key: cord-0822401-2pmpspuj
authors: Zayet, Souheil; Kadiane-Oussou, N’dri Juliette; Lepiller, Quentin; Zahra, Hajer; Royer, Pierre-Yves; Toko, Lynda; Gendrin, Vincent; Klopfenstein, Timothée
title: Clinical features of COVID-19 and influenza: A comparative study on Nord Franche-Comte cluster
date: 2020-06-16
journal: Microbes Infect
DOI: 10.1016/j.micinf.2020.05.016
sha: 794d5f2758013d4fce619ed54d25a30764994204
doc_id: 822401
cord_uid: 2pmpspuj

Clinical descriptions about influenza-like illnesses (ILI) in COVID-19 seem non-specific. We aimed to compare the clinical features of COVID-19 and influenza. We retrospectively investigated the clinical features and outcomes of confirmed cases of COVID-19 and influenza in Nord Franche-Comté Hospital between February 26(th) and March 14(th) 2020. We used SARS-CoV-2 RT-PCR and influenza virus A/B RT-PCR in respiratory samples to confirm the diagnosis. We included 124 patients. The mean age was 59(±19[19-98]) years with 69% female. 70 patients with COVID-19 and 54 patients with influenza A/B. Regarding age, sex and comorbidities, no differences were found between the two groups except a lower Charlson index in COVID-19 group (2[±2.5] vs 3[±2.4],p=0.003). Anosmia (53% vs 17%,p<0.001), dysgeusia (49% vs 20%,p=0.001), diarrhea (40% vs 20%,p=0.021), frontal headache (26% vs 9%,p=0.021) and bilateral cracklings sounds (24% vs 9%,p=0.034) were statistically more frequent in COVID-19. Sputum production (52% vs 29%,p=0.010), dyspnea (59% vs 34%,p=0.007), sore throat (44% vs 20%,p=0.006), conjunctival hyperhemia (30% vs 4%,p<0.001), tearing (24% vs 6%,p=0.004), vomiting (22% vs 3%,p=0.001) and rhonchi sounds (17% vs 1%,p=0.002) were more frequent with influenza infection. We described several clinical differences which can help the clinicians during the co-circulation of influenza and SARS-CoV-2.

Influenza-like-illness 45 46 patients. Other symptoms were present in less than 30% of cases (Table II) . We noticed that one of 119 the patients had a febrile confusion. Patients were symptomatic on average for 10 days (±5). 120

Concerning the outcome, 33 patients (47%) were hospitalized for a mean duration of 7 days (±6). 121

During hospitalization, 23 patients (33%) required oxygen therapy and 11 patients (16%) were 122 admitted in Intesive Care Unit (UCI) for acute respiratory failure and needed artificial ventilation for 8 123 days (±7). By March, the 24 th , 57 patients of the COVID 19 group (81%) had been discharged from 124 hospital and 4 (6%) patients had died; the other patients (9%, n=6) were still in hospital. 125

In the group influenza A/B, 51 patients (94%) were diagnosed with influenza A, and 3 (6%) with 127 influenza B. No significant differences were found between the two groups (COVID 19 and influenza 128 A/B) with regard to age, sex and the different comorbidities: cardiovascular diseases, COPD or 129 asthma, immunosuppression, diabetes and malignancy. However, patients with COVID-19 had a 130 lower Charlson comorbidity index than patients with influenza A/B (2 (±2.5) vs 3 (±2.4); p=0.003). 131

The mean incubation period was longer in patients with COVID-19 than patients with influenza (6 132 days (±2) vs 4 days (±3) respectively, p=0.01). Fever or feeling of fever, fatigue, cough and pain 133 symptoms (myalgia, arthralgia and headache) were the fourth most prevalent symptoms for both 134 diseases (COVID-19 and influenza A/B) without significant statistical differences except for frontal 135 headache and other localization of headache. In two groups patients without fever or a feeling of 136 fever were scarce: 4 patients in COVID-19 group and 1 patient in influenza group (p=0,386). However, 137 fever ≥38°C was significantly higher in influenza group than COVID-19 group (93% vs 76% 138 respectively, p=0.042) but the mean highest temperature was not significantly different (39°C vs 139 38.7°C respectively; p=0.064). Apart from the fourth main symptoms, most of the other symptoms 140 differed with significant differences. The third table (Table III) summarized significant diagnostic  141 criteria based on symptoms between infection with SARS-CoV-2 and influenza. 142

