Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative agent of COVID-19, which was discovered for the first time in December 2019 in Wuhan, China (1, 2), although COVID-19 is believed to have spread unnoticed throughout the Asian region much earlier (3). From this initial discovery, new cases soon began to be reported all over the world. The virus showed significant infectivity, reaching over 100 mln cases globally in one year (4). The first case in Poland was confirmed on March 4, 2021, and this was to rise to over 5.5 mln cases and over 100,000 deaths by the end of February 2022 (5).

Among the reported symptoms of COVID-19, the most common were fever (83–99%), headache (10–28%), cough (20–82%), fatigue (44–70%) and sore throat (14–19%) in adults (6, 7) and fever (46–64%) and cough (32–56%) in children (8). Although many papers have described COVID-19 manifestations, most have focused on selected symptoms (7), and to our knowledge, none have summarized all the possible signs of COVID-19 in a single population. Moreover most of the available studies only assess hospitalized patients (9) or fail to mention their origin (10). For example, one meta-analysis of COVID-19 symptoms (11) included research from 33 articles conducted on 15,244 hospitalized patients and only 9,011 non-hospitalized patients; in addition, these present only limited number of symptoms, ranging from 13 (12) to 23 (13). Another metanalysis included 24,410 hospitalized patients from four continents; however, no data was included from Central or Eastern Europe (14). While the paper presents a high number of symptoms (n = 30), the authors concede that clear differences exist between countries, and this prevents generalization of findings (14). As such, studies are needed on single populations. While it is important to present individual symptoms, such studies run the risk of ignoring the full picture of the disease, and becoming restricted to the most common cases.

Moreover publications based on hospital rather than community settings may upwardly bias the estimates of symptom prevalence, and not reflect the true numbers in the general population (14). Hospitalized patients also differ significantly from the general population in terms of disease severity, aggravation of symptoms and type of care received. In addition, while most COVID-19 patients are consulted in primary care, which uses different decision making processes from hospitals, most current publications on hospitalized patients focus on major symptoms and lab tests. Therefore it is crucial to have a full overview of all possible symptoms of COVID-19 to allow precise diagnosis; this is particularly true for primary care physicians. Other publications on COVID-19 symptoms have examined population type and ethnicity (15), machine learning (16), mobile applications (17) and social media (18, 19).

In addition to symptoms and clinical presentation, the influence of sex on COVID-19 manifestation is of great interest. It was found soon after the outbreak of epidemic that the course of the disease was depended on the sex of the patient. For example, 73% of the 116 deceased COVID-19 patients from Wuhan Tongji Hospital in China in January–February 2020 were men (20). Data from South Korea also showed a 2:1 female to male ratio of COVID-19 cases, but with twice the mortality among men (21). A report from the Italian National Institute of Health from April 2020 stated that approximately 70% of COVID-19 deaths were men, while the National Centre for Health Statistics in the US reported that 59% out of 37,308 deaths were men (22). Another study found the case fatality ratio for men to women to be 1.7 in Italy, Spain and Sweden and 1.4 in Germany (23). Finally, a meta-analysis of over 3.1 million COVID-19 cases confirmed that despite there being no sex-related difference in the chance of being infected with COVID-19, men were three times more likely to require treatment in the intensive care unit and to have a higher chance death (24).

Despite this, to date, no studies appear to have examined differences in COVID-19 symptoms according to sex. Moreover, no individual publication has examined the vast collection of known COVID-19 symptoms in a single population, including non-hospitalized patients. Therefore, the aim of this article is to provide an overview of the symptomatology of COVID-19, and to support physicians, especially those of outpatients, in the diagnostic process.

The primary aim of the study was to build a reliable list of possible COVID-19 symptoms based on a survey of COVID-19 positive patients about the symptoms experienced during the first 14 days of infection. The secondary aim was to identify sex-based differences in symptom prevalence.

The survey responses were collected between December 23, 2020 (week 52 of 2020) and February 28, 2021 (week 08 of 2021) during the dominance of SARS-CoV-2 alpha variant (Figure 1) (32). A total number of 7,034 participants started the survey. All confirmed that they were taking part in the survey for the first time or writing the survey on behalf of other person (child, elderly).

The completion rate was 1783/7034*100% = 25.25%. Completeness was 1740/7034*100% = 24.74%. In total, 1740 participants answered all questions. As partially-completed questionnaires were included in the final analysis, the number of participants is presented with each result. In general, the later questions in the survey elicited fewer responses.

Some questionnaires were excluded for the following reasons: participants claimed that they had answered the survey previously (80 surveys excluded), participants reported that they have not been tested for SARS-CoV-2 (n = 2,579), participants were younger than 18 years (n = 15), no answer was given to questions about symptoms (or question about ‘lack of symptoms’) (n = 1951) or duplicates of the same answer were found (n = 1). Therefore, 2,408 surveys were included in the final analysis, representing 2,408 patients (397 men −16.49% and 1,370 women—56.89%, 641 no data given—26.62%) with an age range from 18 to 90 years.

