

Current guidelines recommend daily consumption of foods that are a good source of dietary fiber and low in energy density to promote healthy weight maintenance or weight loss. Based on this premise, a study was conducted in Brazil on 49 overweight women with high blood cholesterol levels to determine the effect of fruit intake on blood lipids and body weight All 3 groups were matched for the additional dietary fiber provided by each of the treatments. Results of the study were presented in 2 reports, the most recent in The authors proposed that the weight loss was due in part to the significant decrease in energy density of the diet due to the addition of apples compared to the oat cookies in spite of the comparable fiber content of the two.

The strengths of this diet study included the use of whole fruits rather than extracts in addition to the easily achievable energy level of the weight loss regime and the involvement of a registered dietitian to implement the diet. As such, it would be inaccurate to conclusively state that apples alone induce weight loss on the basis of this study. However, it is plausible that the low-energy density and fiber content of apples make them effective in weight reduction diets. Thus, apples may be potentially important in weight-related disorders. The loss of bone mass is associated with osteoporosis and is viewed by some as a global epidemic.

An estimated 10 million Americans over age 50 y have osteoporosis and another 34 million are at risk It is estimated that 1. Fruits and vegetables provide nutrients that are thought to be associated with improved bone health vitamin C, potassium, magnesium, and vitamin K in addition to producing alkaline metabolites that might improve bone health by reducing calcium excretion Intake of fruits and vegetables is associated with improvement in bone mineral density and other bone markers in epidemiologic studies Only a few studies have examined AP but preliminary observations suggest that AP may have a positive impact on markers related to bone health.

In a cross-over study, 15 healthy female participants 19—50 y mean The test meals were adjusted to provide comparable macronutrients. The fresh peeled apple meal included g of unpeeled apple plus a protein drink and 53 g of candy; the applesauce test meal included An analysis of urinary samples collected postconsumption at 1.

Another study of AP was conducted in ovariectomized rats subjected to inflammation as a physiologic model of the postmenopausal state in humans It has been shown that the estrogen decline associated with menopause is linked to increased production of inflammatory mediators within the bone microenvironment. The rats were provided phloridzin, a flavonoid isolated from apple wood in this study but also present in apples, particularly the peel.

After 80 d of treatment, it was found that phloridzin intake improved femoral bone mineral density and markers of bone turnover. An indirect outcome of inflammation splenomegaly was also reduced in the groups taking the phloridzin. This study focused on a single concentration of one isolated compound; an expansion of work with this model using a wider range of concentrations and varied phytochemicals would be of interest.

A few studies have evaluated the potential of AP to prevent or reduce injury to gastric mucosa by drugs In a combined investigation using cell and animal models to mimic nonsteroidal antiinflammatory drug injury, cultured gastric epithelial cells MKN 28 from a human gastric tubular adenocarcinoma were exposed to oxidative stress via 2- to 3-h exposure to xanthine oxidase and live rats were subjected to indomethacin, each with or without treatment with phenolic-rich extracts of freeze-dried apple flesh only.

The fraction highest in catechin also protected cells from oxidative damage in a dose-dependent manner with a maximal protective effect at 3 h. The protective effect was associated with a corresponding increase in antioxidant activity and reduced lipid peroxidation per measurement of MDA. Very preliminary in vitro evidence indicates that compounds from AP could be protective against gastric ulcer.

Carotenoid extracts from apple peel were effective against H. Another in vitro study with AP demonstrated that there may be other beneficial effects to gastrointestinal health by an alternate mechanism of reducing risk of mutagenesis in gastric cancer Extracts of apple pulp were shown to release NO from human saliva under acidic conditions, prompting the authors to propose a possible gastroprotective role of AP in mediating and scavenging of nitrogen oxides.

The current report focused on studies published since the last review of AP and health in 1. The reviewed studies do not prove cause and effect and further work remains to be done. However, there are convincing data suggesting an association between AP and reduced risk of major diseases and indicating multiple plausible mechanisms by which AP might be protective in humans. Many recent studies demonstrate a beneficial effect of AP on critical processes in the etiology of disease at the metabolic and cellular level. There are current data suggesting that AP might be linked to reduced risk of several forms of cancer, cardiovascular disease, and asthma.