We reconstituted the history of evolution and onset of the main symptoms in COVID-19 and 143 influenza ( Figure A) . We noticed the same natural evolution of symptoms in COVID-19 and influenza: 144 firstly, pain syndrome appeared, secondly, fever, thirdly, cough and fourthly diarrhea. The onset of 145 these symptoms (from illness onset) didn't differ between the two groups except for fever which 146 appeared earlier in COVID-19 than in influenza (respectively 1.9 days [±1.5] vs 2.7 days [±1.5], 147 p=0.045). We also reconstituted the history of clinical aggravation for both groups (Figure A) . 148

Hospitalization and clinical aggravation appeared later in COVID-19 than in influenza: respectively, 149 patients were hospitalized at day 7 (±3) vs day 5 (±2) (p=0.038), patients had a respiratory rate 150 ≥22/min at day 9 (±0.8) vs day 5 (±1.3) (p<0.001) and patients were admitted in an ICU at day 10 151 (±2.7) vs day 7 (±2.4) (p<0.004). 152

There was no significant difference in the evolution of the two diseases (mean number of 153 hospitalized patients, duration, oxygen therapy, hospitalization in the ICU, Invasive mechanical 154 ventilation and outcome) (Table VI) . This study described a population of 70 symptomatic adults (53% outpatient and 47% inpatients), 158 infected with SARS-CoV-2 between February, the 26 th and March, the 14 th , 2020. The mean age of 159 patients was 57 years (±19), 59% were female. In the literature, the mean age of patients with 160 COVID-19 was 46 years without predominance for sex (10). Fifty one percent had comorbidities, 161 including cardiovascular disease, COPD and diabetes mellitus in the COVID-19 group. These 162 comorbidities had a prevalence ≥ 10% in our study as in other studies (10-12). 163

In our study, the most common symptoms in COVID-19 group were fever, cough, fatigue and myalgia 164 as in medical literature. In a systematic review and meta-analysis (including 46248 COVID-19-infected 165 patients) by Jing Yang et al. (10), the most common symptoms were fever, followed by cough, fatigue 166 and dyspnea. Fever was reported as the main symptom in most cohorts with clinical description of 167 COVID-19, followed by cough (mostly dry) (13). Myalgias and fatigue were present in 44-60% of cases 168 in China's series (12). However, we noticed two otorhinolaryngological symptoms recently described 169 with SARS-CoV-2: anosmia and dysgeusia, present in half of our patients. Knowing that anosmia and 170 dysgeusia are part of COVID-19 clinical features is a major point for the medical community in order 171 to suspect this diagnostic in case of a COVID-19 with a predominance of otorhinolaryngological 172 symptoms. Anosmia appeared on average 5 days after the onset of the first other symptoms and 173 may persisted for up to 28 days with a mean duration of 7 days, while usually the duration of 174 anosmia with viral rhinitis with nasal obstruction were less than 3 days (14). Furthermore, in our 175 patients anosmia was rarely associated with nasal obstruction, but often with dysgeusia. These 176 notions led to suspect another pathogenesis than a nasal obstruction for anosmia, as it is described 177 in post-viral olfactory loss (POL) which can also be associated with dysgeusia (15). The pathogenesis 178 of POL involves probably a damage of the sensory receptors (16) or a lesion of the neural system 179 (olfactory cranial nerve or central lesion) (17). 180

In our study, among patients with COVID-19, 40% had diarrhea and 31 had nausea. In a study with 73 181 patients with confirmed COVID-19, 36% (26/73) had diarrhea (18). It is known that the entry of SARS-182

CoV-2 into human host cells is mediated mainly by a cellular receptor angiotensin-converting enzyme 183 2 (ACE2), which is expressed in human airway epithelia, lung parenchyma, but also in small intestine 184 cells, which may explain this clinical features (19). One of our patients in the COVID-19 group 185 presented with confusion without any respiratory symptoms. There is increasing evidence that 186 coronaviruses are not always confined to the respiratory tract and that they may also invade the 187 central nervous system inducing neurological diseases (20). 188

Our populations of COVID-19 and influenza didn't differ in age, sex, different comorbidities, rate of 190 hospitalization and ICU admission. The only difference was about the number of comorbidities with a 191

