Long COVID: to investigate immunological mechanisms and sex/gender related aspects as fundamental steps for tailored therapy

Abstract

Around a quarter of people who have had COVID-19 experience symptoms that continue for at least a month but one in ten are still unwell after 12 weeks. This very debilitating condition has been defined by patient groups as “Long COVID” elsewhere called post-COVID, whereas the patients are frequently called COVID-19 long-haulers [1]. Long COVID has a serious impact on patient ability to go back to work or school, to have a social life and may have significant economic consequences for patients, their families and for society. The condition is characterized by long-term sequelae and can involve a range of about 200 different and overlapping symptoms such as persistent fatigue, chest and muscle pain, headache, shortness of breath, anosmia, muscle weakness, fever, cognitive dysfunction (brain fog), tachycardia, intestinal disorders and skin manifestations. It can affect anyone but women appear to be twice as likely to develop Long COVID as men, but only until around age 60, when the risk level becomes similar [2–4]. Long COVID has also been described in paediatric age [5]. An Italian study reported that at least one symptom persisted 4 months after COVID-19 infection [6] whereas an Australian analysis suggested that only 8% of children had ongoing symptoms 3–6 months after mild SARS-Cov-2 infection [7]. No gender difference was observed in the prevalence of Long-COVID in this population [5].

One-Year Multidisciplinary Follow-Up of Patients With COVID-19 Requiring Invasive Mechanical Ventilation

“…Several hypothesis have been made to explain the long-COVID, and as well as for the post-intensive care syndrome its pathophysiology is probably multifactorial: an excessive inflammatory response, the persistence of the virus in certain reservoir tissues, the immune dysregulation leading to reactivation of pathogens, the role of the host microbiome, coagulation and clotting abnormalities, autoimmunity, and a direct role of the virus. 60 Inside this complex disease, we found a relatively low prevalence of neurologic impairment at 1-year as compared with previous literature and studies with shorter follow-up. 61 Indeed, among COVID-19 survivors, anxiety, depression, sleep disturbance and PTSD were reported up to 30-40%.…”

Post–COVID-19 syndrome and humoral response association after 1 year in vaccinated and unvaccinated patients

“…Post-coronavirus disease 2019 (COVID-19) syndrome is a heterogeneous, multisystemic, post-acute sequelae impacting health and the quality of life of all ages ( 1 , 2 , 3 ). The potential pathophysiological mechanisms are unknown and may encompass a complex interaction between the virus-specific cytopathic effects, the inflammatory damage, the allo- and autoimmune responses to the acute infection on the one hand, and the expected sequelae of post-critical illness due to organ and microvascular damage on the other ( 4 ). To date, there is still a gap on how natural immunity and hybrid immunity, which refer to the immune-strengthening effect of exposure to infection followed by vaccination, function in post-COVID 19 ( 5 , 6 , 7 ).…”

Multiomics integration-based molecular characterizations of COVID-19

“…Clinical manifestations differ with age, although populations of all ages are susceptible to SARS-CoV-2 infection [ 17 ]. For instance risk factors for developing severe respiratory disease include higher age, male sex, and a number of pre-existing chronic disease, particularly multi-morbidity [ 17 ]; female gender is a risk factor for the long-term symptoms of fatigue combined with vagual and/or respiratory dysfunction associated with post-acute COVID syndrome (PACS), whereas the majority of previously healthy young adults, youth and children present with mild or even asymptomatic disease [ 23 , 24 ]. Multiple symptoms have been reported in COVID-19, including but not limited to fever, cough, myalgia, hemoptysis, diarrhea and olfactory and taste disorders [ 25–29 ].…”

“…The latter group typically consists of patients who are young, previously healthy, and mentally and physically strong [ 63 , 64 ]. In addition, the female gender appears to be twice as likely to develop long COVID as males [ 24 ]. The most common long-term sequelae symptoms include fatigue, dyspnea, chest pain, recurring fever, neurological complaints, olfactory dysfunctions, tachycardia, intestinal disorders and skin manifestations, and possibly unrelated to the severity of the initial acute infection [ 9 , 24 , 62–64 ].…”

“…In addition, the female gender appears to be twice as likely to develop long COVID as males [ 24 ]. The most common long-term sequelae symptoms include fatigue, dyspnea, chest pain, recurring fever, neurological complaints, olfactory dysfunctions, tachycardia, intestinal disorders and skin manifestations, and possibly unrelated to the severity of the initial acute infection [ 9 , 24 , 62–64 ]. In the Coverscan study [ 65 ], damage to at least one organ was observed in 70% of patients, with multiple organ damage appearing in 25% of patients with long COVID.…”