Post-COVID syndrome: the aftershock of SARS-CoV-2

Significant time has passed since the coronavirus disease of 2019 (COVID-19) pandemic outbreak, which led to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in hundreds of millions of individuals all around the globe. Accumulation evidence along the pandemic raised an association between the SARS-CoV-2 and autoimmunity (1). SARS-CoV-2 infected patients have a high presence of various autoantibodies (1). Moreover, numerous cases of new-onset of autoimmune-related disorders had been documented following the infection, including both organ-specific and systemic autoimmune diseases (1).

Recent studies focused on analyzing recovered COVID-19 patients demonstrate a broad spectrum of persistent and systemic symptoms, which had got the novel terms of “post-COVID syndrome”, “long COVID” and “chronic COVID-19” (2). This new disorder had led to the understanding that the absence of SARS-CoV-2 following COVID-19 does not necessarily mean full recovery (2).

Studies conducted follow-ups on COVID-19 patients indicate that 50-80% of symptomatic COVID-19 patients who recovered report non-specific symptoms, most commonly fatigue, headache, dyspnea, anosmia, and memory complaint (3–5). An Italian study that examined patients after a mean of 60 days from the first COVID-19 symptom on-set had found only 12.6% of the patients completely recovered; 55% had three or more symptoms, and worsened quality of life was observed among 44% of patients (3). Intriguingly, a systematic review and meta-analysis reported more than 50 possible long-term effects of the SAR-CoV-2 infection (6). The chronic phase of COVID-19 is also presented in objective findings; for example, a study conducted in Germany had found that 78% of recently recovered symptomatic COVID-19 patients had at least one chronic symptom; the most common abnormality was myocardial inflammation (60%) (4).

In this issue of the journal, Bertin D et al. documented a case of post-COVID syndrome with a one-year follow-up. This case describes persistent anti-cardiolipin IgG autoantibodies and eosinopenia with ongoing neurologic symptoms, demonstrating the long-term disease course of COVID-19 in many patients. Anti-cardiolipin autoantibodies and eosinopenia were defined as independent factors associated with COVID-19 severity, indicating their active involvement in the progression of the disease (7,8). Additional studies that included follow-up on recovered COVID-19 patients describe similar findings: patients report respiratory, neurologic, and non-specific symptoms, accompanied by the presents of autoantibodies (6). Interestingly, in a one-year prospective cohort study, neurocognitive symptoms frequency were found significantly higher in patients with ANA titer of ≥1:160 in comparison to <1:160 at 12 months post–COVID-19 symptom onset (9). It should be emphasized that the development of autoantibodies, which appears to be common following symptomatic SARS-CoV-2 infection, could act as the preclinical stage of many autoimmune diseases. Thus, the long-term autoimmune implications of SARS-CoV-2 could be severe.

Many viruses are well known to contribute to autoimmunity in genetically pre dispositioned individuals, such as those with human leukocyte antigen B27 (10). SARS-CoV-2 had been associated with numerous autoantibodies (1); some are believed to be the basis of the severe forms of COVID-19 (11). Furthermore, these autoantibodies, along with others, could lead to the multi-organ involvement of post-COVID syndrome, which manifests as broad and unspecific symptoms (6). Autoantibodies against the autonomic nervous system compounds are believed to be an incremental part of the post-COVID syndrome etiology. A study that included post-COVID syndrome patients had unidentified in all the subjects between 2 and 7 different functionally active autoantibodies that acted as receptor agonists, such as β2-adrenoceptor, α1-adrenoceptor, and angiotensin II receptor type 1 receptor (12). Functionally active autoantibodies such as those were present in several neurological and cardiac disorders, which might clarify the onset of neurological and cardiovascular symptoms of the post-COVID syndrome (12).

Post-COVID patients commonly have a clinical presentation similar to the encephalomyelitis/chronic fatigue syndrome (ME/CFS): severe fatigue, sleep disorders, cognition impairments, and different manifestations of autonomic dysfunction exacerbated in physical exercise (6,13–15). ME/CFS has an autoimmune etiology, which can be demonstrated by high titers of autoantibodies against autonomic receptors, such as beta-adrenergic and muscarinic receptors (16,17). These autoantibodies, similar to those found in patients with post-COVID symptoms, lead to unspecific symptoms due to autonomic nervous system dysregulation. In addition to ME/CFS, many features of the post-COVID syndrome are shared with fibromyalgia patients. It had been shown that 189/616 (30.7%) of COVID-19 recovered patients satisfied the American College of Rheumatology criteria for fibromyalgia, 43.4% of which were men (18).

ME/CFS and fibromyalgia have solid evidence of dysregulated immune involvement (16,17,19). Moreover, current studies suggest that immunosuppression, such as monoclonal anti-CD20 antibody and cyclophosphamide, may benefit patients suffering from ME/CFS (20,21). Such immunosuppressive therapeutic options can assist in the depletion of B cells, thus reducing the functionally active autoantibodies linked to autonomic dysfunction. Beneficial effects had also been demonstrated by the use of anti-ß2 adrenergic receptor-binding immunoadsorption (22). It should be emphasized that such treatment can diminish other pathogenic antibodies that the medical community had not yet recognized. Due to the possible involvement of autoantibodies against the autonomic nervous system in the post-COVID syndrome, similar immunosuppressive options in these patients may be effective, thereby should be investigated.