Charlson comorbidity index higher in the group influenza than COVID-19. Possibly the high number of 192 health care workers (which is a younger population able to work) in the group COVID-19 explain this. 193

There was a significant difference between the two groups in terms of health care workers infected 194 (31.4% vs 5.6%, p<0.001). Reports describes physical and mental exhaustion in this community, the 195 torment of difficult triage decisions, and the pain of losing patients and colleagues, all in addition to 196 the infection risk. Early detection will contribute to breaking the cycle of SARS-CoV-2 transmission in 197 community hospital (21). Fever (or feeling of fever), fatigue, cough, myalgia and arthralgia were the 198 most prevalent symptoms (>50% of cases) for both diseases (COVID-19 and influenza) without 199 statistical differences about the frequency found for each symptom between the two groups. In our study, anosmia and dysgeusia were present, in 17% and 20% in influenza group vs 53% and 207 49% in COVID-19 group respectively (p<0,001 and p=0.001 respectively) which confirms that these 208 symptoms were clearly more associated with COVID-19 than with influenza. Furthermore, the mean 209 duration of anosmia was shorter in influenza than in COVID-19, respectively 3 days vs 7 days 210 (p=0.046). This short duration of anosmia conducts to suspect a banal viral rhinitis with nasal 211 obstruction during influenza (14) in contrast with the mechanism suspected for the pathogenesis of 212 anosmia in patients with COVID-19. As described in the first part of the discussion, diarrhea was 213 present in 40% of patients with COVID-19. On the contrary, in a cohort from an emergency 214 department including 119 patients with confirmed influenza no one had diarrhea. Pedersen et al. 215 conclude that the absence of gastrointestinal symptoms was one of the factors that can help 216 distinguish influenza from other acute respiratory illnesses in the ambulatory population (25). During 217 pulmonary auscultation, cracklings sounds were statistically more frequents in COVID-19 group than 218 influenza group (39% vs 20%, p=0,032), especially bilateral cracklings (24% vs 9%, p=0.034). In 219 patients with COVID-19, lung parenchymal involvement is bilateral, hence the bilateral character of 220 the crackling sound (26). 221

On the other hand, sore throat, conjunctival hyperemia, tearing, sneezing, sputum production, 222 dyspnea, vomiting and rhonchi at pulmonary auscultation were more frequently described in 223 influenza group than COVID-19 group with statistically significant differences. Sore throat was a well-224 known symptom in influenza, found in about 30-40% of the patients in the literature as in our study 225 (25,27,28). Conjunctival hyperemia seems to be rare with COVID-19, less than 5% of cases in our 226 study vs 30% of cases in influenza group (p<0.001). Ocular symptoms as conjunctival hyperemia and 227 tearing were described in influenza. Souty et al. proved that conjunctivitis was associated with 228 influenza compared to others respiratory viruses (OR 1.27, 95% CI 1.08-1.50) (29). About respiratory 229 symptoms, sputum production and dyspnea were statistically more frequents in influenza group than 230 in COVID-19 group (respectively 52% vs 29%, p=0.010 and 59% vs 34%, p=0.007). In a study with 470 231 patients with confirmed influenza, 286 (64%) had a productive cough (27). Dyspnea was also 232 described in more than half of patients with influenza A (28,30). In our study, 17% of patients had 233 rhonchi in influenza group vs 1% in COVID-19 group (p=0.002). In the study of Erçen Diken, rhonchi 234 sounds on pulmonary auscultation were found in more than a third of 91 patients with confirmed 235 influenza (30). In our study, the only patient who had rhonchi sounds in COVID-19 group had a past 236 history of COPD. In our study, patients with COVID-19 never had rhonchi sounds on pulmonary 237 auscultation without a past of COPD. 238

