Refining "Long-COVID" by a Prospective Multimodal Evaluation of Patients with Long-Term Symptoms Attributed to SARS-CoV-2 Infection

Abstract

Introduction: COVID-19 long-haulers, also decribed as having "long-COVID" or post-acute COVID-19 syndrome, represent 10% of COVID-19 patients and remain understudied.

Methods: In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation, including clinical, psychologic, virologic and specific immunologic assays and were followed longitudinally. A group of 17 convalescent COVID-19 individuals without persistent symptoms were included as a comparison group.

Results: The median age was 40 [interquartile range: 35-54] years and 18 (60%) were female. At a median time of 152 [102-164] days after symptom onset, fever, cough and dyspnea were less frequently reported compared with the initial presentation, but paresthesia and burning pain emerged in 18 (60%) and 13 (43%) patients, respectively. The clinical examination was unremarkable in all patients, although the median fatigue and pain visual analog scales were 7 [5-8] and 5 [2-6], respectively. Extensive biologic studies were unremarkable, and multiplex cytokines and ultra-sensitive interferon-α2 measurements were similar between long-haulers and convalescent COVID-19 individuals without persistent symptoms. Using SARS-CoV-2 serology and IFN-γ ELISPOT, we found evidence of a previous SARS-CoV-2 infection in 50% (15/30) of patients, with evidence of a lack of immune response, or a waning immune response, in two patients. Finally, psychiatric evaluation showed that 11 (36.7%), 13 (43.3%) and 9 (30%) patients had a positive screening for anxiety, depression and post-traumatic stress disorder, respectively.

Conclusions: Half of patients seeking medical help for post-acute COVID-19 syndrome lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity, or not, had no consequence on the clinical or biologic characteristics of post-acute COVID-19 syndrome patients, all of whom reported severe fatigue, altered quality of life and psychologic distress.

Keywords: Disability; Long-COVID; Pain; Patient perspective; SARS-CoV-2.

© 2021. The Author(s).

Figures

Fig. 1

Initial and residual clinical features of patients with persistent symptoms self-attributed to COVID-19. a Residual symptoms collected at a median of 152 days (IQR 102–164) after initial presentation (n = 30 patients). Horizontal rectangles indicate symptom prevalence, and bars are standard error measure. P-values were calculated with McNemar’s test with Bonferroni correction for multiple comparisons. b Comparison of initial/residual symptoms between immunized (red rectangles; positive for SARS-CoV-2 IFN-γ ELISPOT and at least one serologic assay) and non-immunized (blue rectangles) patients. Horizontal rectangles and black bars are mean ± standard error measure. *p < 0.05 by chi-square or Fisher’s exact test (if appropriate)

Fig. 2

Specific immunologic responses to SARS-CoV-2 in 30 patients reporting persistent symptoms self-attributed to long-COVID. a Results of SARS-CoV-2 serologic assays, according to the result of the SARS-CoV-2 interferon-γ (IFN-γ) ELISPOT (n = 15/group). Results for the following assays are shown: anti-RBD total antibody (Wantai total antibody); anti-RBD IgG/IgM (Biosynex BSS IgM/IgG assay); anti-S IgG (Euroimmun); anti-N IgG (Abbott Architect). Columns show the prevalence of test positivity, and black bars represent SEM. b Two patterns of patients were identified: those with objective signs of SARS-CoV-2 immunity (cellular AND humoral response, n = 15) and those without (n = 15). Positive IgG was defined as a positive result against spike, receptor binding domain or nucleocapsid protein. *One patient with virologically unproven initial presentation had an isolated anti-S IgG–positive assay result. IFN-γ ELISPOT and 3 other serologic assays were negative

Fig. 3

Normal levels of IFN-α2 for patients with persistent symptoms attributed to COVID-19 compared to convalescent COVID-19 individuals. Ultra-sensitive IFN-α2 levels were measured by using Single Molecule Array (SIMOA) in patients with persistent symptoms self-attributed to COVID-19 (post-acute COVID-19 syndrome) whether they were immunized against SARS-CoV-2 (positive for SARS-CoV-2 IFN-γ ELISPOT and at least one serologic assay, n = 15) or non-immunized (n = 15). As a comparison, results from individuals with confirmed COVID-19 (serology and IFN-γ positive) without persistent symptoms (sampled at least 12 weeks after infection; n = 17) and patients with active systemic lupus erythematosus (n = 18) are shown. Each point corresponds to a single patient; the central bar shows the median with interquartile ranges. The red dotted line shows the lower limit of detection. Ns, non-significant; ***p < 0.001 versus all other groups by non-parametric Kruskal-Wallis test with Dunn’s correction for multiple testing

Fig. 4

Prevalence of anxiety/depression disorders and post-traumatic stress syndrome in patients seeking medical help for persistent symptoms self-attributed to COVID-19. Total population (n = 30, gray bar), patients immunized to SARS-CoV-2 (positive for SARS-CoV-2 IFN-γ ELISPOT and at least one serologic assay, n = 15, red bar) and non-immunized (n = 15, blue bar) are shown. Data are mean and black bars show SEM