Comparison of the clinical differences between COVID-19, SARS, influenza, and the common cold: A systematic literature review

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Introduction
The outbreak of the COVID-19 coronavirus epidemic in the Chinese city of Wuhan and its spread have become a global threat. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a β-coronavirus and the 7 th coronavirus to be identified that causes human disease. Overall, SARS-CoV-2 was the 3 rd zoonotic human coronavirus of the century. 1,2 It is spread by human-tohuman transmission via droplets over short distances (1.5 m), direct contact or (potentially) the gastrointestinal tract. [3][4][5] It creates a high risk for virus transmission during ears, nose and throat (ENT) examination, especially during the direct examination of patients' respiratory tract. Moreover, recent studies indicate that ENT specialists are among the groups at a higher risk of exposure to the virus. 6 COVID-19 is similar to the disease caused by SARS-CoV. Although SARS-CoV-2 is less virulent, it is more infectious and its rapid spread has led to the coronavirus pandemic. 7,8 According to present clinical data about COVID-19, the symptoms of the disease may affect the upper respiratory tract, similarly to SARS, influenza and common cold. These similarities can pose a major diagnostic problem for any physician.
Every year, the world faces seasonal flu caused by influenza viruses. Three types of influenza viruses affect humans, the most common being type A and type B. 9 Approximately 30-50% of cases of common cold are caused by rhinoviruses. The second-most common agents are human coronaviruses (HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63), which account for 10-15% of cases of this disease. The other causes associated with the common cold are adenoviruses, human respiratory syncytial virus (orthopneumovirus), enteroviruses, and human parainfluenza viruses. 10 This review focuses on the frequency of symptoms in COVID-19 in comparison to SARS, influenza and common cold. Additionally, the research assesses the incidence of upper respiratory tract symptoms and influenza-like symptoms for the abovementioned viral diseases. To the best of our knowledge, no previous reports have focused on the differential diagnosis between those infectious diseases. The data presented herein are important for ENT specialists, who are often the first-line doctors for patients with upper respiratory tract infection.

Objectives
The aim of the study was to evaluate and compare information about the clinical features, symptoms and differences between patients with COVID-19, SARS, influenza, and common cold. The research can help ENT specialists and other health practitioners around the world manage patients in the current COVID-19 pandemic.

Material and methods
The database presented in the study was built from the results of 9 studies published after March 2003. [11][12][13][14][15][16][17][18][19] Only articles with data about symptoms of upper respiratory tract infection, such as fever, cough, muscular pain, headache, sore throat, and rhinorrhea, were included. Based on the search strategy, 1729 studies were found in the online database. Then, 1676 articles were excluded after the titles and abstracts were reviewed. The full texts of 53 articles were evaluated. Finally, 9 articles were included in the systematic literature review (Fig. 1).
PubMed was the biomedical database used in the study. To identify the studies for potential review, the following search terms were used: "COVID-19," "SARS," "influenza," "common cold," "upper respiratory symptoms," "influenzalike symptoms," "otolaryngology," "ENT," and "otolaryngological manifestation." The Boolean operators "NOT," "AND" and "OR" were also used in succession to narrow and widen the search.
Only the following symptoms were taken into consideration while comparing the diseases: fever, sore throat, rhinorrhea, headache, cough, and myalgia. Our review was focused on studies about COVID-19, SARS, influenza, and common cold in which upper respiratory tract symptoms and influenza-like symptoms were considered, since they are the most common, mutual shared symptoms. Therefore, a large number of studies focusing on other symptoms (such as gastrointestinal symptoms or cardiologic symptoms) were excluded, which may have led to the omission of some important studies.
The search was limited to publications in English. Articles that did not address the selected topics, low-quality studies, case reports, and studies based on non-significant cohorts were excluded. The full texts of the remaining high-quality articles were examined and elaborated on.  The data analysis involved frequency tables with numerical and percentage values, descriptive statistics, and statistical tests. Statistical analysis was performed using IBM SPSS Statistics v. 25 software (IBM Corp., Armonk, USA). The tests involved in the data analysis were the χ 2 and Z-score tests. The non-parametric χ 2 test was used to assess the differences in the appearance of symptoms in studied diseases: COVID-19, influenza, SARS, and common cold. The level of statistical significance was set at p = 0.05.
The Z-score test was used to compare the results of independent studies with large sample sizes. It was used to compare patients with COVID-19 and patients with other diseases under study in pairs in terms of the frequency of symptom appearance. Such an approach can determine which symptom was more likely to be observed in COVID-19, and can possibly lead to its diagnosis. Each studied disease was compared separately with COVID-19. The level of statistical significance was set at p = 0.05.

Results
The data regarding the symptoms in viral diseases was analyzed and the results are presented as descriptive and percentage values (Table 4). Moreover, the statistical significance was assessed with a p-value <0.05. The analyzed cases of patients with viral diseases indicated that the distribution of symptoms was differentiated. Among individuals with COVID-19, the most frequently reported symptoms were fever (74%), cough (70%), muscular pain (29%), and headache (21%), whereas sore throat (12%) and rhinorrhea (4%) were observed at lower rates (Table 4). Regarding patients with influenza, all of the symptoms were identified in the majority of cases: myalgia (94%), cough (93%), rhinorrhea (91%), headache (91%), sore throat (84%), and fever (68%) ( Table 4). In common cold, 94% of patients endured muscle pain, the most frequent symptom in that disease. Furthermore, 89% of the patients reported headache, 84% sore throat, 81% rhinorrhea, and 80% cough; however, a fever was reported in only 40% of cases (Table 4). When it comes to individuals with SARS, fever was the symptom observed most often (100%). A cough was reported in 179 patients (63%), headache in 128 (45%) and rhinorrhea in 34 patients (12%). On the other hand, sore throat was identified only in 18% of patients with SARS (Table 4). These results, showing differences in the frequency of symptoms in viral diseases were found to be statistically significant (p < 0.05; Table 4).

