SARS-CoV-2 and Seasonal Influenza: Similarity and Disparity

doi:10.21203/rs.3.rs-1552697/v1

Background: A discussion is ongoing regarding the severity of coronavirus disease-2019 (COVID-19) compared to seasonal influenza. In addition, early differentiation between COVID-19 and influenza viruses is essential in hospitalized patients. We try to assess differences in disease severity and clinical presentaion of the two diseases.

Methods: The clinical characteristics and outcomes of patients hospitalized due to COVID-19, between June and August 2020 were compared with those of patients hospitalized due to influenza during the 2019-2020 influenza season.

Results: A total of 136 influenza patients and 152 COVID-19 patients were included. Patients with influenza have more runny nose (p<0.001, OR 7.46), cough (p<0.001, OR 3.64), dyspnea (p=0.004, OR 2.0), myalgia (p=0.039; OR 2.0) or underlying disease (p=0.046, OR 1.67). Also, hypoxemia on admission (p<0.001, OR 4.42), smoking (p<0.001, OR 4.63) or elevated liver enzymes (p=0.028, OR 8.33). However, patients with COVID-19 were overweight (p<0.001, OR 3.111), have lymphopenia <1,500 (p<0.001, OR 54.69), CRP > 5mg/dL (p=0.011, OR 1.88), or radiographic abnormalities (p<0.001, OR 2.757). Although patients with influenza have a severe disease (NEWS > 6) on admission (p<0.001, OR 3.17), length of hospital stay, need for ventilatory support and 30-day mortality were similar in both groups (p=0.26, 0.47 and 0.50 respectively).

Conclusions: Influenza patients admitted to the hospital were more severely ill at the time of admission than COVID -19, but in-hospital mortality and clinical outcomes are similar. In addition, the two diseases have different characteristics that allow them to be distinguished at the time of admission until laboratory identification.

COVID-19

Influenza

SARS-CoV-2

Respiratory illness caused by influenza viruses shares clinical and radiological findings with SARS-CoV-2 infection. Based on clinical presentation alone it is difficult to distinguish between these two causative viruses(1). This becomes even more important now as health care systems are coping with the ongoing SARS-CoV-2 pandemic and seasonal influenza. The comparison between coronavirus disease 2019 (COVID -19) and influenza has been made since the beginning of the COVID-19 pandemic.

Both viruses can cause mild, severe, or even fatal illness(2,3). Although SARS-CoV-2 and influenza share the same characteristics in terms of symptoms, higher transmissibility and mortality have been reported in association with COVID-19(4,5). In addition, COVID -19 was associated with worse clinical outcomes, including length of invasive ventilation and hospitalization, acute respiratory distress syndrome, systemic inflammatory response syndrome, and acute kidney injury(4).

Although both viruses spread primarily via droplets over short distances, SARS-CoV-2 is more infectious and spreads more rapidly. The potential for airborne transmission, epidemiologic impact, limited preliminary herd immunity, and different treatment strategies underscore the need to distinguish between influenza- and SARS-CoV-2-infected patients(3,6).

In the present study, we try to assess whether COVID -19 differs in severity from seasonal influenza infection and to explore the differences in presentation between SARS-CoV-2 and influenza in hospitalized patients.

Study design

This is a retrospective study conducted at Rambam Health Care Campus (RHCC), a 1000-bed university-affiliated tertiary hospital serving more than two million citizens in northern Israel. All adult patients admitted to RHCC with confirmed SARS-CoV-2 respiratory illness during the second "wave" of COVID -19 in Israel between June 1, 2020 and August 31, 2020 were included. They were compared to patients admitted with respiratory disease caused by influenza viruses between November 1, 2019 and August 31, 2020. Data were extracted from the hospital's electronic medical records. The following variables were recorded for each patient:

Demographic and clinical data: age, sex, presenting symptoms, comorbidities including malignancy, immunosuppression, chronic kidney disease, pulmonary disease, diabetes mellitus, cardiovascular disease, overweight determined as body mass index (BMI) > 25, smoking, hypertension and hyperlipidemia.
Laboratory measurements on admission: white blood count (WBC), lymphocyte count, C-reactive protein (CRP), creatinine, albumin, aminotransferases, liver enzymes and bilirubin.
Radiological findings on chest radiographs reviewed by a pulmonary specialist: abnormal radiographs were classified as "bilateral opacities," "unilateral opacities," or "other" abnormal findings.
Disease severity was graded using the National Early Warning Score 2 (NEWS2), which is based on an overall assessment of six physiologic parameters: respiratory rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new confusion, body temperature, and two additional points for patients requiring supplemental oxygen(7). A NEWS2 score ≥6 was considered indicative of severe disease(8)
Treatment measures including respiratory support in the form of inhalations, supplemental oxygen, noninvasive and invasive ventilation or hemodynamic instability, and inotropy treatment.
Outcome measures including length of stay (LOS) at hospital, in-hospital mortality, and 30-day-mortality.

