Research on COVID-19 and influenza risks and clinical outcomes is crucial because it enables medical professionals to provide patients with these diseases with the best preventive and supportive care. The current study found that, while COVID-19 and influenza patients had similar durations of hospital stay, COVID-19 patients were at a higher risk of mortality, in-hospital complications, ICU admissions, mechanical ventilation use, and longer ICU stays.
According to our findings, the mortality rate in COVID-19 patients was three times that of influenza patients (17% (17510/103264) vs. 5.2% (3765/72659), respectively). These findings agree with a Danish nationwide cohort study that found that the 30-day mortality rate for hospitalized COVID-19 patients was three times that of influenza patients (RR: 3.00; 95% CI: 2.65 to 3.39; p < 0.001).[14]. Similar findings were made by a comparative study conducted in the United Kingdom, which discovered that COVID-19 patients had a significantly higher mortality rate (42% vs. 24% for COVID-19 and viral pneumonias, respectively)[15]. Cobb and colleagues also noted that patients with COVID-19 had considerably higher hospital fatality rates than patients with influenza (p = 0.006)[16]. Further statistical analysis revealed that the relative risk (RR) for mortality was twice as high in COVID-19 patients as in influenza patients (adjusted RR, 2.13; 95% CI, 1.24–3.63; P = 0.006). The high mortality rate among COVID-19 patients observed in these studies appears to support the notion that COVID-19 is a more severe illness than influenza. Furthermore, the high mortality rate in COVID-19 patients can be attributed to a spontaneous influx of patients over a short span of time, which caused constraints in the medical structure and forced healthcare providers to prioritize patients based on clinical status and prognosis. Contrast to the results provided in these studies, Tang and colleagues reported higher mortality rates among patients with H1N1-induced acute respiratory distress syndrome (ARDS) than those with COVID-19-induced ARDS[17]. The difference in this study can be attributed to several factors. First, the study used data from two hospitals, which may not have accounted for the differences in local practice patterns and other factors. Secondly, the study only included patients with ARDS, meaning that the study only accounted for critically ill patients. The study also revealed that about 36% of patients were still in the hospitals at the completion of the study, which may have led to an underestimation of in-hospital mortality.
The mortality rates among patients with COVID-19 and influenza can be associated with various risk factors. The first factor associated with mortality rates is the demographic factor, age. Beatty and colleagues discovered that mortality rates rose with age. That study found no discernible differences in mortality rates between COVID-19 and influenza patients under the age of 40. However, in participants over the age of 40, the COVID-19 group had significantly higher mortality rates, with ORs increasing from 2.27 (95% CI 1.4–3.61, p0.001) in the 40–60 year age bracket to 4.99 (95% CI 3.54–7.03, p0.001) in the 85 and older age bracket[11]. Xie et al. [7] also reported higher mortality rates among older patients. According to the study's findings, overall mortality increased from 9.3% in the group of people under 65 years old to 19.4% in the group of people between 65 and 75 years old, and 27.8% in the group of people over 75 years old. Talbot and colleagues also collaborated on these findings by showing that the mortality rates were more prominent with increasing age[13]. Another study evaluating patients with different subtypes of influenza showed that age was highly associated with mortality rates[18]. In that study, influenza A (H1N1) patients who were 65–74 years old and ≥ 75 years old had an increased risk of death (AOR 2.46, 95% CI: 1.22–4.97 and 2.13, 95% CI: 1.05–4.30, respectively). Similar to patients with influenza A, patients with influenza B had a higher risk of dying if they were 65 to 74 years old or older than 75 years old (AOR 27.42, 95% CI 4.95-151.93 and 15.96, 95% CI 3.01–84.68, respectively).
Additionally, studies have demonstrated the impact of race and gender on the mortality rates of COVID-19 and influenza patients. According to a study by Talbot and colleagues, non-Hispanic African American patients had a higher risk of dying in the hospital than non-Hispanic White patients (AOR = 58.6; 95% CI:13.3,258.8; P < 0.01 vs. AOR = 16.6; 95% CI:9.1,30.4; P = 0.08, respectively) [13]. However, the study attributed the disparities in the mortality rates between the different races to undiagnosed and untreated comorbid conditions. When the authors of the study considered gender influence, they found that in-hospital death was higher among male patients than female patients (AOR = 26.3, 95% CI: 11.8, 58.7, P < 0.01 vs. AOR = 16.5, 95% CI: 8.3, 32.6, P = 0.02, respectively). Similarly, a previous case series study reported that gender could be an independent factor for COVID-19 severity and mortality. According to the study's findings, men had a 2.4 times increased risk of death than female patients [19]. On the other hand, Price-Haywood and colleagues investigated how race affected mortality rates among COVID-19 patients and discovered that race was not on its own a significant risk factor for in-hospital mortality. (hazard ratio, 0.89; 95% CI, 0.68 to 1.17) [20].
