Nasopharyngeal shedding of severe acute respiratory syndrome-associated coronavirus is associated with genetic polymorphisms

Abstract

Background: A high initial or peak severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) load in nasopharyngeal specimens was shown to be associated with a high mortality rate. Because all infected individuals were devoid of preeexisting protective immunity against SARS-CoV, the biological basis for the variable virus burdens in different patients remains elusive.

Methods: The nationwide SARS database in Taiwan was analyzed, and genotyping of 281 single-nucleotide polymorphisms (SNPs) of 65 genes was performed for 94 patients with SARS, to identify SNPs for which distribution between patients with or without detectable nasopharyngeal shedding of SARS-CoV was biased.

Results: Titers of SARS-CoV shed in nasopharyngeal specimens varied widely, ranging from nondetectable to 10(8) SARS-CoV RNA copies/mL, and they were correlated positively with a high mortality rate (P<.0001, by trend test) and with early death (i.e., death occurring within 2 weeks of the onset of illness) (P=.0015, by trend test). Virus shedding was found to be higher among male patients (P=.0014, by multivariate logistic regression) and among older patients (P=.015, by multivariate logistic regression). Detectable nasopharyngeal shedding of SARS-CoV was associated with polymorphic alleles of interleukins 18 (P=.014) and 1A (P=.031) and a member of NF kappa B complex (reticuloendotheliosis viral oncogene homolog B [RelB]) (P=.034), all of which are proinflammatory in nature, as well as the procoagulation molecule fibrinogen-like protein 2 (P=.008).

Conclusion: The SARS-CoV load is a determinant of clinical outcomes of SARS, and it is associated with polymorphisms of genes involved in innate immunity, which might be regulated in an age- and sex-dependent manner. The findings of the present study provided leads to genes involved in the host response to SARS-CoV infection; if substantiated with functional studies, these findings may be applicable to other newly emerged respiratory viruses (e.g., the influenza pandemic strain).

Table 1

Genes studied.

Figure 1

Scatter plot of titers of severe acute respiratory syndrome—associated coronavirus (SARS-CoV) in nasopharyngeal specimens from 154 patients vs. the day of specimen collection.

Table 2

Distribution of 265 patients with severe acute respiratory syndrome (SARS), according to nasopharyngeal (NP) SARS-associated coronavirus (SARS-CoV) load at the time of admission, by demographic and clinical characteristics.

Figure 2

Rate of detection of shedding of severe acute respiratory syndrome—associated coronavirus (SARS-CoV) in nasopharyngeal specimens from 265 patients, as determined by RT-PCR, according to sex and age.

Table 3

Nasopharyngeal severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load and length of survival for 71 patients with fatal cases of SARS.

Table 4

Genetic polymorphisms and nasopharyngeal virus loads of 94 patients with severe acute respiratory syndrome (SARS).

Figure 3

Power plotted against the allele frequency of each single-nucleotide polymorphism. Power is calculated based on the allele frequencies and the sample size of patients with severe acute respiratory syndrome (SARS) with (no. of case patients, 49) or without (no. of control patients, 45) detectable virus shedding. The curved lines denote the zones of differences between the allele frequencies of the case patients and control patients. Each black dot (·) denotes one single-nucleotide polymorphism plotted according to the allele frequency of the control patients with SARS without detectable SARS-associated coronavirus.