Data were analysed using SPSS software (version 26). Univariate analysis was performed using the χ2-test or Fisher's exact test for categorical variables and the independent t-test for continuous variables. All tests were two-tailed and p <0.05 was considered statistically significant.

The study was approved by the local institutional ethics committee (0252-20-RMB).

During the study period, 136 patients with influenza and 152 patients with COVID-19 were included. The mean age was similar for influenza (60.25+19.65 years) and COVID-19 (60.32+18.24 years), p 0.266. No sex differences were observed between the two groups.

Patients with influenza had 4-fold higher risk for hypoxemia (O₂ saturation <92%) on admission compared to patients with COVID-19 (39.5% vs 12.9%, p<0.001). In addition, influenza was more associated with runny nose (23.5% vs 3.9%, p<0.001, OR 7.46), cough (80.1% va 52.6%, p<0.001, OR 3.64), dyspnea (55.9% vs 38.8%, p 0.004, OR 2.0) and myalgia (19.1% vs 10.5%, p 0.039; OR 2.0) and with higher rates of smoking (42.6% vs 13.8%, p<0.001, OR 4.63) and underlying diseases (73.5% vs 62.5%, p=0.046, OR 1.67) compared to patients with SARS-CoV-2. However, overweight was more represented in patients with COVID-19 (80.0% vs 56.3%, p<0.001, OR 3.11) Table 1.

Patients with influenza are also more likely to have elevated liver enzymes (5.7% vs 0.7%, p=0.028, OR 8.33). However, patients with SARS-CoV-2 were more likely to have lymphopenia <1,500 (88% vs 11.9%, p<0.001, OR 54.69), elevated CRP > 5mg/dL (54.6% vs 39.1%, p=0.011, OR 1.88), or an abnormal findings on chest radiographs (77.9% vs 56.2%, p<0.001, OR 2.76). Of the patients with COVID-19 who had abnormal chest radiographs, 104 (92%) had bilateral findings consistent with viral pneumonia as assessed by a pulmonologist (Table 2).

Patients with COVID-19 more frequently needed intravenous fluid support (12.5% vs 3.7%, p=0.011, OR 3.74) but less inhalation therapy (19.1% vs 40.4%, p<0.001, OR 0.35).

Although patients with influenza have more severe disease (NEWS > 6) (27.2% vs 10.5%, p<0.001, OR 3.17), length of hospital stay, need for ventilatory support, in-hospital mortality, and 30-day mortality were similar in both groups (p=0.26, 0.47, 0.83 and 0.50 respectively) (Table 3).

In the present study, we examined the clinical presentations and outcomes of SARS-CoV-2 and influenza infections in hospitalized patients. This is a discussion that has been ongoing since the emergence of SARS-CoV-2 epidemic.

Although patients with influenza had more severe disease on admission (NEWS score > 6), outcomes, including length of hospital stay, need for ventilatory support, in-hospital mortality, and 30-day mortality, were similar to SARS-CoV-2. In contrast to our study, a previous study from Germany found that hospitalized patients COVID -19 had higher in-hospital mortality and worse clinical outcomes including duration of ventilation and hospitalization, acute respiratory distress syndrome, and acute kidney injury(4).

Another study by Pannu et al. showed similar results to our study in terms of severity of illness and mortality, which were similar for COVID -19 and other respiratory infections; however, COVID -19 required a longer hospital stay(9).

In this study, patients with influenza on admission were more likely to have classic "flu-like" symptoms such as runny nose, cough, dyspnea, myalgias, and hypoxemia than COVID -19 patients. This finding is consistent with previous studies(1,10).

Patients with COVID-19 had fewer comorbidities compared with patients with influenza. This may be due to the permissive admission policy for patients with COVID -19 during the second "wave" in Israel, compared with the stricter admission policy for patients with influenza, in which more complicated cases and patients with underlying diseases were admitted. This could also be due to people seeking medical attention earlier and despite good general health for fear of contact with an emerging virus and its consequences.

