Comparison of Prevalence of Influenza and COVID-19: A Report From Hormozgan Province-Iran, 2019-2021

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses produce a wide range of clinical disease severity, which varies from asymptomatic infection to death. The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, Hubei, China, followed a seasonal influenza pandemic. The prevalence of influenza has changed since the outbreak of COVID-19. In this study, we have compared the prevalence of influenza and COVID-19 since the onset of the pandemic. Clinical symptoms were also assessed among patients. Materials and Methods: The present study was conducted in a single center on 229456 patients with the SARS in Hormozgan province, Iran, during 2019-2021 before and after the COVID-19 pandemic . Clinical features including age, sex, fever, cough, shortness of breath, nausea, dizziness, headache, body aches, and diarrhea were also analyzed. Results: The results indicated that out of a total of 229 456 samples of patients, 71142 (31.00%) and 527 (.22%) cases were diagnosed with positive COVID-19 and positive influenza, respectively. Influenza activity decreased in March 2020 and remained low until September 2021, but it increased to near pre-pandemic seasonal levels since October 2021. The outbreak of influenza decreased by starting the restrictions and health protocols. Furthermore, the analysis of patients’ symptoms indicated that the most prevalent symptoms in influenza patients were fever, cough, and body pain, while the symptoms in COVID-19 patients were cough and headache. Conclusion: Social restrictions and adherence to health protocols could significantly reduce the incidence of seasonal influenza even after controlling the COVID-19 pandemic. Influenza and COVID-19 have similar symptoms in patients, so diagnostic tests are necessary for proper diagnosis and management.

distinguish from influenza illness. COVID-19 outbreak shares a coincidence with influenza season, posing double threats to public health and complicating the disease diagnosis and management. The accurate and rapid diagnosis of COVID-19 infection is essential to control the transmission pathway and create suitable treatment methods (5).
Research has demonstrated that the SARS-CoV-2 virus binds to surface cell receptor angiotensin-converting enzyme 2 of epithelial cells in the respiratory and gastrointestinal tracts and may cause organ failure and even death (6). Recent studies suggest that COVID-19 pneumonia is likely to become a chronic influenza-like illness until effective vaccines or therapeutic measures are available. Given the potential for long-term coexistence with humans globally, the current priority is to develop methods for identifying and evaluating infected individuals. The influenza virus is another infectious disease which caused the global pandemics of the H1N1 swine influenza in 2009 and resulted in the death toll up to 575 000 people (7,8). In the recent century, mutations and the creation of novel strains of influenza led to the outbreak of new epidemics that caused widespread illness, death, and disruption, generally accompanied by serious symptoms, which caused increases in mortality in young adults. The influenza viruses (e.g., influenza A and B viruses) and the novel coronavirus are both infectious and can cause severe respiratory diseases. Abdominal pain, conjunctivitis, cough, fever, headache, myalgia, nausea or vomiting, seizure, and skin rash are common symptoms of influenza disease. However, symptoms such as calf pain, diarrhea, and rhinorrhea are the symptoms that differentiate influenza A and B (7). Infections caused by influenza A and influenza B viruses can have clinical symptoms similar to the COVID-19; therefore, it is difficult to diagnose COVID-19 pneumonia from influenza, especially during the influenza season. Typically, the incubation period of influenza infection is from 1 to 4 days after infection, but in COVID-19 infection symptoms can appear 1 to 14 days after infection, which can be different (9). The most common symptoms of COVID-19 are fever, tiredness and dry cough, skin rash, myalgia, nausea or vomiting, muscle pain, sore throat, and loss of taste or smell (9). Some patients may have aches and pains, nasal congestion, runny nose, sore throat, or diarrhea. COVID-19 was found to indicate a higher mortality rate than influenza. Currently, in outpatients, the rapid differentiation of COVID-19 patients from influenza A or B is the main issue (8).
Symptoms of COVID-19 disease could be difficult to distinguish from influenza illness (5,10). COVID-19 outbreak shares a coincidence with influenza season, posing double threats to public health and complicating the disease diagnosis and management. The accurate and rapid diagnosis of COVID-19 infection is essential to control the transmission pathway and create suitable treatment methods (11).
The aim of this study was to determine the prevalence of influenza and the COVID-19 with the onset of the COVID-19 pandemic and before the onset of the COVID-19 pandemic and also to compare their disease symptoms in samples sent to the laboratory of Hormozgan Health Center and gathered from patients with the acute respiratory syndrome.

Data Collection
This is a descriptive, cross-sectional study, and the study population included patients with COVID-19 and influenza symptoms referred to medical centers in Hormozgan province from October 2019 to December 2021. In this study, total samples were taken from 229 456 patients with symptoms of the acute respiratory syndrome and were characterized to the reference laboratory of Bandar-E-Abbas, Iran. Further, samples were categorized into two groups: COVID19 and influenza (type A and B). The clinical data including age, gender, fever, cough, shortness of breath, nausea, dizziness, headache, body pain, and diarrhea were recorded for all patients. Then, patients suspected of having influenza or COVID-19 were sampled from the nasopharynx with a special swap.

Ribonucleic Acid Extraction and Reverse Transcription Polymerase Chain Reaction
Two nasopharyngeal and oropharyngeal throat swab samples were collected and tested for SARS-CoV-2 and influenza A and B for each patient with the onset of the COVID-19 pandemic. Viral RNA was extracted from 140 μL of each clinical sample using the High Pure Viral Nucleic Acid Kit (RNJia Virus Kit, Yazd, Iran) according to the manufacturer's instructions. The RNA was immediately kept at -70°C. For 229 456 of the samples, real-time RT-PCR assays were performed separately including influenza A and B and COVID-19 viruses. We used primer/probe sets in SARS-CoV-2 and influenza A and B that are listed in Table 1 (12)(13)(14). The result of SARS-CoV-2 was reported as positive when the cycle threshold value for the E gene was ≤ 40. Likewise, the result of influenza was reported as positive when the cycle threshold value for the HA gene was ≤ 40.

