Co-circulation, Co-infection of SARS-CoV-2 and Influenza Virus, Where Will it Go?

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EFFECTS OF COVID-19 INTERVENTIONS ON THE INCIDENCE RATE OF INFLUENZA
The outbreak of COVID-19 greatly altered the epidemiology of respiratory tract infections in several ways.Inf luenza data from China have shown that the positivity rate of specimens collected from cases of inf luenza-like illness decreased since the onset of the COVID-19 pandemic in early 2020 and was subsequently maintained at a very low level in the following months of 2020 [5].Global surveillance data have indicated similar trends.Inf luenza and COVID-19 have similar clinical symptoms and transmission routes [6,7].The implementation of nonpharmaceutical interventions including social distancing decreased both the number of reported cases of COVID-19 and the incidence of inf luenza [8].Since the second half of 2020, some countries have decreased the use of NPIs, thus diminishing the effects of COVID-19 control measures on inf luenza virus transmission.
Global inf luenza activity increased in 2021 but remained below pre-pandemic levels overall [9].In China, despite the absence of a clear epidemic peak of inf luenza in the winter of 2020-2021, an inf luenza epidemic peak was observed in the winter of 2021-2022 [10].With the arrival of the 2023 inf luenza season, both COVID-19 and seasonal respiratory pathogens, particularly inf luenza, are likely to co-circulate at different levels.
Fortunately, no evidence indicates that inf luenza and COVID-19 can be highly prevalent simultaneously.Global surveillance data released by the WHO [11] have indicated that COVID-19 and inf luenza were not highly prevalent simultaneously in the past 3 years (Fig 1).Detailed analysis of data from 22 representative countries globally from week 1 of 2019 through week 45 of 2022 have demonstrated alternating prevalence of SARS-CoV-2 and inf luenza virus [12].These findings may be explained by the ability of inf luenza A virus and SARS-CoV-2 to block each other in cell studies [13].However, robust epidemiological data remain lacking.Learning how SARS-CoV-2 and other viruses interfere with each other outside laboratory settings will require prospective studies that closely monitor the same populations for several seasons.

CO-INFECTION WITH COVID-19 AND INFLUENZA
SARS-CoV-2 and inf luenza viruses spread through similar mechanisms.Moreover, both COVID-19 and inf luenza diseases present with overlapping clinical features ranging from mild inf luenza-like symptoms to pneumonia [14,15], including cough, sore throat, headache, muscle aches, breathlessness, fever, acute respiratory distress syndrome, and death.Therefore, co-infection with SARS-CoV-2 and inf luenza virus increases patient risk and complicates patient condition.

Co-infection rate of SARS-CoV-2 and influenza virus
The rates of co-infection with inf luenza viruses in COVID-19 have varied among studies, according to the period of study and region.A cohort study of 307 SARS-CoV-2 infected patients with severe acute respiratory syndrome in Wuhan has indicated that co-infection with SARS-CoV-2 and inf luenza viruses was highly prevalent (inf luenza A: 49.8% and inf luenza B: 7.5%) soon after the COVID-19 outbreak ( January 12 to February 21 2020) [16].However, inf luenza diagnosis was based on a single IgM antibody test, which is generally not recommended for inf luenza diagnosis.The SARS-CoV-2 co-infection rates with inf luenza significantly differed in March 3-25, 2020, in northern California (0.9% and 0% for inf luenza A and inf luenza B, respectively) [17] and in March 10 to May 10, 2020, in Turkey (0.5% for inf luenza infection) [18].This difference might potentially have been caused by several factors.On the one hand, the spread of respiratory viruses is affected by geographical factors such as the temperature, humidity, and population density.On the other hand, influenza incidence is low as expected when exiting the influenza season.
Therefore, to decrease the effects of regional differences and inf luenza seasons, Dao et al. have conducted a meta-analysis to determine the proportion of co-infection with inf luenza viruses in SARS-CoV-2 positive patients (including 54 research articles; most recent search conducted on July 15, 2021) [19].The data indicated that the overall proportion of co-infection was 0.7%, and a very low co-infection rate between COVID-19 and inf luenza was observed.

