Influenza and COVID-19 coinfection: Report of six cases and review of the literature

Abstract

Coronavirus disease 2019 (COVID-19) pandemic caused infection in a season when influenza is still prevalent. Both viruses have similar transmission characteristics and common clinical manifestations. Influenza has been described to cause respiratory infection with some other respiratory pathogens. However, the information of COVID-19 and influenza coinfection is limited. In this study, we reported our coinfected cases and reviewed the literature. We included all COVID-19 diagnosed patients. All patients with a presumed diagnosis of COVID-19 were routinely screened for influenza. Their thorax radiology was reviewed for COVID-19-influenza differentiation. During the study period, 1103 patients have been diagnosed with COVID-19. Among them, six patients (0.54%) were diagnosed coinfected with influenza. There have been 28 more coinfected patients reported. Laboratory-based screening studies reported more patients. Thorax radiology findings were compatible with COVID-19 in five and with influenza in one of our patients. Our cases were mild to moderate in severity. The reported cases in the literature included patients died (n = 2) and those living ventilator dependent or under mechanical ventilation. COVID-19 and influenza coinfection is rare. Screening studies report more cases, suggesting that unless screening patients with COVID-19, the coinfection remains undiagnosed and underestimated. Increasing experience in thoracic radiology may contribute to diagnose the responsible virus(es) from the clinical illness. Influenza vaccine for larger population groups can be recommended to simplify clinicians' work.

1 INTRODUCTION

A novel coronavirus causing respiratory illness was first noted in December 2019 in Wuhan, China and became a global pandemic within a couple of months.¹ The virus, referred to as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is transmitted through respiratory tract and could induce pneumonia.² Coronavirus disease 2019 (COVID-19) pandemic caused infection in a season when influenza is still prevalent. Influenza virus has similar transmission characteristics with COVID-19, including direct contact (human-to-human transmission) and transmission via airborne droplets.^{3, 4} Both diseases present with common clinical manifestations including fever, cough, rhinitis, sore throat, headache, dyspnea, and myalgia. On the other hand, there are epidemiologic and clinical differences: patients with influenza can be asymptomatic due to herd immunity and if develops, the disease is mild to moderate in severity in the majority of the patients with influenza, while most of the patients with COVID-19 develop symptoms within 5 to 7 days of infection and severe infection can be seen.^3-5 Acute respiratory distress (ARDS) is less common in influenza and mortality is <1%, while ARDS is more common and mortality is 3% to 4%. Viral shedding usually takes place 5 to 10 days in influenza, whereas it does 2 to 5 weeks in COVID-19.^{6, 7}

Advanced technologies allowed for increased detection of respiratory infection pathogens. Beside conventional diagnostics, such as tests for rapid detection of viral antigens or antiviral antibodies, new diagnostic strategies, including multiplex nucleic acid amplification and microarray-based assays, are emerging. Multiplex assays provide simultaneous detection of multiple respiratory viruses from a clinical sample in a short time.³ Influenza has been described to cause respiratory infection with some other respiratory pathogens. However, the information of COVID-19 and influenza coinfection is limited. Coinfections with viral respiratory pathogens, including coronavirus-influenza coinfections⁸ and influenza-Middle East respiratory syndrome coronavirus infection,⁹ have been reported in a substantial number of patients. There are few case descriptions of COVID-19-influenza coinfections. Recognition of coinfection with more than one respiratory virus can allow understanding differing clinical features and appropriate therapeutic management, and control of infections.

In this study, we reported six cases of coinfections with COVID-19 and influenza, and reviewed the literature of the coinfected patients.

2 PATIENTS AND METHODS

We included all COVID-19 diagnosed patients from 10 March to 10 May 2020 in Medilife Health Group. The group includes three hospitals located in different locations of Istanbul, Turkey.

The patient management was carried out according to the “COVID-19 Diagnosis and Treatment Guide” released by the Turkish Ministry of Health.¹⁰ All patients with a presumed diagnosis of COVID-19 were routinely screened for influenza by direct fluorescent antigen (DFA).