AP may also have beneficial effects on outcomes related to Alzheimer's disease, cognitive decline of normal aging, diabetes, weight management, bone health, and gastrointestinal protection from drug injury. The antioxidant mechanisms described in many studies have important implications for a protective effect of AP on not only cancer but also cardiovascular disease, Alzheimer's disease, asthma, and potentially diabetes.

However, there are provocative data suggesting that mechanisms beyond antioxidant effects are important, including suppression of neurotoxic mediators in Alzheimer's disease. Daily updates posted on the WHO website for travelers and the public sought to counter rumors with reliable information. CDC, which spearheaded the U. In addition, it provided an arena for discussions relevant to both biomedical research and disease control, and it monitored the economic impact of SARS in its member countries, which comprise 2.

While many aspects of the public health response to SARS benefited from such technological developments as global broadband telecommunications, the containment of the epidemic ultimately depended on the venerable strategies of identifying and isolating persons who fit the case definition and tracing and quarantining their contacts. In countries such as Vietnam and Singapore, where these measures were imposed soon after the identification of index cases, the chain of infection was broken quickly.

March 31, Hong Kong health authorities issue quarantine order requiring some residents of the Amoy Gardens apartment complex to remain in their homes until April 9. Only in high-risk settings such as health care facilities or airline flights carrying passengers exposed to SARS-infected individuals did CDC suggest the use of quarantine by definition, the isolation of asymptomatic individuals believed to have been exposed to a contagion.

In the absence of an outbreak, the agency directed its efforts toward informing the traveling public about high-risk areas, issuing travel advisories, distributing millions of health alert notices in seven languages at airports and U. However, several other countries quarantined travelers arriving from SARS-affected areas. The relative effectiveness of various strategies applied to SARS containment—the use of standardized case definitions and laboratory testing to identify the infected, the isolation of ill persons, and the quarantine of contacts—remains to be determined.

Based on the present understanding that asymptomatic infected individuals transmit SARS at a low rate, if at all WHO, j , and that transmission occurs primarily through contact with ill individuals, workshop participants suggested that quarantine of contacts was the least effective of these strategies. However, they also recognized that quarantine could facilitate the containment of a SARS-like disease by reducing the number of contacts by infected individuals during the delay between the onset of symptoms and diagnosis.

This would be particularly effective when, as in the case of SARS, symptoms are nondescript and difficult to distinguish from those of other illnesses. It was also emphasized that quarantine should not be viewed as an impermeable cordon sanitaire confining those at risk for illness with the known ill, but as a scalable, self-protective measure that can be adapted to local conditions. Less problematic than quarantine, the isolation of infected individuals clearly played a central role in containing SARS.

Although isolating SARS patients within hospitals could be viewed as increasing the risk of infection for health care workers and other hospital staff, evidence from Toronto indicates that hospital personnel can be protected through strict infection-control practices, such as washing hands, wearing masks and gloves, and requiring patients to wear masks. The most effective type of mask remains to be determined, however.

Finally, even if it were known which of the various strategies used to contain SARS were most effective, it is far from certain whether they would continue to be effective should SARS return. For example, although it appears that quarantine helped control SARS in China and Toronto, it did so largely because of the limited contagiousness of the virus.

The likelihood that SCoV. April 4, Role of Metropole Hotel in global epidemic identified. To plan rationally for the containment of a future SARS outbreak, it will be important to know the relative effectiveness of the various measures taken to contain the recent epidemic. In the absence of such information, the strategy for containing SARS should emphasize overall preparedness at the local level in every community and hospital, participants agreed.

Participants discussed techniques and equipment to protect frontline caregivers of SARS patients in the hospital and at home. Simple habits such as frequent handwashing with soap and water are very important to prevent the transmission of any infectious agent. Other measures include wearing a mask that covers the nose and mouth, protective eyewear, gloves, gowns, or a containment suit. Participants noted that masks are effective only if they fit snugly and are not removed when the wearer coughs.

During the discussion of masks, participants debated the relative protectiveness of standard surgical masks compared with N masks so named because 95 percent of the time, they filter out any particle equal to or greater than 0. Coronaviruses are smaller than 0. Participants discussed a case control study in five Hong Kong hospitals in which wearers of surgical masks and N masks did not contract the SARS coronavirus, while a few wearers of paper masks became infected Seto et al. A larger study to validate this finding was proposed. One workshop presentation described a relatively inexpensive mobile technology that potentially could be used to isolate individual patients during transport to and within hospitals, to protect staff during high-risk procedures such as intubation or bronchoscopy, to decontaminate large areas such as hospital waiting rooms or airplanes, and to create air exchange systems for isolation facilities or areas within hospitals see Schentag et al.

