The SARS-CoV-2 virus has been spreading globally since 2019, causing over 664 million infections and 6.7 million deaths as of January 14, 2023 [1]. The epidemiology and clinical characteristics of COVID-19 have been widely studied; however, SARS-CoV-2 has continued to mutate from the dominant Alpha to Delta variants and now the Omicron variant and subvariants, and the clinical characteristics of COVID-19 also change according to the particular virus variant [2-4]. The Omicron variant has been the dominant variant in the fourth wave of the global COVID‐19 pandemic having infected an estimated 300 million people worldwide as of January 2023. Since December 2022, infection with the Omicron variant has been spreading rapidly across China.

Omicron is recognized as being highly contagious with a high capability for immune escape [5,6]. Over half of patients are reported to have at least one symptom during the infection period, including fever, cough, sore throat, fatigue, dyspnea, headache, and body pain [2,4,7]. Among these symptoms, cough is one of the most common [8,9]. Experiencing a chronic cough is associated with a significant decrease in quality of life, with symptoms such as incontinence, chest pain, headache, and poor sleep [10]. Studies in the United Kingdom [3] and the United States [4] have shown that the prevalence of acute cough during Omicron infection ranges from approximately 67.4% to 78%. A study conducted in a mobile cabin hospital in Shanghai demonstrated that cough was present in 57.5% of 1139 patients [7]. In addition, nearly 2.4%-7.2% of patients still experience cough as a symptom 1-2 months after Omicron infection is resolved [8,9]. However, few studies have described the specific cough features such as its severity, pattern, and risk factors.

We hypothesized that certain risk factors might be related with severe cough, productive cough, and persistent cough after Omicron infection. Additionally, there has been no nationwide survey concerning the clinical characteristics of Omicron infection in China to date. Therefore, we investigated the prevalence, severity, and associated risk factors for cough in nonhospitalized individuals with Omicron infection during the latest COVID-19 wave (2022-2023) in China.

To the best of our knowledge, this is the first study with a large sample size to investigate the characteristics of cough and associated factors in nonhospitalized individuals infected with the SARS-CoV-2 Omicron variant in China. In this study, the prevalence of cough was 92.6%, followed by fever, fatigue, myalgia/arthralgia, nasal congestion, headache/dizziness, sore throat, and runny nose. Productive cough (35.0%) with white thick sputum or yellow purulent sputum was common, which developed into a persistent cough in a subset of the surveyed individuals. Female sex, being a current smoker, and having comorbidities (such as asthma, chronic cough, GERD, and/or diabetes) were factors associated with severe, productive, and persistent cough.

Early reports showed that the prevalence of cough during COVID-19 infection ranged from 44% to 72.5% [15], with a higher prevalence associated with Omicron variant infection than with Delta variant infection [4], although one survey from the United Kingdom [3] indicated that the prevalence of cough was similar between infections with the Omicron and Delta variants. In this study, the prevalence of cough was 92.6%, which was higher than that reported in previous studies [2-4,7], especially those based on data collected prior to emergence of the Omicron variant [16-18], suggesting that the prevalence of cough might be higher with the Omicron variant than with previous variants. In addition to cough, other symptoms such as fever, fatigue, myalgia, nasal congestion, and sore throat were also common, and over 60% of individuals reported having severe symptoms in our study.

With 15 amino acid substitutions in the receptor-binding domain, Omicron has been identified as being highly transmissible and possessing a remarkable capability of immune escape [19]. It has been reported that Omicron caused less damage to the lungs compared with Delta [20] and was more likely to target the upper airways [21]. The vagal sensory nerves play essential roles in regulating cough, which terminate primarily in the larynx, trachea, carina, and large intrapulmonary bronchi [22]. This may explain the greater prevalence of cough among patients with Omicron variant infection. The other possibility for the higher proportion of cough and other symptoms identified in this study might be related to the reduced herd immunity against SARS-CoV-2. After the outbreak of COVID-19 in early 2020, a very strict prevention and control policy was implemented in China; thus, most people have not been exposed to COVID-19 in recent years [23]. In addition, the latest pandemic outbreak in China occurred during the winter, when viruses multiply more rapidly and spread more quickly on the one hand and the immune response of the airway is decreased on the other hand.

Previous studies have reported that compared to female patients, male patients with COVID-19 are at a higher risk of hospitalization, with worse outcomes and a higher mortality rate, independent of age [24]. In our study, all participants had mild-to-moderate disease and had not been hospitalized for COVID-19. We found that the female participants reported a higher proportion of cough and more severe cough. There was also a female predominance in the group reporting a chronic cough, which could be related to the heightened cough sensitivity among female patients [25]. This female preponderance in the chronic cough population and enhanced cough sensitivity may be explained by sex-related differences in the central processing of cough sensation [26]. However, further studies are needed to determine whether female patients with COVID-19 also present with increased cough sensitivity.

In China, 25.6% of adults (50.7% of men and 1.9% of women) are smokers [27]. The high proportion of nonsmoking female respondents in our study may explain why the proportion of smokers in our data was lower than that of the general population. Smoking has been reported as a risk factor for severe symptoms and/or progression of COVID-19 [28,29], and the prevalence of chronic cough and sputum was reported to be greater among current smokers [30]. Interestingly, smokers tended to report a nonsevere cough in the current survey. Many cigarette smokers usually have a chronic cough, but they scarcely seek medical attention unless a change in the pattern or intensity of their cough is noticed [31]. Cough reflex sensitivity and sensitivity to airway irritation were reported to be significantly decreased in current smokers compared to those of a similar population of nonsmokers [32,33]. Smoking was also found to be accompanied by increased activation in brain regions known to be involved in both cough sensory processing and cough suppression. Therefore, the smoking-induced sensitization of central cough neural circuits could be offset by concurrently enhanced central suppression [32].