Medical history, clinical signs and symptoms, laboratory studies, radiologic studies, and treatment and outcomes data were obtained with standardized data collection forms. The collected data were independently reviewed by one researcher (RO). Radiological images were reviewed by an independent radiologist (RC) blind to the clinical features and diagnoses, according the criteria described by Wang et al¹¹: Wang et al compared thorax computed tomography (CT) of 13 patients confirmed with COVID-19 and 92 patients confirmed with influenza and evaluated 13 imaging parameters: lesion distribution (central, peripheral, diffuse, and nonspecific), lobe predomination (superior lobe, inferior lobe, middle lobe, and balanced predomination), lesion number (single lesion, multiple lesions in one lobe, multiple lesions in lung, and multiple lesions in bilateral lungs), lesion attenuation (ground-glass opacity [GGO], consolidation, and GGO with consolidation), lesion margin (clear and vague), GGO involvement pattern (patchy GGO, cluster-like GGO, combination of GGO and consolidation opacities, and whole consolidation), lesion contour (shrinking and nonshrinking), bronchial wall thickening, air bronchogram, tree-in-bud sign, interlobular septal thickening, intralobular septal thickening, and pleura effusion. Among these 13 parameters compared, following 6 were found significantly different between influenza and COVID-19 patients; lesion distribution (central in influenza while nonspecific and peripheral in COVID-19), lobe predomination (inferior in influenza, while balanced predomination in COVID-19), lesion margin (vague in influenza while both vague-54% and clear-46% in COVID-19), GGO involvement pattern (cluster-like GGO in influenza while combination of GGO and consolidation opacities and patchy GGO in COVID-19), lesion contour (nonshrinking in influenza while shrinking in COVID-19), and bronchial wall thickening (none in influenza while 33% in COVID-19).

COVID-19 disease was diagnosed by real-time reverse transcription-polymerase chain reaction (RT-PCR) and/or thoracic CT under appropriate clinical setting. Influenza diagnosis was established by clinical, laboratory (DFA), and radiologic studies.

The patients gave informed consent and study was approved by ethics board of the hospital.

Influenza and COVID-19 coinfection was searched through Medline (Pubmed) using keywords of “influenza,” “flu,” “co-infection,” “coinfection,” “COVID-19,” and “SARS-CoV-2.” Cross-references were also included.

3 RESULTS

During the study period, 1103 patients have been diagnosed with COVID-19 with the clinical, radiologic, and microbiological findings. Among patients with COVID-19, six patients (0.54%) were diagnosed coinfected with influenza. Three male and three female patients were admitted; age ranged from 25 to 58 years (Table 1). Radiological features of the patients were given in Table 2. Patients 1 to 5 showed COVID-19 characteristics of thorax CT findings, while patient 6 exhibited those of influenza (central lesion, inferior lobe involvement, single lesion, and cluster-like GGO).¹¹

Table 1. Characteristics of our six patients with COVID-19 and influenza coinfection

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Age (y)/sex	25/F	49/F	51/M	34/M	58/M	26/F
Comorbidity	None	None	DM	None	None	None
WBC × 10^9/L	6.4	5.9	5.8	5.9	5.9	8.7
CRP, mg/L (normal: 0-5 mg/L)	28	10.7	59	23	68	5.6
Ferritin, ng/mL (12-150 ng/mL females, 12-300 ng/mL males)	ND	25	345	120	152	32
D-dimer (normal: <500 ng/mL)	ND	0.2	9.3	ND	0.53	0.8
ALT, U/L	23	22	17	33	168	22
Duration of symptoms, d	2	3	4	5	4	4
Treatment	HCQ, azithromycin, oseltamivir	HCQ, azithromycin, oseltamivir	HCQ, azithromycin, oseltamivir	HCQ, azithromycin, oseltamivir	HCQ, azithromycin, oseltamivir	HCQ, azithromycin, oseltamivir

• Abbreviations: ALT, alanine aminotransferase; CRP, C-reactive protein; F, female; HCQ, hydroxychloroquine; M, male; ND, not defined; WBC, white blood cell.