On recently published articles since December 2019, symptoms of SARS-CoV-2 infection appeared 239 after a mean incubation period of 5.2 days (31). In our study, the mean incubation period was 6 days 240 (±2.1), longer than the mean influenza's period, which was 4.4 days (±2.9) (p=0.010). About the 241 natural history of both diseases it's interesting to notice that the 5 first days don't differ, the three 242 main symptoms appeared in the same order for both diseases: firstly, pain syndrome, followed by 243 fever and cough. In the literature, the period from the onset of COVID-19 symptoms to conventional 244 hospitalization ranged from 1 to 13 days with a mean of 6.7 days (32); in our study we have also a 245 mean of 7 days. Patients with COVID-19 were hospitalized later than patients with influenza (7 days 246 vs 5 days, p=0,038). In the same way, patients with COVID-19 became critically ill later than patients 247 with influenza (considering the period after which a respiratory rate ≥ 22/min appeared, or the 248 period after which the patients had to be admitted in ICU). The fatality of COVID-19 infection was higher in our hospital as compared with the mortality 267 described in China (5.7% vs 2.4%). New ICD-10 codes were attributed for COVID-19. Both categories 268 U07.1 (COVID-19, virus identified) and U07.2 (COVID-19, virus not identified; clinically-269 epidemiologically diagnosed COVID-19) may be used for mortality coding as cause of death. This 270 higher case fatality rate in our cluster might impact the diagnostic criteria seen based on clinical 271 features. Symptoms reported by critically ill patients may be underestimated due to the severity of 272 illness. However, most patients had positive outcome in both groups; the rate of patients discharged 273 from hospital was 81% (in COVID-19 group) and 87% (in influenza group). 274

One of the limitations of our study was the limited number of patients; a bigger study would be 275 interesting to confirm and support our results. Knowing the differences between COVID 19 and 276 influenza A/B symptoms seems essential and may help clinicians in the diagnosis of these diseases. 277

To conclude, natural evolution of symptoms with COVID-19 and influenza were similar during the 278 first 5 days, however, the evolution differed afterwards; indeed, patients with COVID-19 may became 279 critically ill during the second week, around day 10, later than patients with influenza, in the end of 280 the first week, around day 7. ILI was the main presentation of COVID-19 and influenza A/B. We 281 described several differences among other symptoms than fever, cough and pain syndrome. 

Preliminary estimation of the basic 332 reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven 333 analysis in the early phase of the outbreak

WHO | Emergency use ICD codes for COVID-19 disease outbreak [Internet]. WHO. World 336 Health Organization

Neurologic 339 Features in Severe SARS-CoV-2 Infection

Olfactory 341 and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus 342 disease (COVID-19): a multicenter European study

Features of 345 anosmia in COVID-19

Coronavirus disease 347 2019: new things to know

En ambulatoire : recommandations COVID-19 et prise en 349 charge

Detection of 2019 354 novel coronavirus (2019-nCoV) by real-time RT-PCR

First cases of 357 coronavirus disease 2019 (COVID-19) in France: surveillance, investigations and control measures

Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis

Clinical course and risk factors for mortality of 363 adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical features of patients infected with 366 2019 novel coronavirus in Wuhan, China

Olfactory threshold and nasal mucosal changes in 370 experimentally induced common cold

Prevalence and Risk 372 Factors of Self-Reported Smell and Taste Alterations: Results from the 2011-2012 US National Health 373 and Nutrition Examination Survey (NHANES). Chem Senses

Olfactory mucosal findings and clinical course in 375 patients with olfactory disorders following upper respiratory viral infection

Central presentation of postviral olfactory loss 378 evaluated by positron emission tomography scan: a pilot study

Evidence for gastrointestinal infection of SARS-381 CoV-2

System Inhibitors in Patients with Covid-19

The neuroinvasive potential of SARS-CoV2 may play a role in the 385 respiratory failure of COVID-19 patients

Protecting Health Care Workers during the COVID-19

Coronavirus Outbreak -Lessons from Taiwan's SARS response. Clin Infect Dis Off Publ Infect Dis Soc 388 Am

Identification of viruses in 390 patients with postviral olfactory dysfunction. The Laryngoscope

Influenza and Viral Pneumonia

Factors Associated With Influenza in an Emergency 394 Department Setting

The epidemiology and pathogenesis of coronavirus disease 396 (COVID-19) outbreak

The effects of age on clinical 398 characteristics, hospitalization and mortality of patients with influenza-related illness at a tertiary 399 care centre in Malaysia. Influenza Other Respir Viruses

Demographic, 401 clinical, and virological characteristics of patients with a laboratory-confirmed diagnosis of influenza 402 during three consecutive seasons

Baseline characteristics and 405 clinical symptoms related to respiratory viruses identified among patients presenting with influenza-406 13

Crackling sounds heard on pulmonary auscultation (Number

Fever ≥ 38 (objective) (Number, (%

Conjunctival hyperemia (Number