The characteristics of the participants are provided in Table 1. Most of the participating men were overweight while most women were of normal weight (Table 2). Most participants were living cities with populations of 10,001 to 100,000 inhabitants (Table 2) and did not require hospitalization, oxygen therapy, respiratory therapy or a stay in the isolation unit (Table 2).

Among all the respondents, the three most prevalent symptoms were fatigue (87.61%), anosmia (73.74%) and headache (69.89%) (Figure 2, Table 3). These symptoms were present in most patients on day 5 (67.32% of surveyed patients), day 7 (56.64%) and day 2 (46.14%) respectively (Figure 5). Most patients reported fatigue (58.07%), headache (44.12%) and myalgias (37.39%) on the first day (Figure 5).

Statistically significant differences in the prevalence of COVID-19 symptoms were found between man and women (Figure 3). Women were generally more symptomatic than men, with 31 symptoms occurred significantly more often in women than in men; their frequencies in descending order were as follows (as given in Table 4 and Figure 4): anosmia (reported by 76% of women), headache (74%), myalgias (62%), lack of appetite (52%), back pain (52%), chills (48%), arthralgias (45%), hyperosmia (39%), chest tightness (36%), rhinorrhea (34%), sore throat (34%), dizziness (33%), nasal dryness (33%), sinusitis (33%), insomnia (31%), palpitations (31%), chest pain (29%), amnesia (28%), ophthalmalgia (28%), limbs pain (27%), xerostomia (24%), nausea (23%), diaphoresis (22%), abdominal pain/ache (21%), sneezing (21%), hoarseness (20%), polydipsia (20%), alopecia (19%), ear pain/ache (11%) and vomiting (8%). Only three symptoms were more prevalent in men: subfebrility (reported by 70% of men), fever (55%) and hemoptysis (4%).

Seven symptoms occurred in over 50% of participating men: fatigue (86%), subfebrility (70%), anosmia (65%), myalgias (56%), headache (55%), fever (55%) and cough (53%). Nine symptoms were declared by over 50% of women: fatigue (88%), anosmia (76%), headache (74%), subfebrility (64%), myalgias (62%), ageusia (59%), cough (53%), lack of appetite (52%) and back pain (52%).

Regarding the duration of COVID-19 symptoms 12 lasted significantly longer in women than in men: hypothermia, fatigue, sneezing, nausea, vomiting, lack of appetite, hyperhidrosis, diaphoresis, palpitations, insomnia, hypersomnia and xerostomia. The minimum duration of each symptom was 1 day, maximum was ‘15 days or more’. Only 21 participants (1.19%) chose ‘no symptoms’ in the survey: 2.02% of responding women and 0.95% of responding man. The difference was not statistically significant (p = 0.084).

Despite the growing knowledge of the SARS-CoV-2 virus acquired since the end of 2019, its symptoms are not well recognized and a full list is still being researched. As the symptoms of COVID-19 are mostly very similar to those of other infectious diseases, it is problematic to differentiate the condition from other respiratory tract diseases (34). It may be hard to tell the difference between novel coronavirus infection and common cold or influenza, especially in primary care where diagnostic procedures are limited and number of cases is significant, especially in infectious seasons. Hence, there is a need for a better understanding of the symptoms, their occurrence in time and their relationship with patient sex. Knowing the prevalence of COVID-19 symptoms in a single population will help diagnose COVID-19 on many levels. Knowing the specific combination of symptoms that are most likely to occur in COVID-19 will make it easier to isolate COVID-19 patients from a group of similar infectious diseases at the clinical stage, especially in primary care. It will also help in screening patients who need to be diagnosed further, e.g., using antigen tests. Better knowledge of the symptoms characteristic of a given disease is associated with easier recognition at the stage of the patient, and therefore easier self-isolation and better control of the spread of this disease, thus being highly clinically and epidemiologically important.

In the studied population, the most prevalent symptoms of COVID-19 infection were fatigue, anosmia, headache, subfebrility and myalgia; these were reported by 61–88% participants. These findings are different from those obtained in other studies of COVID-19 symptoms. For example, one of the first publications summarizing the findings associated with hospitalized COVID-19 patients found cough to be the most common symptom (presented by 67.8% patients) followed by fatigue (38.1% patients) (9). Amongst the population in our study, cough was not that prevalent, being the seventh most common symptom (53%). This difference could be due to the fact that Guan’s study was based mostly on hospitalized patients (93.6%) while only 4.7% were admitted to the hospital in the present study (9).