Table 2. Thoracic computed tomography findings of our six patients with COVID-19 and influenza coinfectionaa According to Wang et al.¹¹

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Lesion distribution
Central						√
Peripheral	√
Diffuse
Nonspecific		√	√	√	√
Lobe predomination
Superior lobe					√
Inferior lobe		√		√		√
Middle lobe
Balanced predomination	√		√
Lesion number
Single lesion						√
Multiple lesions in one lobe
Multiple lesions in lung	√				√
Multiple lesions in bilateral lungs		√	√	√
Lesion attenuation
GGO		√		√	√	√
Consolidation
GGO with consolidation	√		√
Lesion margin
Clear	√	√				√
Vague			√	√	√
GGO involvement pattern
Patchy GGO		√		√	√
Cluster-like GGO						√
Combination of GGO and consolidation opacities	√		√
Whole consolidation
Lesion contour
Shrinking
Nonshrinking	√	√	√	√	√	√
Bronchial wall thickening
Air bronchogram			√
Tree-in-bud sign
Interlobular septal thickening
Intralobular septal thickening				√
Pleura effusion

• Abbreviations: COVID-19, coronavirus disease 2019; GGO: ground-glass opacity.
• a According to Wang et al.¹¹

At the same study period, there were 443 patients with influenza (164 adults, 279 children; 220 male, 223 female; and median age 9 years, range 2 months to 91 years).

There have been 28 COVID-19-influenza coinfected patients reported: coinfected patients were reported from China (14 patients),^12-15 Germany (1 patient),¹⁶ Iran (6 patients),^{17, 18} Japan (1 patient),¹⁹ Spain (4 patients),²⁰ and USA (2 patients).^{5, 21}

In their laboratory-based study, Zhu et al¹⁵ reported coinfection with COVID-19 and influenza A (n = 2), and influenza B (n = 5), both detected by PCR, without giving specific characteristics of the patients in China. Apart from these seven cases, the characteristics of all the coinfected patients in the literature and our cases are given in Table 3.

Table 3. The characteristics of COVID-19 and influenza coinfected patients in the literatureaa Zhu et al¹⁵ reported coinfection with influenza A (n = 2) and influenza B (n = 5), both detected by PCR, without giving specific characteristics of the patients.