These mobile units remove and destroy airborne viral particles and droplets; the latter are widely believed to be the vector for SCoV transmission. Importantly however, it was. A coronavirus comprises single-stranded RNA inside a lipid envelope. Coronaviruses cause a substantial fraction of human colds and a number of common respiratory infections in other animals, including livestock and poultry Holmes, Since its emergence, several veterinary and biomedical scientists have been called on to share their considerable knowledge of coronaviruses with a vast new audience and to join the research response to the epidemic.

This experience—and the high value evident in available knowledge and understanding of coronavirus biology and molecular biology, gained at a time when coronaviruses were not recognized to be the causative agent of any severe infectious disease—attests to the value of basic research. Based on their genetic sequences, the 14 previously known coronaviruses have been divided into three major groups. While SCoV has been linked with Group II coronaviruses, whose members include human and bovine respiratory viruses and the mouse hepatitis virus, there is still some debate over whether its genetic features might be sufficiently distinct to warrant classification within a separate, fourth class of coronaviruses.

Although coronaviruses generally cause disease in a single species, it has been demonstrated that some coronaviruses can cross species barriers. These findings lend credence to the hypothesis that SCoV is a zoonosis. Viruses resembling human SCoV reportedly have been detected in wild mammals of southern China that were brought to marketplaces where they were sold as exotic food. Immunological and genetic tests of these SCoV-like viruses suggest that human SCoV may be an animal virus transmitted to humans in the recent past Guan et al.

As one would expect of a newly characterized disease, much knowledge about the microbiology, pathogenesis, natural history, and epidemiology of SARS. How was the virus transmitted to humans, and under what circumstances might transmission across species recur? What is the potential for back-and-forth transmissions between humans and animals? How important are routes of transmission other than infectious respiratory droplets? Under what circumstances do alternative modes of transmission occur? How does pathogenesis unfold at the cellular level, and especially in nonrespiratory tissues?

For example, scientists have not yet identified the animal source of the infectious agent and have not determined whether a persistent animal reservoir of the infectious agent exists. It is also unclear whether SARS, like influenza, is a seasonal disease that would have receded on its own. Along the same lines, it remains to be seen whether SARS will reemerge on a seasonal basis, and if so, how virulent future manifestations of SCoV will be.

These and other unanswered scientific questions, listed in Box S-1 , were a prominent theme of workshop presentations and discussions. The recent reemergence of human SARS infections in would indicate both an animal reservoir and a seasonality to disease emergence, but further investigation will be required for conclusive evidence. Considerable effort already has been applied to finding the animal source of SCoV. For example, viral isolates from suspected animal sources were genetically characterized and compared with samples of SCoV see Guan et al.

Such an endeavor may provide direction to further laboratory surveys of animal viruses to reveal the source of SCoV and, perhaps, its animal reservoir. SARS researchers benefit from the wealth of literature on coronaviruses in general. Presentations by two coronavirus experts at the workshop summarized the current understanding of coronavirus biology and pathogenesis and suggested promising directions for research on SARS and other emerging zoonoses see Saif and Denison in Chapter 3.

The pathogeneses of animal coronaviruses conform to a basic model of either intestinal enteric or respiratory infection. Enteric coronaviruses can cause fatal infections in young, seronegative animals. Respiratory coronavirus infections in adult animals have shown increased severity in the presence of several factors, including high exposure doses, respiratory coinfections, stress related to shipping or commingling with animals from different farms, and treatment with corticosteroids.

It is unknown whether SCoV is a respiratory virus or a pneumoenteric virus. This knowledge gap will stymie efforts to develop a vaccine or drug against SCoV. Studies of coronavirus replication reveal several mechanisms that account for the repeated, persistent infections typical of coronaviral disease. High rates of mutation and RNA-RNA recombination produce viruses that are extremely adaptable and capable of acquiring or regaining virulence.

