Is the XFG variant of COVID-19 (Coronavirus Disease 2019) causing diagnostic dropouts in molecular assays?

XFG Variant of COVID-19 and Molecular Assay Dropouts

There is currently no evidence that the XFG variant of COVID-19 is causing significant diagnostic dropouts in molecular assays. While viral mutations can potentially affect diagnostic targets, current guidelines do not specifically identify XFG variant as causing widespread testing failures.

Current Understanding of SARS-CoV-2 Variants and Diagnostic Testing

Impact of Mutations on Molecular Testing

• SARS-CoV-2 continues to evolve, with mutations occurring across the viral genome that can potentially affect diagnostic targets 1
• The nucleocapsid (N) gene has been identified as one of the most non-conservative genes in the SARS-CoV-2 genome, showing the most mutations on targets of various primers and probes 1
• Molecular diagnostic assays that target multiple gene sequences are less susceptible to false negatives from mutations 2

Current Diagnostic Recommendations

• The Infectious Diseases Society of America (IDSA) recommends SARS-CoV-2 nucleic acid amplification tests (NAATs) that target at least two distinct viral gene sequences 3
• This multi-target approach helps mitigate the risk of diagnostic failures due to mutations in any single region of the viral genome 3
• For symptomatic individuals, IDSA strongly recommends NAAT testing with specimens collected from nasopharyngeal, anterior nares, oropharyngeal, or midturbinate regions; saliva; or mouth gargle 3

Surveillance and Variant Monitoring

Tracking Viral Evolution

• Ongoing genomic surveillance is critical for monitoring the emergence and spread of new variants 4
• COVID-19 CG and similar resources track SARS-CoV-2 single-nucleotide variations, lineages, and clades, allowing researchers to monitor mutations that might impact diagnostic sensitivity 5
• Public health genomics has played a crucial role in identifying new variants and understanding their characteristics 3

Diagnostic Challenges with Variants

• While mutations can theoretically affect diagnostic targets, most commercially available molecular assays continue to perform well against circulating variants 2
• The practice of using assays that target multiple gene regions helps maintain diagnostic sensitivity even as the virus evolves 3
• For immunocompromised patients or those with high clinical suspicion but negative initial tests, repeat testing may be warranted 3

Practical Considerations for Testing

Best Practices for Molecular Testing

• Use NAAT assays that target at least two distinct viral gene sequences to minimize the risk of false negatives due to mutations 3
• Consider the possibility of false negatives, especially early in infection (100% false-negative rate on day 1,68% on day 4,20% three days after symptom onset) 2
• If clinical suspicion is high despite negative testing, consider repeat testing and manage as COVID-19 positive while awaiting results 2

Pitfalls to Avoid

• Relying on a single target region for molecular testing, which increases vulnerability to mutation-related test failures 1
• Assuming that a negative test definitively rules out COVID-19, especially in the context of high clinical suspicion 2
• Failing to consider the timing of testing relative to symptom onset, which significantly affects test sensitivity 2

While ongoing surveillance for the impact of emerging variants on diagnostic testing remains important, current evidence does not indicate that the XFG variant specifically is causing widespread diagnostic dropouts in molecular assays. Following current testing guidelines that recommend multi-target molecular assays remains the best approach for accurate diagnosis.