key: cord-0704468-nv0m8jep authors: Ortona, Elena; Buonsenso, Danilo; Carfi, Angelo; Malorni, Walter title: Long COVID: an estrogen-associated autoimmune disease? date: 2021-04-13 journal: Cell Death Discov DOI: 10.1038/s41420-021-00464-6 sha: 9390639bee23ea6050fac68bc79eb582fb8b89f8 doc_id: 704468 cord_uid: nv0m8jep nan Some people who have had severe to a moderate or mild form of COVID-19 disease may suffer from variable and debilitating symptoms for many months after the initial infection 1 . This condition is commonly called "Long COVID". An exact definition is missing, but symptoms with a duration of more than 2 months are typically considered as Long COVID. The condition is characterized by long-term sequelae and can involve a range of symptoms such as persistent fatigue, headache, shortness of breath, anosmia, muscle weakness, fever, cognitive dysfunction (brain fog), tachycardia, intestinal disorders, and skin manifestations. Long COVID syndrome bears a similarity to the post-infectious syndromes that followed the outbreaks of chikungunya 2 and Ebola 3 . In general, 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. In addition to being a woman, older age and a higher body mass index also seem to be risk factors for having Long COVID 4 . What are the factors responsible for this syndrome? Organ damage caused by an excessive inflammatory response activated by the virus, but also an autoimmune reaction "unmasked" by the virus itself, perhaps due to molecular mimicry with some components of our body, could be responsible for the symptoms of Long COVID 5 . The autoimmune hypothesis could justify the higher incidence of this syndrome in women. In fact, the immune response for both genetic and hormonal factors is stronger in women than in men and this represents a double-edged sword: the outcome of acute COVID-19 is more severe in men but autoimmune reactions are more frequent in women 6, 7 . Hence, the study of the appearance of autoantibodies in patient serum and the characterization of the specificity of these autoantibodies could be an important goal to begin to identify personalized and specific treatments also based on the sex of patients affected by Long COVID. Recently, the persistence of symptoms following the initial diagnosis of acute COVID-19 has also been demonstrated in the pediatric age 8, 9 . In particular, in previous work in a cohort of 129 children with a microbiologically confirmed diagnosis of COVID-19, 27.1% of children have been reported to have at least one symptom more than 120 days after the first diagnosis, whereas three or more symptoms have been reported by 20.6% of children 9 . The most frequent symptoms were muscle and/or joint pain, headache, sleep disturbances, chest pain or chest tightness, palpitations, and sleep disturbances. These symptoms have also been described in children who did not need hospitalization at the time of acute illness or in some with initial asymptomatic SARS-CoV-2 infection. Since sex differences in the occurrence of these symptoms were not considered in the reported study, we now analyzed data disaggregated by sex (Table 1 ). In general, we found that the majority of symptoms were equally distributed in the two sex, with some exceptions such as headache (16.1 vs. 4.5%), altered smell (6.5 vs. 3%) and taste (4.8 vs 1.5%), and insomnia (22.6 vs. 14.9%), which were more frequently reported in females, although without statistical significance, probably due to the overall low number of children reporting those symptoms. According to our data, a recent preprint assessing the impact of sex in 990 children with acute COVID-19 in Latin America, did not show significant differences 10 Although these findings did not show sex differences in pediatric Long COVID, studies on larger cohorts are still needed to achieve stronger conclusions. Conversely, it is also possible that sex differences may be less evident in children compared with adults, due to the lower impact of sex hormones on inflammatory/immune and autoimmune processes in the younger patients. This hypothesis could support the key role of sex hormones in Long COVID clinical features. Long-term consequences of COVID-19: research needs Chikungunya-induced arthritis in Reunion Island: a Long-term observational follow-up study showing frequently persistent joint symptoms, some cases of persistent chikungunya immunoglobulin M positivity, and no anticyclic citrullinated peptide seroconversion after 13 years Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symtoms StudyApp Rogue antibodies could be driving severe COVID-19 Immune response and autoimmune diseases: a matter of sex Immune determinants of COVID-19 disease presentation and severity Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19 Preliminary evidence on Long Covid in children Influence of sex on disease severity in children with COVID-19 and Multisystem Inflammatory Syndrome in Latin America We are grateful to the Family Pediatricians of the Federazione Italiana Medici Pediatri of Rome, Italy. This work was funded by the COVID-2020-12371817 grant from the Italian Ministry of Health. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.