Risk of co-infection between SARS-CoV-2 and influenza virus
Co-infection with SARS-CoV-2 and inf luenza virus is relatively more likely to occur in high-risk groups, such as older people and children.In data from the UK Department of Public Health, most cases of co-infection were in older people, more than half of whom died [3].The reason for this phenomenon may be immunosenescence in the aging process [20].Another study has reported a proportion of co-infection of 3.2% in children and only 0.3% among adult patients [19].
The clinical outcomes of co-infection with SARS-CoV-2 and inf luenza virus have been evaluated in laboratory-based studies.An analysis by Public Health England of cases from January to April 2020 has found that people infected with both viruses are more at risk of severe illness [3].People infected with both inf luenza and COVID-19 are more than twice as likely to die as those with SARS-CoV-2 alone.The mortality rate of co-infected individuals is 2.53 times that (95% confidence interval 1.07-5.12) in people with SARS-CoV-2 alone [21].These results suggest possible synergistic effects on the severity of infections in co-infected people.Similarly, in Wuhan, people co-infected with SARS-CoV-2 and inf luenza B virus have been found to be more likely to have fatigue (13%), abnormalities on chest computed tomography (100%), or decreased lymphocytes (0.84, 0.68-1.27)and eosinophils (0.00, 0.00-0.01),thereby indicating more severe disease.Remarkably, although all patients received similar treatment during hospitalization, patients co-infected with inf luenza B virus had a higher rate of poor prognosis (30.4%) than SARS-CoV-2 single positive patients (7.6%) or inf luenza A virus co-infected patients (5.9%) [16].Furthermore, inf luenza pre-infection has been found to interfere with SARS-CoV-2 replication but to increase disease severity [22].Furthermore, other research has indicated that patients with SARS-CoV-2 and inf luenza co-infection are more likely to need mechanical ventilation (OR 2.01, 95% CI 1.19-3.39)[23,24].In general, co-infection with SARS-CoV-2 and inf luenza virus causes more severe disease in vivo than single infection with either virus.
Further experimental studies have confirmed that co-infection can cause more serious inf lammation in the nasal cavity and lungs.In a mammalian model involving co-infection with inf luenza virus and SARS-CoV-2 in ferrets, on the basis of detection of respiratory and lung tissue related pathological indicators, co-infection has been found to induce significantly more severe inf lammation than either inf luenza or SARS-CoV-2 infection alone [25].Bao et al. have found that co-infection prolongs the duration of clinical manifestations of COVID-19 and aggravates lung injury [26].Furthermore, another study has found that inf luenza virus has a ability to aggravate SARS-CoV-2 infection.Increased SARS-CoV-2 viral load and more severe lung injury have been observed in mice co-infected with inf luenza virus.However, enhanced infectivity of SARS-CoV-2 has not been observed in other respiratory viruses, possibly because inf luenza virus enhances the expression of ACE2 [27].The compounding effects of SARS-CoV-2 and inf luenza viral infection may be partly explained by both viruses primarily affecting alveolar type II cells (AT2 pneumocytes).Therefore, co-infection with these viruses may exacerbate respiratory epithelial damage.
Co-infection is usually accompanied by viral interference.This phenomenon, in which one virus competitively inhibits the replication of another co-infecting virus, is generally believed to decrease viral virulence, cell death, disease severity and transmissibility [28].In hamsters, although inf luenza appears to interfere with SARS-CoV-2 replication, it actually increases disease severity [22].Viral interference can be mediated by the innate immune interferon response, defective interfering particles, viral proteases and proteins, competition for cellular factors, and RNA interference.However, the induction of the interferon response in simultaneous or sequential inf luenza infection may also increase the inf lammatory cytokine storm associated with SARS-CoV-2 infection [22].Moreover, the defense against SARS-CoV-2, including decreased production of interferons [29], makes the existence of interference with other viruses uncertain.
In summary, co-infection with SARS-CoV-2 and inf luenza virus is more likely to occur in people with relatively lower immunity, such as older people and children.Co-infection aggravates injury and increases the severity rate and mortality.

Mitigating the effects of co-infection
With the ongoing COVID-19 pandemic and the arrival of seasonal inf luenza epidemics, early prophylactic measures, including vaccination against SARS-CoV-2 and inf luenza virus, may help decrease disease burden and improve clinical outcomes.Vaccination may have effects beyond preventing single viral infections: some studies have shown that inf luenza vaccination is associated with a decrease in the risk of SARS-CoV-2 infection [30].Preimmunization against inf luenza rather than SARS-CoV-2 can prevent severe disease and mortality [31].Among people with SARS-CoV-2 during the first wave of the pandemic in England, inf luenza vaccination was associated with a 15% -24% lower odds of hospitalization or all-cause mortality [32].A negative correlation (r = −0.5874,n = 21, P = 0.0051) has been found between the inf luenza vaccination rate and deaths caused by COVID-19.A high inf luenza vaccination rate led to lower mortality due to COVID-19.The percentage of COVID-19 deaths in each region was found to decrease by 0.3450 for each percentage unit of adults older than 65 years old and vaccinated against inf luenza [33].In addition, specific antiviral drugs and various vaccines have been developed for the treatment and prevention of inf luenza, and should help prevent the adverse effects of co-infection.
Studies have indicated that inf luenza vaccination may offer an additional means of alleviating severe adverse complications of SARS-CoV-2.Treatment and prevention of inf luenza can mitigate the damage caused by co-infection.Further research should aim to verify these findings in larger more diverse cohorts.The duration from vaccination administration to SARS-CoV-2 acquisition is additionally important.

FUTURE CONSIDERATIONS
Co-infection with viruses may significantly affect morbidity, mortality, and health-service demand.The effects and severity of co-infection with SARS-CoV-2 and inf luenza virus should be further considered in the upcoming inf luenza seasons.Although current research and surveillance data show that the co-infection rate is low, populations with immunocompromise and severe symptoms will face higher risk and are a matter of concern.Prevention and control strategies should include inf luenza and SARS-CoV-2 as well as other respiratory viruses, and measures against inf luenza can mitigate co-infection, including maximizing uptake of inf luenza vaccination, timely recognition of inf luenza virus, and timely use of anti-inf luenza drugs, particularly in groups at elevated risk of both diseases.Further research and investigation are needed to understand the potential mechanisms underlying any synergistic interactions.Strengthening of surveillance must always be emphasized globally.

FIGURE 1 |
FIGURE 1 | Global influenza and SARS-CoV-2 virus detection from sentinel surveillance reported to FluNet.