Examining the SARS Epidemic of 2003, Preparing for 2004
Examining the SARS Epidemic of 2003, Preparing for 2004
The ICAAC Program Committee made a special effort to include updates on severe acute respiratory syndrome (SARS) in several symposia. Sunday, September 14, featured a keynote presentation by Malik Peiris, MD, PhD, from the University of Hong Kong, in which he summarized his experience with SARS.
Dr. Peiris pointed out that it was this season last year (October 2002) when the first cases of SARS were noted in Guangdong Province in China. In March 2003, outbreaks outside of that province were noted. At that point, the World Health Organization and the Centers for Disease Control and Prevention (CDC) alerted the world that the virus had spread beyond China, as cases were reported in Germany, Singapore, and Vietnam.
Dr. Peiris reviewed the early experiences when there was uncertainty about the etiology and speculation about potential roles for chlamydia and metapneumovirus. His lab and others in Germany and at CDC quickly recognized the Coronavirus; they could grow the virus from clinical specimens, they could demonstrate seroconversion of suspect cases, and they could visualize the virus in clinical specimens by electron microscopy. Dr. Peiris reviewed the convincing evidence that fulfill Koch's postulates, establishing Coronavirus as the cause of SARS, and provided some fascinating insights into the problems of pinning down this etiologic relationship.
When patients were initially studied, investigators had difficulty isolating the virus by culture techniques or by polymerase chain reaction (PCR). This was perplexing considering the experience with influenza and respiratory syncytial virus (RSV). There are several explanations for the early difficulty. First, the first-generation PCR assays were not as sensitive as what is available now. Dr. Peiris showed results using more sensitive methods, indicating a rising titer in 104 of 107 clinical cases, as opposed to 0 patients among blood donors and other controls. Seroconversion could be demonstrated in 384 of 417 (92%) patients with clinical SARS vs 0 of 45 controls. Virus could be detected in nasopharyngeal samples from 322 of 537 samples using a first-generation test; only 1 of 184 controls in one group and 0 of 48 controls in another group were positive.
From a biologic perspective, the SARS coronavirus behaves differently from influenza and RSV. The latter 2 viruses are most copious when patients first present with symptomatic disease, and then diminish in quantity as the disease progresses and, ultimately, the patient improves. With SARS, however, the quantity of virus increases over the first 1-2 weeks before diminishing. Thus, it is easier to isolate virus during the end of the first week and during the second week as opposed to earlier in the course of the symptomatic disease.
Investigators were also puzzled initially that they did not find virus in autopsy specimens of lung when immunohistochemistry and culture techniques were used. However, much of the early work with autopsy tissue was done on specimens obtained from patients who died after many weeks of hospital support. When a specimen from a patient who had died during the first 2 weeks was examined, virus was more readily detected.
In terms of transmission, 2 lines of evidence supported the hypothesis that a unique coronavirus was the etiologic agent. First, a group in Rotterdam, The Netherlands, has been able to produce a disease similar to SARS with macaques inoculated with the SARS coronavirus. Second, when the virus was sequenced and phylogenetic trees based on viral RNA were constructed, it was clear that this was a new coronavirus and that there were several different strains of virus that could be distinguished. The physician who spread the disease in Hotel M had a subtype that could be traced via infected guests from the hotel to outbreaks in Hanoi, Singapore, and Canada, providing evidence linking a very specific virus to clinical outbreaks.
An important question is why many more healthcare workers are infected than family members. This experience was also different from patterns established with influenza and RSV. The observation above about the quantity of virus peaking during the second week suggests that patients were probably not as infectious at home or when visiting their family practitioner when they first became ill compared with when their disease was more advanced and they were shedding more virus. This provides some explanation about the extraordinary experience with nosocomial transmission. Dr. Peiris also noted, however, that as antibodies appear during the second or third week, virus rapidly becomes very difficult to culture from clinical specimens; while it is still detectable by reverse transcriptase (RT)-PCR in stool, urine, and respiratory specimens, the patient is probably not highly infectious.
Where did the virus originate? Dr. Peiris reviewed published data and data that will be appearing shortly in Science, documenting the presence of a similar (but not identical) coronavirus in animals that are used for food, namely civets and raccoon dogs. When personnel in a Guangdong market selling such animals were tested for antibodies to the SARS virus, 8 of 20 wild animal trackers and 3 of 15 butchers were antibody-positive, compared with 1 of 20 vegetable workers and 0 of 60 other controls. This at least suggests a link to animal coronaviruses, although the human SARS coronavirus is molecularly distinct from those found in these nonhuman animal populations.
There are many unanswered questions about why some individuals do not become infected and why at least 1 became a "supershedder." Dr. Peiris proposed genetic determination of mannose-binding protein levels as potentially explaining some of the variability in host susceptibility to SARS.
The major questions that clinicians want answers to are: Will the epidemic reappear in 2003-2004, or in subsequent years? Will there be a rapid diagnostic test available to clinicians which will allow rapid and early identification of infected patients? Will standard respiratory isolation techniques really prevent nosocomial spread? How far away are vaccines and therapies? As reports begin to filter in about initial cases being identified in Asia in recent weeks, healthcare workers need to stay tuned for more developments from ICAAC, the Infectious Disease Society of American Annual Convention in October, and other emerging communications.
