October 16, 2003 Access past issues

Reviewed by: Lily Nguyen, MSPH Office of Genomics and Disease Prevention, CDC, Atlanta, GA

The Health Outcome

Severe acute respiratory syndrome (SARS) has been attributed to a new virus in humans, the SARS coronavirus [1]. It is spread by aerosol and direct contact with respiratory secretions, body fluids or excreta. Clinical disease is characterized by fever, dry cough, interstitial infiltrates, and variable progression to respiratory failure. Although no treatment has clearly been shown to be effective, aggressive infection control measures have been the key to outbreak management [2]. The first cases of SARS were reported in China in November 2002. Since then, over 8000 suspect or probable cases have been reported internationally, with a case fatality rate of 9.6% [3].

To date, no human genomic factors have been associated with risk of infection or the severity of SARS. Genes of relevance to infectious disease include the human leukocyte antigen (HLA) complex, consisting of class I and class II alleles. The HLA loci control the immune response by coding for highly polymorphic proteins that play a critical role in antigen presentation during the course of an infection [4]

The Finding

Lin et al. [5] reported that HLA class I alleles were associated with susceptibility to and severity of SARS. A case-control study compared cases in a Taiwanese hospital with several control groups: 28 fever patients ruled out as SARS, 101 exposed but uninfected health care workers, and 190 healthy unrelated Taiwanese. Of 37 probable cases, only 33 unrelated cases were examined. The HLA class I (HLA-A, HLA-B) and class II (HLA-DRB1) loci were typed for all participants. Typing was done at medium resolution, which does not distinguish all closely related alleles. Though probable SARS cases had a high frequency of HLA-B*4601 (22.73%), the allele was significantly associated only with more severe clinical disease, as characterized by the need for intubation or death from SARS. The study also suggested that HLA-B*1301 may confer resistance to SARS infection. The authors speculated that the prevalence of HLA-B*4601 in Southeast Asians may have contributed to the rapid expansion of the SARS epidemic in China and neighboring countries.

Public Health Implications

The diagnostic criteria for SARS were originally based on clinical criteria alone and depended on exclusion of other diagnoses; thus, the case definition could have changed during the course of the study, an issue that the authors do not address. Although HLA-B*4601 was significantly associated with severity after adjusting for multiple comparisons, no associations was found for susceptibility to SARS. While the authors suggest that the genetic contribution of HLA in related ethnic groups influenced the spread of SARS, there are other explanations for why the disease was confined to southern Asia. Epidemics are related geographically to the origin of disease as well as to chance of exposure, the consequence being that other ethnic groups may not have had an opportunity for exposure. The authors’ final statement that these findings justify the mass screening of health care workers seems premature and can not be recommended without additional research.

This is the first report of an association between any human genomic factor in relation to SARS. Other studies have characterized the molecular epidemiology of the SARS coronavirus and its relationship to other viruses [6, 7]. Much work has examined the contribution of HLA alleles to infectious disease, with the most notable findings having been in human immunodeficiency virus type 1, malaria, leprosy, and viral hepatitis [4]. Overall, these are provocative findings that require further studies to assess the immunogenetics of SARS in relation to susceptibility, severity of disease, and transmission.

References

1. Drosten C, Gunther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003 May 15;348(20):1967-76.

2. Hawkey PM, Bhagani S, Gillespie SH. Severe acute respiratory syndrome (SARS): breath-taking progress. J Med Microbiol 2003 Aug;52(8):609-13.

3. No authors listed. Update: severe acute respiratory syndrome--United States, 2003. MMWR Morb Mortal Wkly Rep 2003 Jul 4;52(26):616.

4. Hill, AV. Immunogenetics and genomics. Lancet 2001 Jun 23;357(9273):2037-41.

5. Lin, M, Tseng H-K, Trejaut JA, et al. Association of HLA class I with severe acute respiratory syndrome coronavirus infection. BMC Med Genet 2003 Sept 12;4(9):1-9 [Epub ahead of print].

6. Ruan, YJ, Wei CL, Ee AL, et al. Comparative full-length genome sequence analysis of 14 SARS coronavirus isolates and common mutations associated with putative origins of infection. Lancet 2003 May 24;361(9371):1779-85.

7. Rota, PA, Oberste MS, Monroe SS et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 2003 May 30;300(5624):1394-99.