The current study has also shown that patients with COVID-19 are at a higher risk of developing in-hospital complications. The higher risk of pulmonary embolism among the patients with COVID-19 is consistent with the findings of Fauvel and colleagues, who reported that of the 1240 COVID-19 hospitalized patients referred for a computed tomography pulmonary angiography 103 (8.3%) patients were found to have developed pulmonary embolism [21]. It is also vital to note that the current study used acute respiratory failure to account for respiratory complications and found that COVID-19 patients were at a higher risk of acute respiratory failure than influenza patients. However, evidence shows that the risk of other respiratory complications varies from study to study. For example, Cates and colleagues reported that COVID-19 patients had a 19 times risk for ARDS and 3.5 times risk for pneumothorax than influenza patients. However, influenza patients were 3 times more likely to develop asthma than COVID-19 [9]. The risk of other non-respiratory complications, such as sepsis and acute kidney injury, has also been reported to be high among patients with COVID-19. This increased risk of acute kidney failure/injury among Influenza and COVID-19 is also supported in previous studies [22, 23]. The increased risk of sepsis among COVID-19 patients can be explained by the dysregulated response system in these patients [24].
Other studies show that less common but severe complications, such as hematological and neurologic complications and bacteremia, can be witnessed in influenza and COVID-19 patients. Cates and colleagues reported that the risk of cerebral ischemia was twice as high in the COVID-19 group than in the influenza group [9]. These results are consistent with a United States study which showed that the odds of developing stroke were 7.6 times higher in COVID-19 patients than in influenza patients[25]. Similarly, the results by Xie and colleagues showed that the risk for stroke was higher among COVID-19 patients (AOR: 1.62; 95% CI: 1.17 to 2.24). However, Piroth et al. [10] reported that the risk of developing ischemic stroke was similar in both COVID-19 and influenza patients (0.8% vs. 0.9%, respectively; p = 0.097). Even though our study was not based on patients being treated or vaccinated against COVID-19 or influenza, it is vital to note that some vaccinations may also result in complications. Our recent Case report of a patient receiving the Pfizer-BioNTech COVID-19 mRNA vaccine shows that the patient had developed signs and symptoms of acute pericarditis 10 days after the vaccination. A diagnosis made on the patient confirmed that the patient had developed an acute pericarditis namely pericardial perfusion and typical pain [26].
The complications reported in COVID-19 and influenza patients can be attributed to various risk factors, including age, gender, and race/ethnicity. Cates et al. conducted a statistical analysis to show the effect of race on the risk of developing in-hospital complications and found that Black Hispanic and non-Hispanic patients were at a higher risk of developing sepsis and renal, neurologic, and respiratory complications than White patients. However, the study reports that the difference between these races could not solely be related to underlying comorbidities or age, but other factors such as social, environmental, economic, and structural inequalities could have accounted for the differences. On the other hand, a United Kingdom prospective cohort study including COVID-19 patients also showed that the complication rates were comparable across all the racial groups but were highest among black patients than white patients (57.8% (1433 of 2480) vs. 49.1% (26431 of 53780), respectively) [27]. Further statistical analysis showed that complication rates increased with age of which patients in the ≥ 50 years age had a higher complication rate than patients in the 19–49 age group (51.3% vs. 38.9%, respectively). Male patients also seemed to develop more complications than females. The study also claimed that when the age, sex, and comorbidities were adjusted, the male sex became an independent predictor for developing complications. Pre-existing comorbidities were also associated with an increased risk of complications. The study reported that patients with some existing comorbidities in a particular organ were at a higher risk of developing complications affecting that organ. A prospective study including influenza patients only also showed that with pre-existing comorbidities and patients aged ≥ 50 years were more likely to develop in-hospital complications [28].
