Clinical Information

Viral infections are common in otherwise healthy individuals, but they may also present clinically due to a primary (genetic) immunodeficiency (ie, inborn error of immunity: IEI). Alternatively, secondary immunodeficiencies may have a similar presentation but result from immunosuppressive medication or illness, such as HIV infection. IEIs may cause a susceptibility to an entire group of pathogens (bacteria, fungi, or viruses), a subset of pathogens (eg, RNA viruses), or can cause susceptibility specific to a single pathogen (eg, Epstein-Barr virus [EBV], human papillomavirus [HPV]). IEIs may also lead to a more severe presentation, including fatal infection caused by a pathogen that usually causes only a mild or non-fatal disease (eg, influenza). This panel targets IEIs that lead to susceptibility to viruses or to a subset of viruses, severe viral pneumonia, or a specific virus. Examples of infections where this gene panel is useful include EBV, skin-tropic beta-HPV, influenza, and SARS-CoV-2. IEIs that lead to systemic immune deficiencies and susceptibility to a large variety of pathogens (eg, T-cell deficiencies) are not included in this panel.

EBV is the cause of infectious mononucleosis and persists asymptomatically for life in nearly all adults. It is also associated with the development of T- and B-cell lymphomas, nasopharyngeal and gastric carcinomas, and other malignancies. EBV infection in IEIs can present with fulminant infectious mononucleosis, hemophagocytosis, B-cell proliferative disease (including lymphoma), and hypogammaglobulinemia.

Beta-HPVs circulate silently in the general population and cause no visible lesions in most people. Genetic susceptibility to beta-HPVs leads to warts, pityriasis-like lesions, epidermodysplasia verruciformis, and increased risk of non-melanoma skin cancers.

Seasonal influenza viruses are common RNA viruses that infect the respiratory tract, causing a benign illness in most infected individuals. Influenza pneumonia or acute respiratory distress syndrome are rare, and the case fatality ratio is less than 1%. Children with severe influenza have been found to carry defects in IRF7, IRF9, STAT1, STAT2, and TLR3. Similarly, the COVID-19 pandemic has revealed that SARS-CoV-2 infection can lead to asymptomatic infection as well as fatal pneumonia. Genetic studies showed that approximately 2 to 3% of cases of severe life-threatening SARS-CoV-2 infection resulted from IEI, mainly genetic defects in the TLR3- or TLR7-dependent type 1 interferon pathway (eg, TLR3, TLR7, IFNAR1/2, STAT2, and IRF7), overlapping with that of severe pneumonia susceptibility in influenza infections.