Refining “long-COVID” by a prospective multimodal evaluation of patients with long-term symptoms related to SARS-CoV-2 infection (preprint)

ABSTRACT

Background COVID-19 long-haulers or “long-COVID” 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, psychological, virological, specific immunological assays and were followed longitudinally. Results The median age was 40 [interquartile range 35-54] and 18 (60%) were female. After a median time of 152 [102-164] days after symptom onset, fever, cough and dyspnea were less frequently reported as 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 analogic scales were 7 [5-8] and 5 [2-6], respectively. Extensive biological studies were unremarkable, as were multiplex cytokine and ultra-sensitive interferon-a2 measurements. At this time, nasopharyngeal swab and stool RT-PCR were negative for all tested patients. 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 objective evidence of lack or waning of immune response in two. 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 long-COVID lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity did not cluster clinically or biologically long haulers, who reported severe fatigue, altered quality of life, and exhibited psychological distress. Key points Among 30 consecutive patients reporting persistent symptoms (median 6 months) self-attributed to COVID-19, pain, fatigue and disability were reported in virtually all patients. More than one third of patients suffer from psychological disorders such as anxiety, depression and/or post-traumatic stress disorder, regardless of SARS-CoV-2 immunity. At the time of evaluation, only 50% of patients had cellular and/or humoral sign of a past SARS-CoV-2, and serology positivity varied depending of the kit used. Exhaustive clinical, biological and immunological evaluations failed to find an alternative diagnosis, or to identify specific cytokine signature including type I interferon.