The findings of the current study also seem to suggest that the severity of COVID-19 and influenza is associated with the number of patients being admitted to the ICU. Our study has shown that patients with COVID-19 were more likely to be referred to the ICU and stay longer than those with influenza. This finding is supported by a previous study that reported that COVID-19 patients had significantly higher proportions of ICU admissions than influenza patients (29% vs. 6%, p = 0.034) [29]. Similarly, a German cohort study reported that ICU admissions were substantially higher among COVID-19 patients than among influenza patients (21% vs.13%, respectively) [30]. Contrary to these results, other studies have shown insignificant differences in ICU admissions between COVID-19 and influenza patients. For example, Zayet and colleagues reported similar proportions of ICU-admitted patients with COVID-19 and influenza (15% and 9%, respectively; p = 0.458) [5]. The results also showed that the mean stay in the ICU was not statistically different between the two groups (p = 0.924). Similarly, Cobb and colleagues showed an insignificant difference in the length of ICU stay between COVID-19 and influenza patients (p = 0.22)[16]. The difference in these studies can be attributed to the fact that they mostly included patients with severe influenza and COVID-19.
It is important to note that several factors may have impacted the ICU admissions in both COVID-19 and Influenza patients. Univariate analysis of risk factors associated with ICU admission by Sadeghi and colleagues showed that age was significantly associated with the increased risk of ICU admission among COVID-19 patients (OR: 1.02; 95% CI: 0.89 to 0.89; p = 0.03)[31]. This finding is evident in a German cohort study that reported the highest percentage of COVID-19 ICU admissions among patients in the 70–89 age group (64%) and the least percentage in the 20–49 age group (< 1%) [30]. Pre-existing comorbidities have also been associated with an increased risk of ICU admission. Sadeghi and colleagues reported that patients with a history of kidney diseases or cancer were at a higher risk of being admitted to the ICU (P = 0.04, OR = 2.54, 95% Cl = 1.00-6.41 and P = 0.00, OR = 3.15, 95%Cl = 1.39–7.15; respectively) [31]. Other comorbidities such as hypotension, Type 2 Diabetes Mellitus, Chronic Kidney diseases, and Heart failure have also been associated with an increased risk of ICU admissions [30]. Additionally, a Colombian multivariate analysis showed that among COVID-19 patients, the risk of being admitted was higher for patients with pre-existing ischemic heart disease (OR: OR:3.24; 95%CI:1.16–9.00) and chronic obstructive pulmonary disease (OR:2.07; 95%CI:1.09–3.90)[32]. However, it should be noted that some pre-existing comorbidities, such as acquired immunodeficiency syndrome (AIDs), have some interesting findings. Piroth and colleagues reported that patients with HIV did not seem to be more affected by either COVID-19 or influenza. This finding was attributed to the fact that virologically controlled HIV patients (antiretroviral treated) seem not to have a considerably higher risk of developing severe COVID-19, as shown in countries with low antiretroviral rates[33]. However, this does not mean that HIV patients are at a lower risk of developing severe COVID-19 due to the potentially preventive property of antiretroviral therapy [34].
Evidence from previous studies has also shown that among influenza patients, sex and obesity may influence ICU admissions rates. A Dutch study evaluating the risk factors associated with ICU admission reported that patients with a body mass index (BMI) greater than 30 were at a higher risk of being admitted to the ICU (p = 0.04) [35]. Similarly, Martinez and colleagues reported that obesity was associated with ICU admission, especially for patients with influenza A. However, other studies have found no association between ICU admission and obesity [36, 37]. The contrasting finding in these studies can be attributed to the fact that based on age, obesity is usually accounted for when deciding whether severe cases of influenza should be admitted to the ICU. The study by Martinez et al. [18] also showed a significant association between gender and ICU was observed for patients with type A influenza, of which male patients were admitted to the ICU more frequently than female patients. Moreover, the study explained that seasonal influenza vaccination is associated with reduced ICU admission among patients with Influenza A. However, further analysis showed that the statistical power was too low to associate the vaccine to reduced risk of ICU admission in Influenza B patients.
Limitations
The findings of this systematic review and meta-analysis were subject to various limitations, including high heterogeneity in the analysis of the main outcomes. However, this heterogeneity was expected, given that patients with different variants of COVID-19 and influenza were included in the study. The heterogeneity also did not affect our meta-analysis’s results since most of the studies included in this study had a good methodological quality, meaning that the publication bias was minimized. Some included studies may have under-detected or misclassified some of the patients’ characteristics, such as comorbidities, thereby introducing bias in the outcomes that depend on these characteristics[10]. Additionally, our study only used studies published in English to conduct the meta-analysis. Due to this criterion, many articles written in other languages that could have been used to improve the statistical power and the scientific research of the current study were omitted. Some of the studies had very low sample sizes compared to other studies, and this may have influenced the results of our meta-analysis[5]. The study also allowed the inclusion of both adult and pediatric patients; however, during the meta-analysis, the studies were not grouped based on the patients’ age, making it difficult to directly differentiate the risk of COVID-19 and influenza in adult and pediatric patients.