In general the prevalence of COVID-19 symptoms differ depending on the studied population. For example, in an Iranian study of 23,749 patients from 74 hospitals in Teheran, the most prevalent symptoms were cough (50.51%), respiratory distress (43.55%), muscular pain or fatigue (38.94%), gastrointestinal problems (10.4%) and headache (4.72%) (35). A Chinese meta-analysis of 38 studies with 3,062 patients found these to be fever (80.4%), cough (63.1%) and fatigue (46.0%) but not anosmia or ageusia (36). Similar findings were described in meta-analysis of 54 mainly Chinese publications, where fever (81.2%), cough (58.5%) and fatigue (38.5%) were listed as the most prevalent symptoms (10). Other Chinese meta-analyses listed fever, fatigue and cough as the most common symptoms (37, 38). In our population, fever was ranked 12 among the most common presentations; however, a subfebrility, i.e., a high temperature, was reported by nearly twice as many survey participants as fever (1,154 vs. 768).

Similarly, fever (73.5%) and cough (61.0%) were found to be the most common symptoms in an Egyptian review of 1773 COVID-19 patients (39). A meta-analysis by Ghayda et al. found the most common symptoms to be fever (prevalence - 77%), cough (60%) and fatigue/myalgia (31%); the authors also reported gastrointestinal symptoms including diarrhea (6%) and nausea/vomiting (5%) (40), which were much more common in the present study: 29% for diarrhea, 21% for nausea and 7% for vomiting.

In some cases, our present findings were quite divergent from those of previous studies. In one meta-analysis, the most common symptoms were found to be fever (97%), cough (70%) and myalgia/fatigue (39%), while our respective findings were fever/cough 43%/53% and myalgia/fatigue 61%/88%, also diarrhea was less prevalent than in our study (8% vs. 29%) (41). Another meta-analysis found the pooled prevalence of loss of appetite, nausea/vomiting, diarrhea and abdominal pain/discomfort to be 27, 10, 12 and 9%, respectively (42), compared to 50, 28, 29 and 20% in our study. These differences may be due to variation in populations, regions or SARS-CoV-2 variants among others. In addition, our study mostly includes outpatient subjects, which may also affect the results, since other studies rely on inpatients data mostly. We may only suspect that there may be a correlation between the patient presentation and his further path in the health care system. For example, COVID-19 patients with muscle pain and digestive symptoms are less likely to be hospitalized than those with fever and cough, however this needs further investigation.

Nonetheless, SARS-CoV-2 infection presents with variety of symptoms from different body systems. This is most likely the effect of the wide range of angiotensin converting enzyme 2 (ACE2) expression in human tissues, with the small intestine, testis, kidneys and heart being the highest (43). ACE2 acts to degrade angiotensin II into angiotensin (1–7) which ultimately leads to a decrease in blood pressure (44). Symptoms believed to be specific for COVID-19, i.e., anosmia and ageusia, were not that prevalent the first day (15.27 and 11.93% respectively), but were reported by more than 40% of patients on day five and day six, respectively, (Figure 4). The prevalence of olfactory dysfunctions has been found to range from 5.6 to 98% of COVID-19 patients, with differences between China/Asia and Europe/USA (45), probably due to different expression of the ACE2 receptor in global populations (46). Although they may precede, follow or co-occur with other general symptoms (47), these symptoms were present in more than 50% of participants in the present study, starting from day 5. This suggests that in order to differentiate COVID-19 in the first days of the disease, the patient should be asked about fatigue, rather than anosmia, ageusia or nasal discharge at the first visit, especially in primary care. These symptoms are more common than anosmia or ageusia in the first days of COVID-19. Olfactory and gustatory problems become more prevalent starting from day 5.

Our study confirmed previous findings that anosmia and ageusia are more frequent COVID-19 dysfunctions in women than men (47–50). This may be due to the fact that activation of the Toll-like receptor (TLR), a protein responsible for pathogen recognition in the human innate immune system (51), is related to X chromosomes; this may lead to various inflammatory conditions and clinical courses in both sexes (52). No statistically significant differences in the duration of anosmia or ageusia were observed between men and women; in both cases, the mean duration of symptoms was eight days, which is consistent with the findings of other authors (45). Because smell and taste disorders are more prominent in COVID-19 than other seasonal viral diseases (e.g., influenza (53)) it is of high importance for physicians to recognize it as one of the most common and major symptoms of COVID-19.