Cough is a frequent and common complaint of patients with respiratory diseases such as asthma, chronic obstructive pulmonary disease, and interstitial lung disease. Nevertheless, cough could also be a sole or predominant symptom in extrapulmonary disorders, particularly GERD [34,35]. Most of the available evidence indicates that patients with respiratory diseases or cardiovascular diseases have the greatest odds of cough [9,36,37]. We also found an association of comorbidities, including asthma, chronic cough, coronary heart disease, GERD, and/or diabetes, with severe cough, persistent cough, and productive cough. Many studies have suggested a significant increase in the severity and mortality of COVID-19 in people with diabetes [38]. Self-reported chronic cough/phlegm was more common in patients with diabetes compared to that of the general population [39]. Gliptin, a dipeptidyl peptidase-4 inhibitor used to treat diabetes mellitus, can cause cough as a side effect, which may be attributed to the persistent cough of COVID-19 [40]. In addition, diabetes, as an important risk factor, was found to influence the clinical severity of concomitant viral, bacterial, and fungal infections [41]. Therefore, attention should be paid to the possibility of coinfection or secondary bacterial infection in cases of persistent cough among patients with diabetes with COVID-19.

Approximately one-third of the individuals surveyed in this study reported having a productive cough, indicating the hypersecretion of mucus. In addition, the group with productive cough had a low proportion of individuals with respiratory comorbidities, which could not fully explain the excessive phlegm production. Excessive mucus production and accumulation is a common response to respiratory viral infections such as respiratory syncytial virus, rhinovirus, influenza virus, and SARS virus [42]. Recently, Kato et al [43] reported that SARS-CoV-2 induced the production of mucin (MUC)5AC and MUC5B throughout all airway regions via epidermal growth factor receptor/interleukin-1 receptor signaling activation in patients with COVID-19 [43]. This overproduction of airway mucin may increase the viscosity of the sputum, rendering it difficult to cough up. In addition, respiratory viruses infecting the human airway would impair mucociliary clearance, activate transient receptor potential vanilloid 1, induce the hypertrophy and metaplasia of goblet cells in the airway epithelium and the consequent enlargement of bronchial submucosal glands, leading to excessive fluid secretion and mucus plugs formation [42,44]. Intriguingly, we also observed that many individuals, especially the female participants, coughed up yellow or purulent sputum, suggesting coexistence of a bacterial infection. A previous study also suggested female sex as a susceptibility factor for bacterial infection [45]. However, it remains unclear whether these mechanisms play a pivotal role in mucus hypersecretion during Omicron infection.

Over 91% of individuals in our study had received a vaccine against SARS-CoV-2; however, we did not find a protective effect of the vaccine toward alleviating cough and mucus hypersecretion. The inactivated vaccines against SARS-CoV-2 were used in China; however, less than 15% of individuals had received a vaccine <6 months before the latest SARS-CoV-2 wave. Malik et al [46] demonstrated that the neutralizing antibody titer declines to near or below the seropositive threshold of a protective effect 6 months after vaccination with the inactivated vaccine. In addition, SARS-CoV-2 has been constantly mutating and most of the mutations are associated with the spike protein, a vital target for the action of vaccines [46]. Although a booster dose of the inactivated vaccine was associated with a lower risk of Omicron infection [47], compared with the ancestor strain, the production of neutralizing antibodies against Omicron was considerably impaired [48,49]. Another possible effect of the vaccine is the risk of antibody-dependent enhancement. According to in vitro studies, antibody-dependent enhancement might occur in COVID-19 infection [50,51], but current evidence indicates that this is an unlikely side effect induced by the vaccine [52,53].

There are some limitations of our study. First, all participants were nonhospitalized individuals with COVID-19, which may not fully reflect the cough profiles of severe cases of SARS-CoV-2 infection during the Omicron outbreak. Second, the data were obtained via online survey. Participants with low literacy or those of older age may have been neglected given the difficulties in filling out the survey and/or using a smartphone. In addition, clinical features and medical history were assessed by questionnaires, which may be prone to recall bias. However, most of the participants had been infected with SARS-CoV-2 within 1 month prior to completing the survey and many participants were still in the acute phase of COVID-19 at the time of the survey; hence, the impact of recall bias should be small. Lastly, we are following up with these respondents as we have only analyzed cross-sectional data; since many of the participants were still in acute phase of Omicron infection, the prevalence of persistent cough should be surveyed further.

In conclusion, over 90% of nonhospitalized individuals infected with the Omicron variant of SARS-CoV-2 presented with cough as a major symptom, with approximately one-third of individuals having a severe or productive cough, commonly with white thick and yellow purulent sputum, which developed into a persistent cough in a portion of these individuals. Female sex, chronic cough, asthma, GERD, diabetes, smoking, and/or vaccination for COVID-19 were associated with severe cough, productive cough, and/or persistent cough. Further studies are warranted to investigate the mechanism, treatment, and long-term prognosis of cough associated with Omicron variant infection, which will provide insight into how to treat SARS-CoV-2–induced cough.