Discussion
To the best of our knowledge, this review is the first to compare the upper respiratory tract and influenza-like symptoms in COVID-19, SARS, influenza, and common cold. Knowledge of the frequency of upper respiratory tract symptoms and influenza-like symptoms in COVID-19, SARS, influenza, and common cold could be used in the differential diagnosis.
The clinical classification divides COVID-19 into 4 types based on the severity of the symptoms. The 1 st one, the mild type, is defined as having slight clinical symptoms without pneumonia in radiography, which can be asymptomatic or imitating the common cold. 3,13,15 The 2 nd one, the moderate type, is defined as presenting with fever and/or respiratory symptoms, plus pneumonia in radiography, which may resemble influenza. 3,13 The 3 rd one, the severe type, is diagnosed based on dyspnea (a respiratory rate ≥30 times/min), a resting finger oxygen saturation ≤93% and an arterial PaO 2 /FiO 2 ratio ≤300 mm Hg (1 mm Hg = 0.133 kPa). The last, the critical type, is defined as respiratory failure with shock and multiple organ failure, requiring mechanical ventilation and admission to the intensive care unit (ICU). 3,14 The last 2 types can imitate SARS. The analysis of clinical data in the study indicated significant similarities in the frequency of the symptoms fever and cough in infections caused by SARS-CoV (100% and 63%, respectively) and SARS-CoV2 (74% and 70%, respectively). The results show that it may not be possible to distinguish among the viral diseases under study judging only by the clinical presentation. The study reveals that general symptoms, like headache and myalgia, or nonspecific upper respiratory tract inflammation symptoms, such as sore throat and rhinorrhea, are more likely to be found in patients with influenza or common cold than in patients with COVID-19. Ninety-four percent of patients with both influenza and the common cold reported myalgia, whereas in the case of COVID-19 patients, this symptom was observed in 29% of cases. The results show that an increased number of general symptoms should lead to a diagnosis of influenza rather than COVID-19. In the case of common cold, symptoms like headache, myalgia, rhinorrhea, and sore throat will appear more likely than fever. As in a study by Monto et al., comparing influenza and common cold, those factors can be used in common cold and COVID-19 for the initial differential diagnosis. 17 Therefore, a lack of fever and the presence of headache, myalgia, rhinorrhea, and sore throat could suggest a diagnosis of common cold.
Anosmia and gustatory dysfunction are characteristic signs of SARS-CoV-2 infection. Recently published studies have demonstrated that anosmia and hyposmia can appear before the respiratory symptoms of COVID-19, or even as the only sign of the infection. 20 It should also be pointed out that anosmia and gustatory dysfunction can occur in patients who do not complain of nasal blockage or any other rhinitis symptoms. 21 That could indicate direct damage from the virus on the olfactory and gustatory receptors. Researchers from South Korea, China, Germany, France, and Italy have found that a significant number of individuals with COVID-19 were affected by hyposmia or anosmia. For example, in a study by Lechien et al., anosmia occurred in 86% of patients and gustatory dysfunction was present in 88.8% of patients. 16 Further, in a study by Klopfenstein et al., anosmia occurred in 47% of patients and was associated with dysgeusia in 85% of cases. 21 Those smell disorders are very rare in SARS or other coronavirus infections. 22 Therefore, the British Association of Otorhinolaryngology (ENT-UK) includes a loss of the sense of smell in their list of COVID-19 markers of infection. 20 Lechien et al. also observed that 3% of COVID-19 patients complained of ear pain, 6.97% of postnasal drip and 13% of facial pain/ heaviness. In the other articles analyzed, those symptoms were not found; therefore, these symptoms were not taken into consideration. 16 However, it has to be considered that asymptomatic and mild infections of SARS-CoV-2 are frequent. That is why a physician should always treat their patients as potentially infected and follow appropriate precautions to avoid the further spread of the virus. Due to the non-specific symptoms presented in COVID-19, patients cannot be diagnosed solely by clinical presentation; only laboratory tests can confirm a diagnosis. The presence of a wide range of general symptoms (headache, rhinorrhea, myalgia, and sore throat) should lead physicians to clinically suspect influenza or common cold rather than COVID-19. This could then guide medical decisions to be made before confirmatory tests are available.
Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) is a specific molecular examination for SARS-CoV-2. It is performed on specimens which are obtained mainly from nasopharyngeal swabs or oropharyngeal swabs, but also from the stool. 23,24 Wang et al. recommend samples from the lower respiratory tract of the patients (sputum and bronchoalveolar lavage fluid), although nasopharyngeal swab is more commonly used and easier to obtain. 24,25 Recent studies suggest that chest computed tomography (CT) is a sensitive diagnostic tool for COVID-19 diagnosis with a sensitivity of 97% in a patient with positive RT-PCR tests. 24,26 Interestingly, even asymptomatic patients with COVID-19 had radiological changes in their lungs 1 day after exposure, which is also helpful in differential diagnostics. 14 In influenza, RT-PCR and viral culturing have a sensitivity close to 100%, but the turnaround time for a viral culture is 3-10 days compared to 1-8 h for RT-PCR. 9 In SARS, RT-PCR is the method of the first choice for detection. 27