These differences are most notable between younger age groups (16-59 years) compared to older age groups (60->80 years), and men have different symptoms compared to women in the early stages of COVID-19 infection.
The paper, published today in the Lancet Digital Health, and led by researchers from King’s analyzes data from the ZOE COVID Symptom Study app between April 20th to 15th October 2020. App contributors are invited to get tested as soon as they report any new symptoms, thanks to a joint initiative with the Department of Health and Social Care.
Researchers compared the ability to predict early signs of COVID-19 infection using current National Health Service UK diagnostic criteria and a Hierarchical Gaussian Process model, a type of machine learning.
This machine learning model was able to incorporate some characteristics about the person affected, such as age, sex, and health conditions, and showed that symptoms of early COVID-19 infection are different among various groups.
18 symptoms were examined, which had different relevance for early detection in different groups.
The most important symptoms for earliest detection of COVID-19 overall included loss of smell, chest pain, persistent cough, abdominal pain, blisters on the feet, eye soreness and unusual muscle pain. However, loss of smell lost significance in people over 60 years of age and was not relevant for subjects over 80.
Other early symptoms such as diarrhea were key in older age groups (60-79 and >80). Fever, while a known symptom of disease, was not an early feature of the disease in any age group.
Men were more likely to report shortness of breath, fatigue, chills and fever, whereas women were more likely to report loss of smell, chest pain and a persistent cough.
While these models were generated in the COVID Symptom study app, models were replicated across time suggesting they would also apply to non-app contributors. Although the models were used on the first strain of the virus and Alpha variants, the key findings suggest the symptoms of the Delta variant and subsequent variants will also differ across population groups.
“Its important people know the earliest symptoms are wide-ranging and may look different for each member of a family or household,” says lead author, Claire Steves, Reader from the School of Life Course Sciences.
“Testing guidance could be updated to enable cases to be picked up earlier, especially in the face of new variants which are highly transmissible. This could include using widely available lateral flow tests for people with any of these non-core symptoms.”
Dr Liane dos Santos Canas, first author from the School of Biomedical Engineering & Imaging Sciences, said that “currently, in the UK, only a few symptoms are used to recommend self-isolation and further testing. Using a larger number of symptoms and only after a few days of being unwell, using AI, we can better detect COVID-19 positive cases. We hope such a method is used to encourage more people to get tested as early as possible to minimize the risk of spread.”
Dr Marc Modat, Senior Lecturer from the School of Biomedical Engineering & Imaging Sciences, said that “as part of our study, we have been able to identify that the profile of symptoms due to COVID-19 differs from one group to another.
This suggests that the criteria to encourage people to get tested should be personalized using individuals’ information such as age. Alternatively, a larger set of symptoms could be considered, so the different manifestations of the disease across different groups are taken into account.”
COVID-19 pathogenesis is based on a potent immunological response involving a complex group of innate immune cells such as neutrophils and lymphocytes. In this retrospective study, we found that SARS-CoV-2 infection decreases blood neutrophil and lymphocyte counts in both male and female patients and damages liver function. Notably, we found beneficial sex (female)-related differences regarding reduced COVID-19 disease severity and negative associations with inflammatory responses and liver damage.
We also found harmful age-related differences regarding negative associations with CD8+ T cell numbers and positive associations with inflammatory responses and liver damage. Compared to young males, there were more neutropenia and fewer neutrophilia cases in young females with COVID-19, probably due to greater immunologic responses caused by male sex steroids but not by female sex steroids. In healthy young subjects, spontaneous neutrophil apoptosis is significantly decreased in women compared to men. When physiologic doses of estradiol and progesterone were administrated to both men and women, a delay in spontaneous neutrophil apoptosis occurred in both sexes [10].
On the other hand, the androgen receptor (AR) is broadly expressed in neutrophil-lineage cells from the myeloblast stage to the mature neutrophil stage. The androgen stimulates proliferation and differentiation of committed granulocytic precursors and increases neutrophil production [11,12]. Thus, higher neutrophil counts in young males than in females might reflect that young men were exposed to higher androgen levels in the present study.
It is well known that the male and female immune systems differ in significant ways, especially after puberty. Particularly, females experience sex-protective responses, such as lower rates of infections and chronic inflammatory diseases. Biologically, genes encoded on sex chromosomes, as well as sex hormones, likely contribute to these differences [8].
In previous studies, data from age- and sex-confluent studies demonstrated that males may be more prone to SARS-CoV-2 infection than females and have a higher risk of poor outcome and fatality [5,13–18]. In Middle East respiratory syndrome coronavirus and SARS-CoV, the same trend has also been observed [19,20]. As shown in Table 1, patients of both sexes without comorbidities showed similar COVID-19 incidences in this study.