The longest-lasting symptoms were fatigue, cough, nasal dryness, xerostomia and polydipsia (15 days or more). Although our study focuses on the first two weeks of COVID-19 infection, these six persisting symptoms lasted over 14 days, may be assumed to be prolonged and be a part of condition known as long COVID (54). Although prolonged illness is well documented in hospitalized patients (55), it also affects individuals with mild infection who do not need hospitalization (56). Neither nasal dryness, xerostomia or polydipsia were not included in a list of 48 clinical symptoms given by a previous meta-analysis (57). Thanks to our study, these symptoms may be added to the rich symptomatology of novel coronavirus infection. Lopez-Leon et al. found study fatigue and headache to be the most prevalent symptoms of long-COVID (80 and 58% respectively), similar to our study; however, attention disorder was also listed in third place (27%) (57). In the present study, the highest ranking psychiatric symptom was depression, which was ranked 21 with a similar prevalence (30%). It is possible that, in our population, psychiatric problems were not the most common within the first two weeks of COVID-19, but could become more apparent over the course of longer-term infection as other symptoms subside. Similarly, alopecia was also not that prevalent in our study (15.5%) compared to Lopez-Leon (25%) (57).

Our findings suggest that women suffering from COVID-19 are more symptomatic within the first 14 days of the disease and that many of their symptoms persist longer than for men. Many sex-dependent factors affecting COVID-19 have been confirmed previously. A large cohort study of 17 million patients in England found a hazard ratio of 1.59 for higher risk of death due to COVID-19 in men (58). Higher ratio of male-to-female death was also confirmed in France, Spain, Italy, Switzerland, Germany and China (59). Although the cause of these differences is currently unknown, it is thought that differences in sex hormones may contribute to different immunologic responses between the sexes (60). Takahashi et al. report that cytokines IL-8, IL-18, CCL5 were significantly elevated in male COVID-19 patients, and that CD38 and HLA-DR-positive activated T cells in female COVID-19 patients (61). Meng et al. found significant differences between male and female COVID-19 patients in eleven laboratory parameters including glucose, CRP and creatinine concentration (62).

ACE2 is more strongly expressed in men than women, particularly under pathological conditions (63), its tissue expression is also higher in men than women (64); moreover, angiotensin II receptor type 1 (AT1R; which SARS-CoV-2 binds to) is downregulated by estrogens (65). In addition to AT1R, the expression of TMPRSS2, a protein that primes SARS-CoV-2 entry into cells, is upregulated by androgens (66). Low levels of baseline serum testosterone in men may also contribute to increased cardiovascular risk in COVID-19 (67). This hormone also affects cytokine production (e.g., suppresses IL-6, IL-1beta and TNF-alpha, enhances production of IL-10) (68), suppresses T-helper cells, enhances regulatory T-cell differentiation (69), and reduces B-cell proliferation and humoral response (70). Moreover men with lower testosterone levels are predisposed to pulmonary and systematic inflammation and develop worse general parameters (67). The response to pathogens also differs between sexes: adult women demonstrate twice the protective antibody response after vaccination against various viral diseases compared with men (71).

Our findings confirm previous observations that sex affects the COVID-19 presentation. Sex-based differences were also found during the MERS outbreak in 2013–2014, with the fatality rate being 52% in men, while in women it was 23% (72). Other factors may also be involved in these observed differences: for example, the presence of comorbidities such as hypertension, cardiovascular disease, chronic obstructive pulmonary disease, which are more prevalent in men than women (73). These may also be caused by higher smoking and alcohol consumption observed in men (74, 75). In Poland, although 54.3% of COVID-19 cases were confirmed in women, 56.5% of COVID-19 deaths were confirmed in men, which also supports the thesis of gender differences in COVID-19 presentation (76). Nonetheless, the evidence for influence of patient’s sex on COVID-19 course is increasing and our study also supports this thesis with its findings.

COVID-19 research on its symptomatology is evolving. Our study have found that out of 54 identified symptoms occurring during the first 14 days of infection, the most common were fatigue, anosmia and headache. Symptom presentation was also found to differ between the sexes, shedding new light on the nature of COVID-19 presentation in men and women.

Although studies have summarized the symptoms of long COVID-19, there is still lack of good quality data concerning the symptoms of acute SARS-CoV-2 infection. In response, our findings describe not only a broad symptomatology of acute COVID-19 but also its dependence on sex. The full clinical profile of COVID-19 cannot be limited to a few major symptoms. Future studies are therefore needed to examine its presentation against the background of other factors such as COVID variant, geographical location or population type.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Bioethical Commission of the Medical University of Lodz, decision number RNN/319/20/KE, December 15, 2020. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

PL conceived and planned the study and collected the data. PL and PK designed the questionnaire and contributed to the writing of the manuscript. IB designed the figures and contributed to the interpretation of the results and to the discussion. KW worked on the manuscript and contributed to the interpretation of the results. JL performed statistical analysis and contributed to the interpretation of the obtained results. PK contributed to planning the study and supervised the project. All authors discussed the results and contributed to the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.