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The relatively large coronavirus genome tolerates deletions, mutations, and substitutions and can recover from deleterious mutations. Molecular biological studies have also identified. Cellular functions on which the virus depends, such as cholesterol synthesis, membrane trafficking, and autophagy, also present opportunities for antiviral design see Matthews et al. The tendency of coronaviruses to undergo mutation and recombination represents a significant challenge for vaccine development.

To date, no vaccine has been produced that can provide highly effective, long-term protection against respiratory coronavirus infections. Genetic approaches represent the best hope of overcoming this propensity for mutability, according to workshop presenters. Promising approaches to these challenges include the use of reverse molecular genetics to make specific mutations in the virus genome and test their functional effects. Workshop presenters emphasized that appropriate animal models are needed immediately to advance the development of a SARS vaccine.

Participants also noted that studies in existing animal models of coronavirus infection could play a role in the development of antiviral therapies against SARS. Ultimately, a range of natural and transspecies disease models will be critical to understanding the pathogenesis of this and other emerging zoonoses.

Coordinated, multidisciplinary research drawing on expertise in veterinary sciences, medicine, molecular biology, and virology will be needed to meet these goals. However, the coronavirus experts who presented at the workshop lamented that there is little encouragement or support for such critical cross-disciplinary research at present. Considering the likelihood of a return of SARS under a variety of circumstances is an important first step in planning for a broad range of contingencies.

May 3, Taiwan outbreak grows to cases; WHO sends team. A trio of plausible scenarios was presented at the workshop see Monaghan in Chapter 5. The first scenario entailed a resurgence of SARS in China, followed by limited spread to other countries in the region. Heightened surveillance and rapid response could quickly contain such an outbreak, but might also cause SARS to be viewed less as a threat and more as a public nuisance; this attitude could lead to a decline in vigilance, raising the risk of a future epidemic.

In the second scenario, SARS spreads to poor countries in Asia and Africa, where inadequate health systems, preexisting health problems, high population density, and weak government leadership result in high infection rates and mortality. Such an epidemic would prove difficult to contain and create a humanitarian emergency that would place costly demands on international policy makers and institutions as well as developed countries compelled to respond for reasons that were both humane and self-protective.

And even if this epidemic produced fewer cases of SARS than in , it would be likely to cause major disruptions in trade and investment flows. In considering further preparations for the reemergence of SARS, workshop participants discussed the development of surveillance and containment strategies in case SARS reappears during the winter of ; ongoing efforts to develop diagnostic tools for SARS and other infectious diseases; and long-term prospects for the discovery and development of antiviral drugs and vaccines against this newly emergent disease.

For a number of reasons, workshop participants agreed that continued vigilance in light of SARS is warranted for a number of reasons. First, it is very likely that an animal reservoir for the virus exists in China. Second, the continued sale of live, small wild mammals in marketplaces and the preparation of these animals as food perpetuates a hypothesized route of SCoV transmission to humans. Third, the possibility that SARS, like influenza, is a seasonal disease means it could reappear during the winter of Finally, initial low-level transmission of the virus could elude clinical recognition and reporting of the disease.

May 21, WHO declares travel advisory for all of Taiwan. It was suggested that in the absence of inexpensive, accurate, and widely available SARS diagnostics, syndromic surveillance—particularly in populations at high risk for reemergence—might be important for spotting nascent outbreaks. This methodological strategy, which involves monitoring groups of signs and symptoms associated with disease activity—unusual spikes in the purchase of commonly available health remedies, for example, or surges in particular symptoms reported among routinely collected information from clinical sources—has shown some promise in the early detection of disease outbreaks in the United States Institute of Medicine, However, because SARS symptoms are variable and difficult to distinguish from those of influenza and seasonal human coronavirus infections that emerge in the same populations, it is not clear that such methods would be capable at present of distinguishing the emergence of novel infections such as SARS without careful consideration of the utility, quantity, and specificity of the surveillance data to be collected.

Until a specific diagnostic test becomes available, there will continue to be a substantial risk of both missed cases and false alarms, and syndromic surveillance methods should be evaluated as possible complements to rather than replacements for maintaining and strengthening traditional clinical reporting systems. A rapid, specific, reliable, and inexpensive clinical diagnostic test for SARS would be a valuable tool for improving surveillance and limiting the transmission of SCoV. First, however, scientists must determine which tissues contain the highest concentrations of virus during the presymptomatic stage of infection.