However, males experienced more critical illness, liver damage (as indicated by ALT and AST levels), higher neutrophil counts, and higher CRP levels than did females. Consistent with previous reports, the present study showed a male predominance in COVID-19-related critical illness incidence, indicating that the more severe illnesses and liver damage in males compared to females were sex-specific effects. This may be partly due to the high expression of angiotensin-converting enzyme-2 (ACE-2), the cell-binding receptor of SARS-CoV-2, which mediates virus entrance in the lungs of men [21], and that 17β-estradiol downregulates lung ACE2 mRNA and protects females from viral pathogenesis by suppressing inflammatory responses [22].
In terms of laboratory findings, leukocytosis (≥ 10 × 109/L) and neutrophilia (≥ 6.3 × 109/L) were more common in young males than in young females. The higher NLR in males than in females was because of neutrophilia in males, as lymphocyte counts did not differ between sexes in the young cohort. The inflammatory marker, CRP, was significantly higher in young males than in young females, suggesting that, at least partly, inflammatory responses might be associated with sex-specific effects of COVID-19.
It is well known that sex-specific disease outcomes may be explained by sex steroids and their activities on X-linked genes and that males and females differ in both innate and adaptive immune responses. The sex-unique mode of inheritance of the X chromosome is attributed to the differences in sex-specific inflammatory responses [23,24].
Previously, age- and sex-confluent results have shown that severe SARS-CoV-2 infection decreases CD4+ T cells, CD8+ T cells, and NK cells [25,26]. Regarding the age-specific effects of COVID-19, in this study, older patients had lower lymphocyte and CD8+ T cell counts, resulting in a higher CD4+/CD8+ T cell ratio in both sexes. The mechanism underlying significant age-dependent lymphopenia in patients with COVID-19 is unknown and is possibly attributable to aging-related immune senescence [27]. Both human and animal studies have shown that CD8+ cytotoxic T cells are critical in mediating viral clearance in human respiratory syncytial virus and influenza A virus infections [28–32].
Thus, cytotoxic immunity (particularly CD8+ T cells) might be the key player in determining the age-dependent antiviral processes in patients with COVID-19. Regarding differences in innate immune cells between sexes, interestingly, post-menopausal males had more cases with NK cells below the NLL when compared to post-menopausal females. Another parameter associated with sex-and age-dependent characteristics was the coagulatory marker, FIB, again suggesting that the activation of coagulation/fibrinolysis might be associated with an age-dependent reduction in CD8+ T cells.
This might reflect the hypothesis that CD8+ T cells effectively cleared virus-infected endothelial cells in younger patients but failed to do so in older patients. ACE-2 is the critical receptor on cell membranes for mediating SARS-CoV-2 entry into host cells [33]. Endothelial cells and smooth muscle cells are rich in ACE-2 receptors [34], indicating that these cells may be the targets of virus assault. Therefore, SARS-CoV-2-induced vasculitis might be one of the factors leading to overt disseminated intravascular coagulation, which has been shown in 71.4% of non-survivors with COVID-19 [35].
In this study, patients with SARS-CoV-2 infection developed a weak innate immune-cell ability to produce cytokines, such as IFN-γ, and showed decreased CD4+ and CD8+ T cells. SARS-CoV infection increases cytokine expression (e.g., IFN-γ, IL-1, IL-6, IL-10, IL-12, and IL-16) dramatically, and T lymphocytes and their CD4+ and CD8+ T cells subsets are decreased after the onset of infection [36].
In contrast, HIV-infected patients showed increased mean absolute CD3+ T-cell numbers and absolute CD8+ T-cell numbers [37]. These data indicate that the inflammatory features of SARS-CoV-2 infection are similar but weaker than that of SARS-CoV infection.
There are limitations to this study. First, this retrospective study mainly analyzed the data related to T cell subset, B cell and NK cell counts, and the function of these cells, while the role of other immune and inflammatory cells infiltrating the pulmonary interstitium remains to be determined. Second, the sex- and age-specific groups had a relatively small number of patients; therefore, these data should be interpreted with caution, and statistical non-significance might not rule out differences among different age-groups.
Third, sex and age disparities in COVID-19 cases could be partly explained by differences in sex- and age-related comorbidities; however, the present study did not identify these differences.
In conclusion, SARS-CoV-2 infection mainly induced 1) beneficial sex (female)-related differences regarding reduced COVID-19 disease severity and negative associations with inflammatory responses and liver damage, and 2) harmful age-related differences regarding negative associations with CD8+ T cell numbers and positive associations with inflammatory responses and liver damage. Apparently, sex and age are biological variables that should be considered in the prevention and treatment of COVID-19. Hopefully, the simultaneous evaluation of sex and age disparities in COVID-19 may help clinicians provide timely and specific therapy.
reference link : https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009420
More information: Liane S Canas et al, Early detection of COVID-19 in the UK using self-reported symptoms: a large-scale, prospective, epidemiological surveillance study, The Lancet Digital Health (2021). DOI: 10.1016/S2589-7500(21)00131-X