COVID-19 patients were more likely to be overweight. Much evidence suggests that excess adiposity and chronic inflammation caused by obesity increase susceptibility to viral infections and disease severity due to increased levels of proinflammatory cytokines and immune system dysregulation (11,12).

In this study, smokers were less represented in COVID-19 than in patients diagnosed with influenza. Previous studies have shown that the proportion of smokers among patients diagnosed with COVID -19 varies(13–16). Increased awareness of this anamnestic detail was noted during the pandemic, resulting in optimal documentation of smoking status.

Lymphopenia was the most prominent laboratory finding in patients with COVID -19 and was 54 times more common than in influenza patients. Two hypotheses explain the marked lymphopenia in COVID -19: direct infection of lymphocytes by the virus due to expression of ACE2 receptors on their cell membrane and induced lymphocyte deficiency due to pro-inflammatory cytokines (17,18).

For radiological assessment of SARS-CoV-2 lung involvement, computed tomography (CT) of the chest is more sensitive to minor changes than chest-x-ray (CXR), and previous studies showed significant differences in chest CT between patients with SARS-CoV-2 and influenza-related disease (19–21). However, CXR is the preferred method in the initial evaluation of both influenza and COVID-19 patients since CXR is associated with lower radiation and it is more available compared to CT in some facilities. Accordingly, CXR was the preferred imaging modality in our institution during the study period. CXRs from patients with COVID-19 were abnormal at a higher proportion and manifested mainly as bilateral infiltrates. This was similar to previously published studies(22,23) and contradictory to other smaller one(20).

Patients with COVID-19 were more likely to be dehydrated on admission; this may be due to intravascular depletion caused by the direct action of the virus on ACE2 receptors in the kidneys (24).

This main limitation of this study is its retrospective design, which may affect the quality of data and follow-up; to overcome this limitation, great efforts were invested in data collection. In addition, the study compares only the second "wave" of the COVID -19 pandemic in Israel, and there are differences in severity between the different waves related to the emergence of new variants, future study should includes the whole cohort of COVID-19 and influenza patients throughout the pandemic.

Our results suggest that influenza patients admitted to the hospital are more severely ill at the time of admission, but in-hospital mortality and clinical outcomes are similar. In addition, the two diseases have different characteristics that allow them to be distinguished at the time of admission in order to take the necessary precautions and infection control measures from the time of arrival at the hospital.

Conflict of interest: the authors declare that they have no competing interests.

Funding: there is no source of funding.

Availability of data and material: data are available in the hospital's electronic medical records.

Code availability: data were collected from the electronic medical records using identification numbers. After data extraction, cases were coded by sequential numbers and stored anonymously. The list linking the study code to the participant's information is stored on the investigator's computer.

Ethical approval: this study was approved by the hospital ethics committee.

Author contributions: All authors contributed equally to the study. Dr H. Dabaja Younis compiled the medical and laboratory data, actively participated in the statistical analysis, prepared the tables and figures, and wrote and edited the manuscript. Dr. E. Fucks assisted in the analysis of the patients' radiographs and in editing the manuscript. Dr N. Shorbaji, Dr T. Appel, and Dr N. Carmon assisted in collecting data from the medical records and in reviewing the manuscript. Dr. Y. Shachor-Meyouhas and Prof. M. Green edited and reviewed the manuscript, and Dr. K. Hussein guided and supervised this study.

Consent to participate: informed consent was waived because this was a retrospective study.

Informed Consent for publication: All authors consented to the publication of the manuscript.

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Table 1. The demographics and clinical characteristics of patients with influenza compared to patients with COVID-19