It was also noted that in confirmed cases of SARS, the virus appears to be located deep in the respiratory tract, making specimens difficult to collect. Absent a clinical diagnostic test, suspected cases of SARS must be confirmed in the laboratory using reverse-transcription polymerase chain reaction RT-PCR or much slower methods involving serology or viral culture, isolation, and identification by electron microscopy Yam et al.

Seroconversion or a fourfold increase in titer between the acute and convalescent phases of infection as determined by immunoassay. Recent incidents have highlighted the critical need for both specificity and sensitivity of laboratory diagnostic procedures. To address these issues, WHO and the CDC continue to work to standardize test protocols, reagents, and controls and to establish procedures for evaluation and quality control throughout the global network of diagnostic laboratories that may handle suspected SARS cases WHO, m. Workshop participants considered several platforms that could potentially be adapted for the rapid, clinical diagnosis of early, asymptomatic SCoV infection.

A recent evaluation of two RT-PCR protocols found them to be highly specific for the SARS coronavirus; however, these protocols were insufficiently sensitive to detect the virus reliably in respiratory specimens. Testing two specimens from the same patient increased the probability of an accurate diagnosis see Yam et al. A different platform discussed at the workshop purportedly can identify the family, and possibly the genus, of known or novel infectious agents see Sampath and Ecker in Chapter 4 ; Hogg, Unlike many RT-PCR techniques, which target nucleic acid sequences unique to a specific organism, this test amplifies strategically chosen, highly conserved sequences from the broadest possible grouping of organisms.

The molecular weight of the amplimers is measured by electrospray ionization mass spectrometry. Then the relative amounts of each base i. The base-pair composition of the selected genetic sequence serves as a signature to identify and distinguish organisms in a sample. Originally designed for the environmental surveillance of biowarfare agents, such technology could potentially diagnose SARS directly from a tissue sample, obviating the need for time-consuming viral culture. According to workshop presenters, their method can distinguish between SCoV and other coronaviruses and perhaps even between genetic variants of SCoV.

As noted earlier, until basic research on the pathogenesis of SARS elucidates whether the infection is respiratory or pneumoenteric, it is unclear which tissues a therapeutic agent should target. That being said, preparing for a reemergence of SARS might include the strategic development of a vaccine and an antiviral drug. Theoretically, an ideal vaccine would contain an epidemic more effectively than an ideal antiviral drug if a large segment of the population were vaccinated.

Yet mathematical models of influenza described at the workshop indicate that an epidemic could be contained effectively by providing an antiviral prophylaxis to close contacts of index cases. Therefore, the parallel development of both a vaccine and a drug for SARS may be an effective course of action. The perceived urgency of developing SARS therapeutics has led several pharmaceutical and biotechnology companies to pursue the development of countermeasures for SARS. Two advantages these companies enjoy are the panoply of veterinary vaccines against coronaviruses and the ease with which SCoV can be grown in culture.

Previous antiviral discovery efforts by researchers from Pfizer Inc. This work has proved advantageous in searching for 3CL protease inhibitors. Army Medical Research Institute of Infectious Diseases, who had developed an assay to test candidate compounds for their ability to prevent death in SARS-infected monkey kidney cells, Pfizer tested existing compounds that had shown activity against the rhinovirus protease.

An X-ray crystallographic atomic-level resolution model of 3C protease of human rhinovirus 14 served as the basis for structural models of the 3CL protease binding site. This structural information enabled the scientists to identify additional compounds that demonstrated significant antiviral activity. The group is currently evaluating the solubility, metabolic stability, and other physicochemical properties of some of these inhibitors in hopes of finding promising compounds for clinical development.

Pfizer researchers are also employing structure-based design and combinatorial chemistry as an alternative, complementary strategy to discovering 3CL protease inhibitors see Matthews et al. Despite the research described earlier in this chapter and the wealth of literature on coronaviruses, it will take more time before a compound designed to. SARS vaccine development programs require biosafety level 3 conditions, which make research efforts slower and more expensive than other targets of less contagious microbes. For this reason and others, such as the genetically unstable nature of the virus and the current lack of an appropriate animal model, a vaccine for SARS could well postdate a return of the disease, perhaps by several years, even if such a product were steered through a streamlined development process.

