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In a recent study posted to the medRxiv* preprint server, researchers assessed the prevalence of antibodies that neutralize the type I interferon (IFN) antiviral activity and reactivate herpesviruses such as herpes simplex virus types 1 and 2 (HSV-1/-2) and/or cytomegalovirus (CMV) infections in patients with critical coronavirus disease 2019 (COVID-19).

Background

Type I IFN deficiency can predispose individuals to severe COVID-19 and herpesvirus reinfections, most significantly infections due to pathogens with novel antigens, against which serological immunity is deficient. Despite the established IFN importance in preserving herpesvirus latency, tamoxifen risks endometrial cancer data on the association between anti-IFN antibodies and the clinical outcomes and herpesvirus reinfections in critical COVID-19 patients are limited. 

About the study
In the present study, researchers assessed the presence of immunoglobulins (IgM, IgA, and IgG) that neutralize the antiviral action of type I IFNs (IFNα2/IFNω/IFNβ) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) critical infections. They also analyzed the severity of COVID-19 in patients with anti-IFN antibodies and investigated whether these antibodies correlated with the HSV and/or CMV reactivations.

This study was a part of the government-registered MicrobiotaCOVID clinical trial conducted at the Institute of Intensive Care Medicine of the University Hospital in Zurich, Switzerland, and the Infectious Diseases and Hospital Epidemiology department of the same university.

Over 100 subjects with COVID-19-associated acute respiratory distress syndrome (CARDS) admitted to the intensive care unit (ICU) during March 2020 and April 2021 were enrolled for the study. For comparison, serum samples of 130 healthy adults were supplied by the Zurich Blood Transfusion Service of the Swiss Red Cross. These control patients had participated in a pre-pandemic study previously. Tracheobronchial secretions were obtained from 88 critical COVID-19 patients.

COVID-19 was confirmed by real time-reverse transcription-polymerase chain reaction (RT-PCR). Viral loads of HSV-1/-2, varicella-zoster virus (VZV), and CMV were assessed in critical COVID-19 patients. Viral reactivation was described as the PCR-confirmed presence of CMV, HSV-1 and 2, or VZV in the serum and/or clinical manifestations of viral reactivation such as herpes zoster, herpes labialis, tracheobronchitis, and mucositis inclusive of genital tract manifestations stomatitis. 

The presence of serum anti-IFN antibodies was detected using multiplexed magnetic bead-based serological assays. Additionally, antibody binding assays were used to evaluate the presence of anti-IFNα2 and anti-IFNω IgG, IgA, and IgM antibodies in tracheobronchial samples to determine whether COVID-19 had direct effects on the IFN system.

The association between the presence of anti-IFN antibodies and herpesvirus reactivations was evaluated using logistic regression models. 

Results

The study cohort comprised mostly middle-aged men (77.7%, mean age 56 years) admitted to the ICU due to critical COVID-19. 

Eleven critical COVID-19 patients (10.7%), but not those with mild infections and healthy controls, had serum neutralizing anti-IFNα2 IgG and/or anti-IFNω IgG. However, anti-IFN IgA or IgM antibodies and anti-IFNβ antibodies were rarely detected. One patient had non-neutralizing anti-IFNα2 IgG. Strikingly, all patients with plasma anti-IFNα IgG also had anti-IFNα IgG in tracheobronchial secretions, thus identifying these antibodies at anatomical sites relevant for critical COVID-19.

Of note, all seven COVID-19 patients with anti-IFN IgG antibodies in the study cohort suffered from one or more HSV reactivations and were significantly more likely to experience CMV reactivation than COVID-19 patients without anti-IFN antibodies, even after steroid treatment adjustments. The presence of anti-IFN antibodies was also associated with worsened clinical outcomes.

About 20% of COVID-19 patients with anti-IFN autoantibodies died, and these deaths were significantly higher in individuals aged above 70 years (4%) compared to those below 70 years of age (0.2%). The presence of these antibodies in pre-pandemic samples obtained from a few individuals who subsequently developed critical COVID-19 indicates that COVID-19 is not directly responsible for the presence of anti-IFN antibodies. Still, these antibodies could predispose individuals to critical COVID-19 infections.

Conclusion

To conclude, IFN deficiency due to the presence of neutralizing anti-IFN antibodies, especially anti- anti-IFNα2 IgG, exacerbated herpesvirus reactivations in critical COVID-19 patients. Thus, an early diagnosis of anti-IFN IgG antibodies could be beneficial in risk assessment of COVID-19 severity and facilitate the most appropriate treatment for an improved standard of care for the COVID-19 patients. However, further research must be conducted with more homogenous samples that would yield more standardized information and enable the development of therapeutic strategies that restore or preserve IFN function.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information. 

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.