Long COVID: Contrary To Earlier Assumptions, U.S. Study Finds That Interferon Autoantibodies Are Not Involved In Long COVID Conditions

Long COVID: Study findings by researchers from University of California-San Francisco-USA has dispelled the hypothesis that interferon autoantibodies are involved in causing Long COVID conditions.


 
For a while now, interferon (IFN)–specific autoantibodies have been implicated in severe coronavirus disease 2019 (COVID-19) and have been proposed as a potential driver of the persistent symptoms characterizing “Long COVID,” a type of postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
 
The study team reported that only 2 of 215 participants with convalescent SARS-CoV-2 infection tested over 394 time points, including 121 people experiencing Long COVID symptoms, had detectable IFN-α2 antibodies. Both had been hospitalized during the acute phase of the infection.
 
The study findings suggest that persistent anti-IFN antibodies, although a potential driver of severe COVID-19, are unlikely to contribute to Long COVID symptoms in the post-acute phase of the infection.
 
The study findings were published in the peer reviewed journal: The Journal of Infectious Diseases.
https://academic.oup.com/jid/article/227/2/246/6696027?login=false
 
Typically, IFNs play a crucial function in innate antiviral immune reactions. It has been demonstrated that SARS-CoV-2 infection inhibits type I and III IFN responses. In addition, the existence of IFN-specific autoantibodies has been suggested as a possible cause of post-acute sequelae of COVID-19 (PASC), particularly long-COVID.
 
A recent provocative investigation established a correlation between IFN-ɑ2-specific autoantibodies and pulmonary symptoms during acute COVID-19, as well as two to three months after initial SARS-CoV-2 infection presentation.
https://pubmed.ncbi.nlm.nih.gov/35216672/

The study team in the current study, obtained samples as well as demographic, clinical, and symptom data from the Long-term Impact of Infection with Novel Coronavirus (LIINC) research participants who had nucleic acid-confirmed COVID-19, many of whom developed post-COVID-19 conditions like long-COVID.
 
For the study, patients with a history of COVID-19 verified by nucleic acid amplification tests were recruited. Whole-blood samples containing ethylenediaminetetraacetic acid were centrifuged to obtain plasma.
 
Blood samples were obtained between April 21, 2020, and June 29, 2021. These specimens accounted for all cohort members who were enrolled prior to receiving the SARS-CoV-2 vaccination.
 
For each visit, long-COVID was diagnosed using cross-sectional analysis. Long COVID was defined in as the presence of COVID-19-attributable symptoms observed at a visit 60 days or more after the onset of initial SARS-CoV-2 symptoms. An immunoprecipitation technique was employed to quantify anti-IFN-ɑ2 antibodies.
 
All biospecimens were collected at 394-time points between 0.5 and 14.7 months after the onset of symptoms from 215 unique subjects. Ninety-nine participants were women, and 48 were hospitalized due to acute COVID-19. Out of the hospitalized patients, 16 were in the intensive care unit, while six needed mechanical ventilation.
 
In all, a total of 272 of the 394-time points that represented 185 unique participants occurred 60 days after the onset of COVID-19 symptoms, which facilitated the detection of long-COVID during the visit.
 
However Long COVID criteria were met only by 121 unique subjects over 182 distinct time periods. The cohort suffering from long-COVID was extremely symptomatic.
 
It was noted that the median number of long COVID symptoms at any time point among individuals who reported long COVID symptoms was five. Approximately 64 unique subjects at 91-time points reported five or more symptoms, while 22 unique subjects at 29-time points reported over ten symptoms.
 
Importantly, autoantibodies specific to IFN-ɑ2 were found in only two of 215 subjects across all time points. Anti-IFN antibodies were identified in the first participant 87 and 115 days after acute COVID-19 infection.
 
Interestingly, ten days after COVID-19 symptom onset, this patient originally presented in the spring of 2020 with pulseless electrical activity arrest necessitating resuscitation and artificial respiration. Following hospitalization, he reported intermittent neuropathic pain condition and persistent anosmia for 18 months or more, and occasional viral shedding confirmed with clinical nucleic acid amplification tests for almost six months.
 
The other patient exhibited measurable anti-IFN antibodies approximately 41 and 90 days after acute COVID-19 and required supplementary oxygen when hospitalized in early 2021. Thereafter, he was diagnosed with long-COVID, characterized by fatigue, headache, shortness of breath, alterations in vision, peripheral neuropathy, and concentration difficulties that were persistent for at least 12 months.
 
It was found that in both patients, chronic symptoms were accounted for by long-COVID, despite the fact that both patients had complex hospital courses that could have led to post-hospitalization disorders.
 
In contrast to these two patients with IFN-ɑ2-specific autoantibodies, most of the study group exhibited no levels of detectable anti-IFN antibodies at any time period.
 
Most importantly, autoantibodies specific to IFN-ɑ2 were not detected in any of the outpatients treated for COVID-19. In addition to the two people described here, IFN-ɑ2-specific autoantibodies were not detected in any additional individuals who developed moderate-to-severe COVID symptoms lasting up to two years.
 
Surprisingly, anti-IFN-ɑ2 antibodies, which serve as a contributing factor to severe acute COVID-19 and play a potential role in long-COVID symptoms, were uncommon in the post-acute COVID-19 sample that included long-COVID patients.
Type 1 IFN responses play a dual role in viral infection; while they exert antiviral activity during the acute phase of many infections, paradoxically they can contribute to the establishment of chronic infection through their immunoregulatory roles.
https://pubmed.ncbi.nlm.nih.gov/25043006/
 
The growing indirect evidence in long COVID including the nature of symptoms, female preponderance, and up-regulation of other cytokines, argues that excess signaling rather than inhibition might be more likely to contribute to this condition.
 
Taken in context, the study findings suggest that while anti-IFN antibodies may contribute to severe SARS-CoV-2 infection, their presence is unlikely to be a primary driver of long COVID symptoms, particularly in those who were not hospitalized during the acute phase of COVID-19.
 
However, the study findings do not negate the hypothesis that other autoreactive antibodies that develop during SARS-CoV-2 infection may target portions of the human proteome leading to tissue damage and the pathophysiological development of long COVID. For example, one study demonstrated the presence of autoantibodies targeting G protein–coupled receptors involved in cardiovascular and neurologic function in patients recovering from COVID-19.
https://pubmed.ncbi.nlm.nih.gov/33880442/
 
Considering the heterogeneous nature of long COVID and the various terminology used to describe the syndrome, understanding the causes of long COVID presents a number of obstacles. This further underscores the necessity for clear and larger mechanistic research in clinical cohorts.
 
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