Most individuals infected by SARS-CoV-2 are asymptomatic or experience mild symptoms (23,24). While the frequency of post-COVID syndrome in such individuals is still uncertain, it seems to be much lower than in symptomatic patients (9). Thus, avoiding COVID-19 with SARS-CoV-2 vaccination could prominently assist in preventing long-term symptoms of COVID-19, lower the prevalence of post-COVID syndrome and help overcome the pandemic. Nonetheless, even with the ongoing heist mass vaccination programs, the COVID-19 pandemic will leave its mark.

Due to the accumulating evidence of persistent post-infectious symptoms reported by numerous recovered patients, the focus of the medical and research communities might need to start shifting focus from the acute phase of COVID-19 to the chronic manifestations of the SARS-CoV-2 infection, referred to as by “post-COVID syndrome”. Post-COVID syndrome presents as non-specific symptoms, most commonly fatigue, headache, dyspnea, anosmia, and memory complaint, which is suspiciously similar to the infection-induced myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (15,18). As current studies suggest an involvement of immune-related dysfunction in the development of post-COVID syndrome, immunosuppressive therapeutic options could be beneficial in parallel to heist SARS-CoV-2 vaccination of the population (15,20,21).

• 1
  Dotan A, Muller S, Kanduc D, David P, Halpert G, Shoenfeld Y. The SARS-CoV-2 as an instrumental trigger of autoimmunity. Autoimmun Rev. 2021 Apr;20(4):102792.
• 2
  Alwan NA. A negative COVID-19 test does not mean recovery. Nature. 2020 Aug 11;584(7820):170–170.
• 3
  Carfì A, Bernabei R, Landi F, for the Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020 Aug 11;324(6):603–5.
• 4
  Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, et al. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020 Nov 1;5(11):1265–73.
• 5
  Mahmud R, Rahman MM, Rassel MA, Monayem FB, Sayeed SKJB, Islam MS, et al. Post-COVID-19 syndrome among symptomatic COVID-19 patients: A prospective cohort study in a tertiary care center of Bangladesh. PLOS ONE. 2021 Apr 8;16(4):e0249644.
• 6
  Lopez-Leon S, Wegman-Ostrosky T, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep. 2021 Aug 9;11(1):16144.
• 7
  Lindsley AW, Schwartz JT, Rothenberg ME. Eosinophil responses during COVID-19 infections and coronavirus vaccination. Journal of Allergy and Clinical Immunology. 2020 Jul 1;146(1):1-7.
• 8
  Jizzini M, Shah M, Zhou K. SARS-CoV-2 and Anti-Cardiolipin Antibodies. Clinical Medicine Insights: Case Reports. 2020 Dec;13:1179547620980381.
• 9
  Seeßle J, Waterboer T, Hippchen T, Simon J, Kirchner M, Lim A, Müller B, Merle U. Persistent Symptoms in Adult Patients 1 Year After Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2021.
• 10
  Shoenfeld Y, Gilburd B, Abu-Shakra M, Amital H, Barzilai O, Berkun Y, et al. The mosaic of autoimmunity: genetic factors involved in autoimmune diseases–2008. Isr Med Assoc J IMAJ. 2008 Jan;10(1):3–7.
• 11
  Khamsi R. Rogue antibodies could be driving severe COVID-19. Nature. 2021 Jan 19;590(7844):29–31.
• 12
  Wallukat G, Hohberger B, Wenzel K, Fürst J, Schulze-Rothe S, Wallukat A, et al. Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms. J Transl Autoimmun. 2021 Jan 1;4:100100.
• 13
  Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. The Lancet. 2021 Jan 16;397(10270):220–32.
• 14
  Wostyn P. COVID-19 and chronic fatigue syndrome: Is the worst yet to come? Med Hypotheses. 2021 Jan;146:110469.
• 15
  Bornstein SR, Voit-Bak K, Donate T, Rodionov RN, Gainetdinov RR, Tselmin S, Kanczkowski W, Müller GM, Achleitner M, Wang J, Licinio J. Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?. Molecular Psychiatry. 2021 Jun 17:1-4.
• 16
  Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, et al. Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Transl Med. 2018 Oct 1;16(1):268.
• 17
  Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, Meisel C, Reinke P, Volk HD, Fluge Ø, Mella O. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain, behavior, and immunity. 2016 Feb 1;52:32-9.
• 18
  Ursini F, Ciaffi J, Mancarella L, Lisi L, Brusi V, Cavallari C, et al. Fibromyalgia: a new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey. RMD Open. 2021 Aug 1;7(3):e001735.
• 19
  Rodriguez-Pintó I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia and cytokines. Immunol Lett. 2014 Oct;161(2):200–3.
• 20
  Tölle M, Freitag H, Antelmann M, Hartwig J, Schuchardt M, van der Giet M, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption. J Clin Med. 2020 Aug;9(8):2443.
• 21
  Rekeland IG, Fosså A, Lande A, Ktoridou-Valen I, Sørland K, Holsen M, et al. Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study. Front Med. 2020;7:162.
• 22
  Scheibenbogen C, Loebel M, Freitag H, Krueger A, Bauer S, Antelmann M, et al. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PloS One. 2018;13(3):e0193672.
• 23
  Salzberger B, Buder F, Lampl B, Ehrenstein B, Hitzenbichler F, Holzmann T, et al. Epidemiology of SARS-CoV-2. Infection. 2021 Apr;49(2):233–9.
• 24
  Gao Z, Xu Y, Sun C, Wang X, Guo Y, Qiu S, et al. A systematic review of asymptomatic infections with COVID-19. J Microbiol Immunol Infect Wei Mian Yu Gan Ran Za Zhi. 2021 Feb;54(1):12–6.