Statistical Analysis
All statistical analyses were performed using SPSS 20.0 software (IBM, Armonk, NY, USA) and GraphPad Prism 5.0 software (GraphPad Software, Inc., San Diego, CA). Demographic, clinical, and outcome variables were compared between the two groups of patients using a t test and chi-square test, and P values less than 0.05 were considered statistically significant.

General Characteristics of COVID-19 Patients
In the present study, which was conducted during 2019-2021 before and after the onset of the COVID-19 pandemic (Figure 1 The clinical symptoms studied in this survey for differentiation between COVID-19 and influenza were fever, cough, body pain, headache, shortness of breath, nausea, dizziness, and diarrhea. The result indicated that fever, cough, and body pain were the most prevalent symptoms in influenza patients (85%, 100%, and 75%, respectively). The most common symptoms in COVID-19 patients were cough and headache (65% and 64%, respectively). As Table 1 illustrates, the cough was a common symptom for the disease in both groups (65% in COVID-19 patients and 100% in influenza patients). Body pain was present in more people with influenza,   Results indicated that in 2019 (before the onset of the COVID-19), influenza patients were more hospitalized; however, after the onset of the COVID-19, patients with COVID-19 symptoms were more common.
According to Figure 2, no differences was observed between males and females.

Discussion
With the onset of the COVID-19 pandemic, the prevalence of many infectious diseases changed (15). In particular, the prevalence of respiratory diseases such as influenza decreased due to social constraints imposed by governments. In this study, we compared the prevalence of influenza and COVID-19 disease between 2019 and 2021 among patients with acute respiratory symptoms referred to the central laboratory of Hormozgan province. The results indicated that out of a total of 229,456 samples of patients, 71142 (30%) cases were diagnosed with positive COVID-19 and 527 (.22%) cases with positive influenza. As shown in Figure 1, prior to the COVID-19 pandemic, there was a wave of seasonal influenza, leading to the identification of 298 patients with influenza symptoms. The number of positive cases of influenza after the onset of the COVID-19 pandemic was 34 in March 2020. The prevalence of influenza virus reached zero in four weeks after the onset of the COVID-19 pandemic and the beginning of restrictions in Hormozgan province for 6 months from October to March 2020. Out of all cases of suspected seasonal influenza, only two cases were positive, while there were 205 cases of influenza in this province in the same period the previous year. In a pattern similar to our study, a report released by the CDC in the United States showed that influenza activity declined in March 2020 and remained stable from October 2020 through May 2021. According to this study, from 2017 to 2021, the peak of influenza was observed every year from October to late December, but no influenza peak was observed in 2020 for the COVID-19 pandemic (16). This decline has also been observed in other countries such as Puerto Rico, Taiwan, Korea, Hong Kong, and Singapore (17)(18)(19)(20). Since influenza virus, similar to SARS-CoV-2, is spread by droplets, low transmissibility of seasonal influenza virus (R0 = 1.28), compared to SARS-CoV-2 (R0 = 2-3.5), and implementation of social restrictions probably have contributed to the reduction of influenza transmission (18).
Similarly, in Hormozgan province, Iran, with the reduction of social restrictions due to the injection of the COVID-19 vaccine, the number of positive influenza cases increased from October to December 2021. In April 2021, the first case of H3N2 influenza was identified in Hormozgan province, Iran. The start of this wave was predictable due to the widespread vaccination of COVID-19 and the reduction of social restrictions. The current increase could represent a return to pre-pandemic seasonality. Since the prevalence of the influenza virus in last autumn and winter was very low, it can be concluded that social restrictions have reduced the activity of influenza. These social restrictions can be applied to reduce the spread of future influenza pandemics, especially in populations at higher risk for severe illness or side effects. However, influenza vaccination is still the best way to prevent the disease for all people over 6 months   (21). Some reports warned that influenza prevalence will return to pre-pandemic circulation patterns even more severely, and the reduced circulation of influenza viruses during the past year might affect the severity of the upcoming influenza season given the prolonged absence of ongoing natural exposure to influenza viruses. For this reason, clinicians are advised to follow preventive health protocols and get vaccinated (16,22). Fever, cough, and headache were the most common symptoms among both groups, but body pain was less common in patients with COVID-19, while it was common in patients with influenza. However, most signs and symptoms were similar between the two groups, making clinical distinction unreliable. Laris-González et al compared clinical characteristics of patients with influenza with COVID-19 in Mexico City, and in agreement with our study, fever and cough were reported as the most common clinical manifestations in both groups (23). In another study, in a retrospective cohort, Song et al found that fever, gastrointestinal symptoms, headache, and myalgia were the most common symptoms in patients hospitalized with COVID-19 than in patients with influenza (24). In sum, influenza and COVID-19 have a similar manifestation in patients, which makes diagnostic tests necessary for proper diagnosis and management.
The study of a single center as well as the frequency of comorbidities among participants may limit generalization of findings. Some data on patients with influenza before the onset of the COVID-19 pandemic was collected retrospectively from clinical records while the COVID-19 cohort was followed-up prospectively. Differences in periods between the two studies may be due to differences in diagnostic and therapeutic approaches.

Conclusion
It can be concluded that social restrictions and adherence to health protocols can significantly reduce the incidence of seasonal influenza, and even after controlling the COVID-19 pandemic, the incidence of seasonal influenza can be controlled by adhering to health protocols along with vaccination. On the other hand, influenza and COVID-19 have similar symptoms in patients, so diagnostic tests are necessary for proper diagnosis and management.