References
The ICAAC Program Committee made a special effort to include updates on severe acute respiratory syndrome (SARS) in several symposia. Sunday, September 14, featured a keynote presentation by Malik Peiris, MD, PhD, from the University of Hong Kong, in which he summarized his experience with SARS.
Dr. Peiris pointed out that it was this season last year (October 2002) when the first cases of SARS were noted in Guangdong Province in China. In March 2003, outbreaks outside of that province were noted. At that point, the World Health Organization and the Centers for Disease Control and Prevention (CDC) alerted the world that the virus had spread beyond China, as cases were reported in Germany, Singapore, and Vietnam.
Dr. Peiris reviewed the early experiences when there was uncertainty about the etiology and speculation about potential roles for chlamydia and metapneumovirus. His lab and others in Germany and at CDC quickly recognized the Coronavirus; they could grow the virus from clinical specimens, they could demonstrate seroconversion of suspect cases, and they could visualize the virus in clinical specimens by electron microscopy. Dr. Peiris reviewed the convincing evidence that fulfill Koch's postulates, establishing Coronavirus as the cause of SARS, and provided some fascinating insights into the problems of pinning down this etiologic relationship.
When patients were initially studied, investigators had difficulty isolating the virus by culture techniques or by polymerase chain reaction (PCR). This was perplexing considering the experience with influenza and respiratory syncytial virus (RSV). There are several explanations for the early difficulty. First, the first-generation PCR assays were not as sensitive as what is available now. Dr. Peiris showed results using more sensitive methods, indicating a rising titer in 104 of 107 clinical cases, as opposed to 0 patients among blood donors and other controls. Seroconversion could be demonstrated in 384 of 417 (92%) patients with clinical SARS vs 0 of 45 controls. Virus could be detected in nasopharyngeal samples from 322 of 537 samples using a first-generation test; only 1 of 184 controls in one group and 0 of 48 controls in another group were positive.
From a biologic perspective, the SARS coronavirus behaves differently from influenza and RSV. The latter 2 viruses are most copious when patients first present with symptomatic disease, and then diminish in quantity as the disease progresses and, ultimately, the patient improves. With SARS, however, the quantity of virus increases over the first 1-2 weeks before diminishing. Thus, it is easier to isolate virus during the end of the first week and during the second week as opposed to earlier in the course of the symptomatic disease.
Investigators were also puzzled initially that they did not find virus in autopsy specimens of lung when immunohistochemistry and culture techniques were used. However, much of the early work with autopsy tissue was done on specimens obtained from patients who died after many weeks of hospital support. When a specimen from a patient who had died during the first 2 weeks was examined, virus was more readily detected.
In terms of transmission, 2 lines of evidence supported the hypothesis that a unique coronavirus was the etiologic agent. First, a group in Rotterdam, The Netherlands, has been able to produce a disease similar to SARS with macaques inoculated with the SARS coronavirus. Second, when the virus was sequenced and phylogenetic trees based on viral RNA were constructed, it was clear that this was a new coronavirus and that there were several different strains of virus that could be distinguished. The physician who spread the disease in Hotel M had a subtype that could be traced via infected guests from the hotel to outbreaks in Hanoi, Singapore, and Canada, providing evidence linking a very specific virus to clinical outbreaks.
An important question is why many more healthcare workers are infected than family members. This experience was also different from patterns established with influenza and RSV. The observation above about the quantity of virus peaking during the second week suggests that patients were probably not as infectious at home or when visiting their family practitioner when they first became ill compared with when their disease was more advanced and they were shedding more virus. This provides some explanation about the extraordinary experience with nosocomial transmission. Dr. Peiris also noted, however, that as antibodies appear during the second or third week, virus rapidly becomes very difficult to culture from clinical specimens; while it is still detectable by reverse transcriptase (RT)-PCR in stool, urine, and respiratory specimens, the patient is probably not highly infectious.
Where did the virus originate? Dr. Peiris reviewed published data and data that will be appearing shortly in Science, documenting the presence of a similar (but not identical) coronavirus in animals that are used for food, namely civets and raccoon dogs. When personnel in a Guangdong market selling such animals were tested for antibodies to the SARS virus, 8 of 20 wild animal trackers and 3 of 15 butchers were antibody-positive, compared with 1 of 20 vegetable workers and 0 of 60 other controls. This at least suggests a link to animal coronaviruses, although the human SARS coronavirus is molecularly distinct from those found in these nonhuman animal populations.
There are many unanswered questions about why some individuals do not become infected and why at least 1 became a "supershedder." Dr. Peiris proposed genetic determination of mannose-binding protein levels as potentially explaining some of the variability in host susceptibility to SARS.
The major questions that clinicians want answers to are: Will the epidemic reappear in 2003-2004, or in subsequent years? Will there be a rapid diagnostic test available to clinicians which will allow rapid and early identification of infected patients? Will standard respiratory isolation techniques really prevent nosocomial spread? How far away are vaccines and therapies? As reports begin to filter in about initial cases being identified in Asia in recent weeks, healthcare workers need to stay tuned for more developments from ICAAC, the Infectious Disease Society of American Annual Convention in October, and other emerging communications.
References
Peiris M. Special Presentation on SARS. Program and abstracts of the 43rd Annual ICAAC; September 14-17, 2003; Chicago, Illinois. Abstract 589.
Kuiken T, Fouchier RA, Schutten M, et al. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet. 2003;362:263-270.
Rota PA, Oberste MS, Monroe SS, et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science. 2003;300:1394-1399.
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