Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Long COVID: an estrogen-associated autoimmune disease?

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 infection1. 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 chikungunya2 and Ebola3.

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 COVID4.

Autoimmune hypothesis and Long COVID

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 COVID5. 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 women6,7. 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.

Long COVID in the child

Recently, the persistence of symptoms following the initial diagnosis of acute COVID-19 has also been demonstrated in the pediatric age8,9. 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 children9. 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 differences10

Table 1 Details of persisting symptoms of children with COVID-19, according to sex.

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.

References

  1. 1.

    Yelin, D. et al. Long-term consequences of COVID-19: research needs. Lancet Infect. Dis. 20, 1115–1117 (2020).

    CAS  Article  Google Scholar 

  2. 2.

    Guillot, X., Ribera, A. & Gasque, P. 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. J. Infect. Dis. 222, 1740–1744 (2020).

    Article  Google Scholar 

  3. 3.

    Clark, D. V. et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect. Dis. 15, 905–912 (2015).

    Article  Google Scholar 

  4. 4.

    Sudre, C. H. et al. Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symtoms StudyApp. Nat Med. https://doi.org/10.1038/s514591-021-01292-y (2021).

  5. 5.

    Khamsi, R. Rogue antibodies could be driving severe COVID-19. Nature 590, 29–31 (2021).

    CAS  Article  Google Scholar 

  6. 6.

    Dupuis, M. L. et al. Immune response and autoimmune diseases: a matter of sex. Ital. J. Gend. Specif. Med. 5, 11–20 (2019).

    Google Scholar 

  7. 7.

    Brodin, P. Immune determinants of COVID-19 disease presentation and severity. Nat. Med. 27, 28–33 (2021).

    CAS  Article  Google Scholar 

  8. 8.

    Ludvigsson, J. F. Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19. Acta Paediatr. 110, 914–921 (2021).

    CAS  Article  Google Scholar 

  9. 9.

    Buonsenso, D. et al. Preliminary evidence on Long Covid in children. Acta Paediatr. https://doi.org/10.1111/apa.15870 (2021).

  10. 10.

    Brizuela, M. et al. Influence of sex on disease severity in children with COVID-19 and Multisystem Inflammatory Syndrome in Latin America. Preprint at medRxiv https://doi.org/10.1101/2021.02.07.21251212 (2021).

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to Walter Malorni.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ortona, E., Buonsenso, D., Carfi, A. et al. Long COVID: an estrogen-associated autoimmune disease?. Cell Death Discov. 7, 77 (2021). https://doi.org/10.1038/s41420-021-00464-6

Download citation

Search

Quick links