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Antinucleocapsid Antibody Detection Can Help Diagnose Postacute Sequelae of SARS-CoV-2, Improve Treatment Access


Researchers investigated methods for measuring prior exposure in patients with suspected, undocumented COVID-19 infection to give better access to care and counsel.

Researchers successfully detected evidence of prior SARS-CoV-2 infection in patients with post-viral syndrome (PVS) who had no documented positive test, according to a new study published in Neurology Neuroimmunology & Neuroinflammation.

Postacute sequelae of SARS-CoV-2 infection (PASC), also referred to as long COVID-19, is identified when physical, cognitive, or mental health symptoms last for an extended period following acute COVID-19 infection. Neurological symptoms often accompany PASC—deemed Neuro-PASC (NP)—such as headache, fatigue, cognitive impairment, autonomic disturbances, myalgia, among others.

It is reported that up to one-third of COVID-19 survivors develop PASC; however, these data cannot account for those with limited access to testing at the beginning of the pandemic or who were tested too late for SARS-CoV-2 detection. As a result, countless individuals who have developed PVS akin to PASC are unaware of their condition and are left without appropriate treatment or diagnosis.

A total of 29 patients with PVS associated with a suspected COVID-19 infection participated in assessments between June 2020 and April 2022 at Northwestern Medicine's Neuro COVID-19 clinic. Their cases were age- and sex-matched with 32 confirmed cases of NP (which had positive laboratory tests), and both groups were compared with a control of 18 nonexposed patients.

Thirty mL of blood were collected from the participants, and the amounts of antigen-specific antibody titers against the Spike receptor-binding domain (S-RBD) and the SARS-CoV-2 Nucleocapsid (N) protein were measured. At the time of their clinic visit, patients also completed a PROMIS quality of life measure to gauge their subjective perceptions of cognitive function, anxiety, depression, sleep disturbance, and fatigue. To objectively assess them for cognitive dysfunction (working memory, attention, processing speed, executive functioning), an NIH Toolbox was also given out.

Patients with PVS had a median age of 43, and most (93% each) were White and female, which did not differ significantly from the NP group. Six of the 29 patients with PVS were vaccinated. Their virus-specific immune responses were determined with a Spike or Nucleocapsid ELISA and an IFN-γ ELISPOT to measure antibody and T-cell production.

Antibodies against S-RBD were detected in 2 of 23 unvaccinated patients with PVS, while 5 of 29 exhibited anti-Nucleocapsid antibodies. Researchers confirmed that the NP group had overall greater titers of both antibodies compared with the control and PVS groups.

Positive responses for T-cell activation occurred in 6 of 24 (25%) tested patients with PVS. The NP group demonstrated a similar response, but both of these groups showed increased levels of IFN-γ compared with the control group.

A SARS-CoV-2-specific immune response registered in 41% (12/29) patients with PVS—these individuals are now deemed PVS responders. These patients held many clinical similarities to their NP counterparts; however, they were appearing for clinical evaluations much later from the onset of their symptoms (10.7 vs 5.4 months; P = .0006).

Individuals with PVS and NP reported similar quality of life measures; their subjective perceptions of anxiety, depression, cognitive functioning, and fatigue were all lower compared to the normative population. Regarding objective cognitive measures, patients with PVS had higher scores for working memory but otherwise similar results for attention, processing speed, and executive functioning to patients with NP.

This study found that adaptive, specific immune responses to SARS-CoV-2 could be seen in a considerable amount of patients with PVS after a suspected COVID-19 infection. The clinical presentation and immune responses in patients with PVS carried many similarities to patients with NP who had previous, laboratory-confirmed COVID-19 exposure.

The researchers mention the importance of anti-Nucleocapsid antibody testing for the future of patient care. Previous data have revealed the promise of measuring for N-specific T-cell and antibody responses to determine SARS-CoV-2 infection associated with PVS. Additionally, because a large population of US individuals have already received Spike COVID-19 vaccinations, focusing on anti–N antibody response is imperative for detecting prior exposure for patients without a documented positive test.

In their concluding thoughts, the authors discuss how COVID-19 and these obstacles in accessing certain health care have revealed a noteworthy disparity in populations reeling from undiagnosed SARS-CoV-2 infection.

Although their small sample size largely consisted of White females, individuals sharing their experiences represent an underserved population because most post-COVID-19 clinics in the US require proof of exposure before administering any treatment. Considering their findings, future screenings for patients with PVS should implement an evaluation of anti–Nucleocapsid antibody responses to guide the course of patient treatment.

“Patients with PVS may benefit from the same clinical care as confirmed patients with NP, and the absence of a positive SARS-CoV-2 test should not preclude or delay treatment.”

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