To the best of our knowledge, this is the first study to directly compare patients with COVID-19 and influenza using laboratory test data in a university hospital. Age 15–70 years (vs. 71 years), difficulty in breathing, malaise, and percentage of lymphocyte > 20% were significantly more frequent in patients with COVID-19 than in those with influenza. However, nausea, body temperature > 38.1°C, and WBC count > 9000/µL were more frequent in patients with influenza than in those with COVID-19.
Other studies have reported that age at the onset of COVID-19 is lower than that at the onset of influenza [14, 20]. The results of these studies support the results of the present study.
SARS-CoV-2 mainly invades respiratory epithelial cells by adhesion to angiotensin-converting enzyme 2; thus, infected patients may develop mild-to-severe inflammatory responses and acute lung injury [21]. Another study has reported that COVID-19 causes acute respiratory failure in the predominance of influenza [14]. These studies support the results of our study, revealing a higher number of cases of dyspnea cases than those of influenza.
Similarly, malaise is a symptom that has been reported in many patients with COVID-19 [14]. According to a previous study, 63% patients with COVID-19 have malaise [22]. These studies support the results of our study, revealing a higher number of cases of malaise than those of influenza cases. Malaise may be related to an increase in viral load and immune response to the infection [23]. In addition, insufficient energy production to meet the required metabolic demands is related to malaise [24].
Many studies have reported low lymphocyte counts in patients with COVID-19 [25, 26]. The host immune responses strongly try to involve all potential cells and cytokines. In chronic COVID-19 cases, natural killer cells and T cells become exhausted, and a decrease in their count leads to lymphopenia. The inability to eradicate the infection in the affected organ causes hyper-initiation of the immune system, which releases excessive amounts of inflammatory cytokines to compensate for the exhausted ones and the low lymphocyte count [25]. Similarly, a low lymphocyte count has been reported in influenza [27, 28]. However, our study shows that the lymphocyte counts are lower in in patients with COVID-19 than in patients with influenza. Furthermore, regarding WBC count, a study has shown that low leukocyte counts are markers of COVID-19 [29]. In our study, WBC counts > 9000/µL were more frequently associated with influenza than with COVID-19. This finding suggests the likelihood of it being useful for the differentiation of COVID-19 from influenza. In addition, our study showed that CRP levels are not useful for the differentiation of COVID-19 from influenza. Similarly, a previous study showed that CRP levels were not an effective discriminator of COVID-19 and non-COVID-19 cases [29]. However, a significantly higher level of CRP was observed in the severe COVID-19 group than in the non-COVID-19 group, which confirms the findings of previous studies regarding the clinical utility of CRP levels as an indicator of severe disease and progressive inflammation [30, 31]. In our study, a significant difference in CRP levels was possibly not observed because none of the patients with COVID-19 had severe disease. In contrast to a previous meta-analysis [32], a recent meta-analysis revealed that procalcitonin levels were not significantly different between the severe and non-severe groups. The procalcitonin level was only assessed in a few cases in this study; therefore, we did not add this in the extraction item; however, we think that it is the contents that procalcitonin level may be argued comparison between COVID-19 and influenza in the future.
Body temperature > 38.1°C was more frequent in patients with influenza than in those with COVID-19. Many cases not involving fever have been reported in COVID-19 [33, 34]. We believe that these findings support our results. However, the result may be effects that patients receiving antipyretics could not be excluded. Furthermore, many patients with COVID-19 had to be hospitalized for isolation owing to the high infectious control, and they underwent laboratory tests even if they were asymptomatic.
Nausea is more frequently associated with influenza than with COVID-19. In a study, nausea occurred in approximately 3.9% patients with COVID-19 [33]. Similarly, the ratio of nausea is unknown, but it can cause digestive symptoms including nausea in influenza. The mechanism to cause nausea is unclear and requires further investigation. Inflammatory reactions may occur when a virus infects gastrointestinal mucosal bleeding cells, and digestive symptoms such as nausea are thought to occur during these reactions. In this study, significantly fewer symptoms of nausea in patients with COVID-19 may reflect the greater strength of the respiratory tract infection than the gastrointestinal cells of COVID-19. Difficulty in breathing was significantly more frequent in patients with COVID-19 than in those with influenza, which may support our hypothesis.
There are some limitations to this study. First, there is a greater possibility that patients with COVID-19 are hospitalized as per law in Japan. Many patients with COVID-19 are hospitalized for isolation, which can help in controlling the spread of the highly infectious disease, even if present in young and asymptomatic patients. Furthermore, an influenza extraction period of several years passed (from December 31, 2020 to January 11, 2015). Annually, the seasonal flu may vary in symptoms, and this effect may have influenced the results of our study. However, the type of influenza did not influence the results, as there were no patients with influenza type B who underwent blood tests. In addition, we did not extract the data of three symptoms (taste disturbance, dysosmia, and conjunctival hyperemia) as they were inaccurate; therefore, these symptoms were not included in the chart review of patients with influenza. Finally, the patient population enrolled in this study was limited to that from a single hospital. Additionally, this was a retrospective study. Hence, a multicenter prospective study should be conducted with a larger number of patients to verify our results.
In conclusion, our results are useful for differentiating patients with COVID-19 from those with influenza. Age 15–70 years (vs. 71 years) years, difficulty in breathing, malaise, and percentage of lymphocytes > 20% were significantly more frequent in COVID-19 than in influenza. However, nausea, body temperature > 38.1°C, and WBC counts > 9000/µL were more frequent in influenza than in COVID-19.