If SARS fails to reappear within the next few years, however, it is unlikely that either antiviral or vaccine development will continue, given the cost of these efforts. These include ensuring the availability of virus isolates for vaccine stock, recognizing research needs and contingencies in areas such as vaccine testing, and conducting public workshops on needed technologies, such as diagnostics.

Recognizing that it would be impossible to address the vast array of potential microbial threats individually, public health policy makers are formulating general strategies to evaluate and respond to outbreaks of all kinds. At the international level, revisions to the International Health Regulations—rules concerning infectious disease that legally bind WHO member nations—have been underway since , and are expected to be completed in Workshop participants concurred that efforts to address microbial threats should encompass and be enriched by existing strategies for defense against bioterrorism.

As one participant noted, authorities do not know until well into an outbreak if it is a naturally occurring or manmade threat—in either case a robust and prepared system will be able to respond rapidly and effectively to contain disease spread. Workshop presentation by Kathryn Carbone, Ph. The importance of collaboration was a common theme among workshop discussions on research.

It was discussed in the context of scientists around the globe who identified the causal agent of SARS, of veterinary and biomedical research communities studying zoonotic pathogens, and of private sector companies working in conjunction with government agencies and academia to develop antiviral drugs and vaccines.

The principal topics discussed include:. The central response to SARS—surveillance and containment, when instituted promptly, rapidly, and effectively—applies to almost any microbial threat. It is clear that the initial delays in not only detecting the novel SCoV, but also alerting national and global health officials to the disease outbreak significantly increased the spread of SARS and its impact on affected countries.

However, soon after the global outbreak alerts were issued, the timely recognition of the emergence of SARS in other countries proved to be an important factor in breaking all chains of transmission. Along with these vital resources, workshop participants identified additional surveillance strategies for microbial threats; these include hospital-based surveillance systems capable of recognizing both known and novel diseases, and occupational clustering, with particular attention paid to illness in health care workers.

Behavior-based surveillance could identify such phenomena as drug sales, or even such phenomena as the rapid rise in vinegar sales that occurred in response to SARS in Guangdong in January Drawing on the SARS experience, a recent WHO global consultation focused on strengthening national capacities for surveillance, response, and control of communicable diseases. While discussing the critical role of laboratories for effective surveillance, concerns about laboratory safety were raised.

Accidents in a Singapore clinical laboratory described earlier in this chapter and a Taiwan research laboratory have been responsible for SARS infections in workers Center for Disease Control Taiwan, These incidents highlight the importance of hospital surveillance procedures and appropriate clinical management and infection control measures in preventing an outbreak.

They should also raise the awareness of the research community, particularly given the many laboratories now conducting research on SARS, to the risks inherent in handling all communicable agents and the need for strict adherence to well established laboratory procedures. Overall, workshop participants observed that surveillance must be backed up with action and reinforced by sufficient laboratory capacity, well-trained personnel, and a legal framework consistent with objectives of transparency, global cooperation, and sensitivity to the balance between public protection and the interests of individual countries and persons.

Workshop discussants emphasized that investments made toward this end should capitalize on the existing networks and need not be prohibitively extensive or expensive. An estimated 75 percent of emerging human pathogens and 61 percent of all human pathogens are zoonotic Taylor et al. Therefore, many predictions. Thus, workshop participants considered the strategies for containing known zoonoses—in particular, influenza—as potential models for the containment of SARS and unidentified zoonotic diseases of the future.

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The same trends that ushered SARS into the human population have been apparent during a century of influenza outbreaks. As with SARS, animal markets provide the breeding ground for recent outbreaks of influenza; laboratory sources also appear to have sparked at least one epidemic. Fortunately, most of the recent influenza outbreaks did not feature the transmission of the virus to humans. However, experts agree that it is only a matter of time until a highly virulent and contagious flu, such as the strain that caused over 20 million and perhaps as many as 40 million deaths during the influenza epidemic, confronts the world see Webby and Webster in Chapter 5.

Vaccines and antiviral therapies play a significant role in containing epidemics of influenza. It is advantageous that the timing of annual outbreaks of influenza and the strain or strains of the virus can, to some extent, be anticipated. However, strategic actions recommended against influenza that could also inform efforts to better prepare for other viral disease outbreaks have yet to be implemented.

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