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.
| Patient and disease features | Total | M | F | P value |
|---|---|---|---|---|
| n = 129 | n = 67 | n = 62 | ||
| Age | 11.0 (4.4) | 11.2 (4.5) | 10.8 (4.4) | 0.585 |
| Symtomatic acute COVID-19 | 96 (74.4%) | 50 (74.6%) | 46 (74.2%) | 1 |
| Hospitalized during acute COVID-19 | 6 (4.7%) | 5 (7.5%) | 1 (1.6%) | 0.247 |
| Admitted in PICU | 3 (2.3%) | 2 (3%) | 1 (1.6%) | 1 |
| Timing of survey after acute COVID-19 diagnosis (days) | 0.56 | |||
| <60 | 31 (24%) | 17 (25.4%) | 14 (22.6%) | |
| 60–119 | 30 (23.3%) | 13 (19.4%) | 17 (27.4%) | |
| 120 or more | 68 (52.7%) | 37 (55.2%) | 31 (50%) | |
| Any persisting symptoms at time of survey | 0.909 | |||
| None | 54 (41.9%) | 28 (41.8%) | 26 (41.9%) | |
| 1–2 | 46 (35.7%) | 23 (34.3%) | 23 (37.1%) | |
| 3 or more | 29 (22.5%) | 16 (23.9%) | 13 (21%) | |
| Signs and symptoms reported | ||||
| Fatigue_ | 0.703 | |||
| Less | 1 (0.8%) | 1 (1.5%) | 0 (0%) | |
| A bit less | 16 (12.4%) | 9 (13.4%) | 7 (11.3%) | |
| Same | 98 (76%) | 50 (74.6%) | 48 (77.4%) | |
| A bit more | 13 (10.1%) | 7 (10.4%) | 6 (9.7%) | |
| More | 1 (0.8%) | 0 (0%) | 1 (1.6%) | |
| Nasal congestion | 16 (12.4%) | 9 (13.4%) | 7 (11.3%) | 0.919 |
| Difficulty breathing | 8 (6.2%) | 4 (6%) | 4 (6.5%) | 1 |
| Pain on breathing | 5 (3.9%) | 3 (4.5%) | 2 (3.2%) | 1 |
| Chest pain | 4 (3.1%) | 2 (3%) | 2 (3.2%) | 1 |
| Persistent cough | 7 (5.4%) | 6 (9%) | 1 (1.6%) | 0.147 |
| Persistent muscle pain | 13 (10.1%) | 8 (11.9%) | 5 (8.1%) | 0.661 |
| Joint pain | 9 (7%) | 5 (7.5%) | 4 (6.5%) | 1 |
| Headache | 13 (10.1%) | 3 (4.5%) | 10 (16.1%) | 0.057 |
| Altered smell | 6 (4.7%) | 2 (3%) | 4 (6.5%) | 0.606 |
| Altered taste | 4 (3.1%) | 1 (1.5%) | 3 (4.8%) | 0.557 |
| Lack of concentration | 13 (10.1%) | 6 (9%) | 7 (11.3%) | 0.883 |
| Insomnia | 24 (18.6%) | 10 (14.9%) | 14 (22.6%) | 0.374 |
| Hypersomnia | 4 (3.1%) | 3 (4.5%) | 1 (1.6%) | 0.668 |
| Weight loss | 10 (7.8%) | 7 (10.4%) | 3 (4.8%) | 0.389 |
| Poor appetite | 10 (7.8%) | 6 (9%) | 4 (6.5%) | 0.84 |
| Diarrhea | 2 (1.6%) | 1 (1.5%) | 1 (1.6%) | 1 |
| Abdominal pain | 3 (2.3%) | 1 (1.5%) | 2 (3.2%) | 0.946 |
| Constipation | 8 (6.2%) | 5 (7.5%) | 3 (4.8%) | 0.801 |
| Skin rash | 9 (7%) | 6 (9%) | 3 (4.8%) | 0.568 |
| Palpitations | 5 (3.9%) | 3 (4.5%) | 2 (3.2%) | 1 |
| Changes menstruation | 2 (1.6%) | 0 (0%) | 2 (3.2%) | 0.442 |
| Do these symptoms distress your child? | 0.976 | |||
| Not at all | 66 (51.2%) | 34 (50.7%) | 32 (51.6%) | |
| Only a little | 36 (27.9%) | 18 (26.9%) | 18 (29%) | |
| Quite a lot | 14 (10.9%) | 8 (11.9%) | 6 (9.7%) | |
| A great deal | 2 (1.6%) | 1 (1.5%) | 1 (1.6%) | |
| Preferred not to say | 11 (8.5%) | 6 (9%) | 5 (8.1%) | |
| Quality of life Before COVID-19 | 96.3 (5.3) | 96.0 (5.5) | 96.7 (5.0) | 0.476 |
| Quality of life at the time of the survey | 92.9 (9.1) | 92.9 (9.1) | 92.8 (9.3) | 0.987 |
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.
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.
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
A list of authors and their affiliations appears at the end of the paper.
Contributor Information
Walter Malorni, Email: Walter.Malorni@unicatt.it.
The Long Covid Kids study group:
Daniel Munblit, Cristina De Rose, Dario Sinatti, Antonia Ricchiuto, and Piero Valentini
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