Anti-nucleocapsid antibody levels and pulmonary comorbid conditions are linked to post–COVID-19 syndrome

Abstract

BACKGROUND Prolonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive. METHODS Adult SARS-CoV-2 reverse transcription PCR–positive (RT-PCR–positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1–3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit. RESULTS Our cohort ( n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution. CONCLUSION We found that all disease severities had a similar risk of developing post–COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration. TRIAL REGISTRATION ClinicalTrials.gov, NCT04373148. FUNDING NIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.

Elevated SARS-CoV-2-Specific Antibody Levels in Patients with Post-COVID Syndrome

“…Some risk factors for post-COVID syndrome have been identified, such as age, body mass index, gender, and severity of symptoms during acute COVID-19 [ 45 , 46 , 47 , 48 ]. In addition, our and other studies have reported on differential SARS-CoV-2-specific humoral immune responses in convalescents with post-COVID syndrome and the role of the SARS-CoV-2-specific humoral immune response in post-COVID syndrome is still a matter of debate as data are incomplete and even partially contradictory, which may be attributable to the different methodological approaches [ 3 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In our cohort, 84% and 75% of convalescents were positive for anti-spike antibodies at T E and T L , respectively, whereas positivity for anti-nucleocapsid antibodies remained stable with a seroconversion rate of 88% at both timepoints.…”

“…Of note, in hospitalized convalescents similar rates (73%) of post infectious symptoms were observed [ 14 ]. Differences in the prevalence of post-COVID syndrome were most likely due to differing assessment with regards to time points and methods, divergent definitions of post-COVID syndrome, and the baseline characteristics of the convalescents [ 9 , 10 , 14 , 33 , 37 , 41 ]. Currently, the definition of post-COVID syndrome relies on the persistence of symptoms, which cannot be explained by an alternative cause 3 months after COVID-19 and a general definition of symptoms for the diagnosis is missing [ 42 ].…”

“…In addition, we observed significantly increased anti-nucleocapsid antibody levels in post-COVID syndrome patients at an earlier time point 5–6 weeks after positive PCR, which might help to identify convalescents with an increased risk for post-COVID syndrome, as anti-nucleocapsid antibodies are not induced by most of the EMA-approved vaccines. Moreover, faster symptom resolution of acute COVID-19 is associated with higher anti-nucleocapsid antibody levels during the first week after diagnosis, which additionally underlines their importance [ 37 ].…”

“…Direct viral toxicity, endothelial damage, endocrine alterations, dysregulation of the renin–angiotensin–aldosterone system, and dysregulated immune responses, including the development of autoantibodies, have been discussed as probable mechanisms [ 6 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. While the development of the SARS-CoV-2-directed humoral immune response, in terms of the induction of SARS-CoV-2-specfic antibodies, is required for viral clearance in infected individuals and has been reported to be increased in patients with severe COVID-19 [ 26 , 27 , 28 , 29 , 30 , 31 ] the association of humoral immune response and post-COVID syndrome, in particular in non-hospitalized COVID-19 convalescents, is still sparse and even contradictory [ 3 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In this study, we analyzed the occurrence of different post-infectious symptoms (5–6 months after the first positive PCR result) related to early (5–6 weeks after PCR-confirmed COVID-19) and late (5–6 months after positive PCR) humoral immune response against SARS-CoV-2 in 51 non-hospitalized COVID-19 convalescents.…”

The impact of early therapies for COVID-19 on death, hospitalization and persisting symptoms: a retrospective study

“…More intriguing are the possible mechanisms underlying this syndrome that seems to be complex, probably multifactorial and not yet elucidated [35]. Some authors argue that the persistence of SARS-CoV-2 or their antigens can induce a lasting immune response including inflammation, autoimmunity, and disruption of the microbiome [36] and all COVID-19 severities seem to have a similar risk of developing long COVID [37].…”