	Influenza (n=136)	SARS-Cov-2 (N=152)	p value	OR (95%CI)
Age, mean±SD (median)	60.25±19.65 (64.30)	60.32±8.24 (60.75)	0.266
Age>60 years	81 (59.6)	80 (52.6)	0.237
Sex (male)	63 (46.3)	80 (52.6)	0.285
Clinical presentation (on admission)
Fever >38 °C	61 (44.9)	79 (52)	0.227
Oxygen saturation <92 %	60 (39.5)	31 (12.9)	<0.001	4.42 (2.69-7.25)
Symptom’s duration >7 days	30 (22.1)	14 (12.7)	0.058
Runny nose	32 (23.5)	6 (3.9)	<0.001	7.46 (3.02-18.52)
Cough	109 (80.1)	80 (52.6)	<0.001	3.64 (2.14-6.17)
Fatigue	52 (38.2)	62 (40.8)	0.658
Headache	19 (14)	16 (10.5)	0.372
Dyspnea	76 (55.9)	59 (38.8)	0.004	2.00 (1.25-3.19)
Sore throat	17 (12.5)	9 (5.9)	0.052
Diarrhea	15 (11)	18 (11.8)	0.829
Nausea/vomiting	27 (19.9)	20 (13.2)	0.125
Myalgia	26 (19.1)	16 (10.5)	0.039	2.01 (1.03-3.94)
Comorbidities
Any underlying condition	100 (73.5)	95 (62.5)	0.046	1.67 (1.01-2.75)
Hyperlipidema	39 (28.7)	57 (37.5)	0.113
Hypertension	64 (47.1)	63 (41.4)	0.338
Diabetes mellitus	51 (37.5)	47 (30.9)	0.239
Ischemic heart disease/ congestive heart failure	44 (32.4)	21 (13.8)	<0.001	2.99 (1.66-5.35)
Immunosupprssion/Malignancy	37 (24.3)	13 (5.4)	<0.001	5.65 (2.88-10.99)
COPD/Asthma	42 (30.9)	12 (7.9)	<0.001	5.21 (2.60-10.42)
Chronic kidney disease	29 (21.3)	23 (15.1)	0.173
Smoking	58 (42.6)	21 (13.8)	<0.001	4.63 (2.62-8.20)
Overweight (BMI>25)	63 (56.3)	96 (80)	<0.001	0.32 (0.18-0.58)

Table 2. The laboratory measures and imaging of patients with COVID-19 compared to patients with influenza

	Influenza (n=136)	SARS-Cov-2 (N=152)	p value	OR (95%CI) Chi²/fisher exact test / t-independent test
Laboratory measures
WBC × 10⁹/L	7.69+4.40	7.42+4.91	0.627
Lymphopenia <1.5 × 10⁹/L	16 (11.9)	125 (88)	<0.001	54.688 (26.424-113.183)
CRP>5 (mg/dL)	50 (39.1)	77 (54.6)	0.011	1.877 (1.155-3.051)
Creatinine >2 (mg/dL)	25 (18.7)	28 (19.3)	0.889
Albumin (g/dL)	20 (18)	8 (9.9)	0.114
ALT or ALT > 5 ULN* (unit/L)	7 (5.7)	1 (0.7)	0.028	0.120 (0.015-0.990)
Bilirubin (mg/dL)	0.56+0.489	0.53+0.453	0.673
Radiological findings (chest x-ray)
Normal	57 (43.8)	32 (22.1)	<0.001		2.757 (1.634-4.654)
Abnormal	73 (56.2)	113 (77.9)
Unilateral	15 (11.5)	5 (3.4)
Bilateral	52 (40)	104 (71.7)
Other	6 (4.6)	4 (2.8)

Note *ULN-upper limit of normal

Table 3. Management and outcome of patients with COVID-19 compared to patients with influenza

	Influenza N=136 (%)	SARS-Cov-2 N=152 (%)	p value	OR (95%CI)
Therapeutic support
Oxygen	61 (44.9)	68 (44.7)	0.984
Inhalations	55 (40.4)	29 (19.1)	<0.001	0.347 (0.204-0.590)
BiPAP/ CPAP/HFNC	10 (7.4)	20 (13.2)	0.104
Invasive ventilation	7 (5.1)	11 (7.2)	0.465
Fluid support	5 (3.7)	12 (12.5)	0.011	3.743 (1.273-1.007)
Hemodynamic instability	7 (5.1)	17 (11.2)	0.064
Inotropes	6 (4.4)	10 (10.4)	0.075
Outcome measures
NEWS-2 > 6	37 (27.2)	16 (10.5)	<0.001	0.315 (0.166-0.598)
LOS >3 days	103 (75.7)	107 (70.4)	0.309
LOS (days) Mean±SD	9.40±15.32	7.87±6.988	0.266
30-days mortality	9 (6.6)	15 (9.9)	0.500
In-hospital mortality	10 (7.3)	14 (9.2)	0.833

Notes BiPAP=bilevel positive airway pressure; CPAP=continuous positive airway pressure; HFNC=high frequency nasal canula

SARS-CoV-2 and Seasonal Influenza: Similarity and Disparity

Status:

Version 1

Abstract

Introduction

Methods

Results

Discussion

Declarations

References

Tables

Status:

Version 1