Clinical Challenge of Co-Infection of SARS-CoV-2 with Influenza During the Influenza Circulation Season: Suggestions for Prevention

The scenario of millions of deaths due to the COVID-19 pandemic since its emergence was horrifying, the bitter truth that a virus suddenly overwhelmed the entire world, and humanity was incapable of dealing with it for a long time. [1,2,3] Over time, when the experience and knowledge of the healthcare system increased, successes were achieved in the field of treating COVID-19; however, the emergence of new variants of SARS-CoV-2 was an excessive burden on healthcare staff. Finally, the efforts of the researchers and the healthcare staff led to the provision of various vaccines. [4,5] Even though vaccines are largely effective, vaccination has remained incomplete in many parts of the world as people’s participation in taking booster doses has decreased due to several reasons. [5] A study performed from 13 September to 18 November 2022 revealed the efficacy of a bivalent mRNA vaccine comprising an ancestral SARS-CoV-2 strain component with a restructured component of the Omicron BA.4/BA.5 sub-lineages (after 2, 3, or 4 monovalent doses) in COVID-19–associated emergency department/urgent care encounters was 56% higher compared with no vaccination, 31% higher compared with monovalent vaccination in those who received the last dose 2–4 months earlier, and 50% higher in comparison with monovalent vaccination in those who received the last dose ≥11 months earlier. Bivalent vaccines provided additional protection compared with previous monovalent vaccination and were shown to inhibit COVID-19 compared with no vaccination after administration of two, three, or four monovalent doses. [6] In addition, the Centers for Disease Control and Prevention (CDC) evaluated that 50-74% of people in the United States were vaccinated against influenza during 2021-2022. Although influenza vaccine effectiveness was 36% for all ages in that period, it varied by age group and was lowest among adults 50-64 years (8%) and highest among children aged between 6 months to 4 years (77%). [7] From 1 January to 31 July 2020, a study was performed on 6921 patients with COVID-19 who had received the influenza vaccine before being diagnosed with COVID-19. The results of this study showed the rates of hospitalization and mortality were lower in these patients by 15-24% and 38%, respectively. [8] It was revealed that patients aged >60 years who received an influenza vaccination had a lower probability of death caused by COVID-19 than unvaccinated patients, and the influenza vaccine had a potential protective effect against COVID-19 mortality in the elderly. Receiving the influenza vaccine before the influenza season can decrease the burden of influenza incidence, provide access to essential medical resources to cope with another wave of COVID-19, and reduce the risk of influenza and COVID-19 co-infection. [9] On the other hand, not only are new variants of the SARS-CoV-2 virus spreading, but simultaneous infection of this virus with seasonal influenza has created a major concern. Overall, studies suggest that co-infection of influenza with COVID-19 can lead to interference in the treatment, diagnosis, prognosis of COVID-19, complications of patients’ conditions, increasing death rate, especially in high-risk individuals such as the elderly and children. [10,11,12,13,14] The CDC estimated that during the 2021-2022 influenza season, there were reports of 9 million influenza cases, 4 million medical visits, 10,000 hospitalizations, and 5,000 deaths; however, these figures surged to 25-51 million influenza cases, 12-25 million medical visits, 280000-630000 hospitalizations, and 18000-56000 deaths between 1 October 2022 and 11 February 2023. [15,16] Most reports of co-infection of influenza and COVID-19 have been observed among patients from Asian countries such as China, which may be due to the high population of these nations. [17,18,19] Injury to respiratory cells infected by certain viruses can facilitate the status of infection with SARS-CoV-2. In the cold months of the year, with the start of the seasonal influenza season, there is a higher chance of a coincidence between influenza and COVID-19. Both SARS-CoV-2 and influenza virus A/B can infect patients by respiratory droplets, close contact, and contaminated surfaces and can lead to a wide range of COVID-19 manifestations, from asymptomatic to mild or severe disease, including loss of taste and smell, flu-like symptoms, pneumonia, and even death. [19,20,21] Hence, clinical symptoms are not helpful for the accurate diagnosis and differentiation of these two viruses, and different molecular and serological techniques are required for the accurate diagnosis of COVID-19 and influenza co-infection. [22,23] In addition, it is considered that SARS-CoV-2 preferably infects AT2 pneumocytes (type II alveolar cells), which are the main site of influenza virus replication; therefore, co-infection can lead to the exacerbated manifestations of COVID-19. [24,25] A systematic review suggested that 0.8% of COVID-19-positive patients suffered from influenza, too, but a retrospective study reported that the co-infection rate of influenza and SARS-CoV-2 was as high as 57.3%, of which 49.8% was caused by influenza A virus. Overall, the rate of coinfection with COVID-19 and influenza has been reported between 0.24 and 49.8%. [19,26] The frequency of co-infection in Asia and America was reported at 4.5% and 0.4%, respectively. The prevalence of COVID-19 co-infection with influenza in women (9.1%) was higher than that in men (5.3%), and clinical manifestations such as fever, cough, and shortness of breath were the most common symptoms. A study showed the death rate of patients suffering the coinfection was 6.9%. [19] Another study indicated that COVID-19-positive and influenza-negative patients had shorter hospitalization periods, lower overall mortality, and lower hospital charges, which supported the idea of administrating the influenza vaccine in patients with COVID-19. [8] The coinfection between COVID-19 and seasonal influenza can put a large population at risk. A study on the role of seasonal influenza in the severity of COVID-19 revealed that the initial infection with the influenza A virus positively affects the entry of the SARS-CoV-2 virus into the cells and the infection of animals. [26]

The co-infection with COVID-19 and influenza is of a great importance as it can cause damage to patients and the healthcare section. Also, if this co-infection affects a large population, the healthcare system will be incapacitated. Therefore, this study provides suggestions on how to prevent and reduce the co-infection of these two diseases:

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Observing the guidelines of the World Health Organization (WHO), such as wearing a mask (especially in closed and crowded spaces), washing hands, maintaining a distance of at least 3 feet, and avoiding unnecessary meetings, should be prioritized.

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Vaccines for new strains of influenza and the fourth dose of COVID-19 vaccines should be administered, especially for the high-risk population, such as the elderly, those with underlying conditions, immune-deficient patients, and healthcare staff.

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The production of new influenza vaccines with new technologies which would be effective against new strains of this virus should be prioritized, and surveillance and control of influenza infections should be applied shortly.

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People with symptoms of a common cold should immediately visit a doctor and receive supportive treatment and observe quarantine conditions to prevent the spread of the disease.

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Since the students are attending schools and universities in-person again, the rapid transmission of COVID-19 and influenza has increased. As infection can spread among them easily, people with symptoms of respiratory disease and cold should refrain from attending school or university until full recovery.

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In this situation, the co-infection with influenza and COVID-19 complicates the treatment of patients; if also a co-infection or a secondary infection with bacteria occurs, treatment will be more complicated. Hence, the use of antibiotics in people with symptoms plays a pivotal role in preventing simultaneous bacterial infections, although doctors should prescribe antibiotics according to guidelines to prevent antibiotic resistance.

Although strict devotion to the protocols recommended by the WHO before vaccination reduced viral respiratory diseases such as influenza, co-infection of influenza and COVID-19 in the cold seasons, and the presence of many social activities may increase since the world has not yet recovered from the COVID-19 pandemic. One of the limitations of this study was the lack of sufficient literature on the co-infection of COVID-19 and influenza, especially about the preventing effect of vaccination against co-infection because this hypothesis is still in its initial stages. Therefore, the suggestions presented in this study can help prevent and reduce the simultaneous occurrence of these two infections.