Author (Reference)	Country	Age, y	Sex	Signs and symptoms	Radiology (chest X-ray and or chest CT)	Lymphocyte count (×10^9 cells/L)	COVID-19 diagnosis	Influenza type	Influenza diagnosis	Outcome
Ding^12	China	47	F	Fever, cough, dyspnea, myalgia, fatigue, headache, nasal tampon, expectoration, and pharyngalgia	Changing CT findings on admission, progression, and remission stages	0.88	ND (clinical, laboratory, and imaging studies provided)	A	Serology	Improved
		50	M	Fever, cough, dyspnea, and fatigue	Changing CT findings on admission, progression, and remission stages	0.81	ND (clinical, laboratory, and imaging studies provided	A	Serology	Improved
		66	F	Fever, cough, dyspnea, nasal tampon, and pharyngalgia	Changing CT findings on admission, progression, and remission stages	0.95	ND (clinical, laboratory, and imaging studies provided	B	Serology	Improved
		39	M	Fever, cough, and dyspnea	Changing CT findings on admission, progression, and remission stages	0.84	ND (clinical, laboratory, and imaging studies provided	B	Serology	Improved
		49	F	Fever, cough, dyspnea, myalgia, headache, chest pain, nasal tampon, expectoration, pharyngalgia, and hemoptysis	Changing CT findings on admission, progression, and remission stages	1.92	ND (clinical, laboratory, and imaging studies provided	A	Serology	Improved
Wu^13	China	Child	ND	ND	ND	ND	RT-PCR of nasopharyngeal swab specimen	A and B	ND	ND
Wu^14	China	69	M	fever and dry cough, then persistent fever, and dyspnea	A mass, ground-glass consolidation in the right inferior lobe of the lungs	0.77	mNGS and RT-PCR of a BALF sample	A	Xpert Flu/RSV Xpress assay of nasopharyngeal swab specimen	ND
Wehl^16	Germany	4-mo	ND	Fever and cough	ND	ND	RT-PCR of nasopharyngeal swab specimen	A	Rapid immunochromatographic assay of nasopharyngeal swab specimen	Improved
Hashemi^17	Iran	78	F	Dyspnea, fever, confusion, headache, and joints pain	Bilateral multi focal GGO with peripheral distribution and mild interalobular septal thickening.	0.82	RT-PCR of nasopharyngeal swab specimen	A	Simple amplification-based assay Flu duplex of nasopharyngeal swab specimen	Died
		75	M	Fever, severe cough, dyspnea, joint pain, nausea, and diarrhea	Centriacinar GGO with peripheral distribution and interlobular septal thickening.	0.53	RT-PCR of nasopharyngeal swab specimen	A	Simple amplification-based assay Flu duplex of nasopharyngeal swab specimen	Died
Khodamoradi^18	Iran	74	F	Cough, dyspnea, fever, body pain, and headache	Diffuse infiltrates in both lungs	0.3	RT-PCR of nasopharyngeal swab specimen	A	ND, nasopharyngeal swab specimen	ND
		40	M	Cough, dyspnea, fever, body pain, chest pain, headache, sweating, diarrhea, and nausea	Diffuse infiltrates in both lungs	1.9	RT-PCR of nasopharyngeal swab specimen	A	ND, nasopharyngeal swab specimen	ND
		64	M	Cough, dyspnea, fever, and headache	Diffuse infiltrates in both lungs	1.1	RT-PCR of nasopharyngeal swab specimen	A	ND, nasopharyngeal swab specimen	ND
		50	M	Cough, dyspnea, fever, and body pain	Diffuse infiltrates in both lungs	0.6	RT-PCR of nasopharyngeal swab specimen	A	ND, nasopharyngeal swab specimen	ND
Azekawa^19	Japan	78	F	Cough, malaise, anorexia, and weight loss.	Bilateral reticular shadow on chest X-ray, GGO adjacent to the pleura on CT	ND	RT-PCR of nasopharyngeal swab specimen	A	Rapid influenza test	Improved
Cuadrado-Payán^20	Spain	53	M	Nonproductive cough, fever, and dyspnea	Chest X-ray normal	0.6	RT-PCR of nasopharyngeal swab specimen	A	Rapid nucleic acid amplification test of nasopharyngeal swab specimen	Under mechanical ventilation
		78	M	Nonproductive cough, fever, and dyspnea	Bilobar infiltrate	0.3	RT-PCR of nasopharyngeal swab specimen	A	Rapid nucleic acid amplification test of nasopharyngeal swab specimen	Improved
		56	M	Nonproductive cough, fever, and dyspnea	Chest X-ray normal	1.2	RT-PCR of nasopharyngeal swab specimen	A and B	Rapid nucleic acid amplification test of nasopharyngeal swab specimen	Improved
		81	F	Nonproductive cough, fever, and dyspnea	Right bilobar pneumonia	0.5	RT-PCR of nasopharyngeal swab specimen	B	Rapid nucleic acid amplification test of nasopharyngeal swab specimen	Under mechanical ventilation
Konala^5	USA	66	F	Cough, shortness of breath, and fever	Right lower lobe infiltrate	1.0	RT-PCR of nasopharyngeal swab specimen	A	ND	Living, ventilator dependent
Nowakbb Patients’ characteristic were not provided.^21 ,^21	USA	ND	ND	ND	ND	ND	RT-PCR of nasopharyngeal swab specimen	A	Cepheid Xpert Xpress Flu/RSV	ND
Current report	Turkey	25	F	Fever and headache	Peribronchial GGO and infiltrations in right upper lobe posterior segment and lower lobe	1.08	RT-PCR of a nasopharyngeal swab specimen	B	DFA of a nasopharyngeal swab specimen	Improved
		49	F	Cough, malaise, nausea, and vomiting	Bilateral multiple peribroncho-vascular and subpleural GGO	1.63	RT-PCR of a nasopharyngeal swab specimen	A	DFA of a nasopharyngeal swab specimen	Improved
		51	M	Cough, malaise, sore throat, dyspnea, abdominal pain, nausea, and vomiting	Bilateral multiple peripheral GGO	0.74	RT-PCR of a nasopharyngeal swab specimen	A	DFA of a nasopharyngeal swab specimen	Improved
		34	M	Abdominal pain, nausea, and fever	Bilateral multiple peripheral GGO	0.74	RT-PCR of a nasopharyngeal swab specimen	B	DFA of a nasopharyngeal swab specimen	Improved
		58	M	Cough, fever, and dyspnea	GGO in right apical and left upper lobe anterior segment	1.18	RT-PCR of a nasopharyngeal swab specimen	B	DFA of a nasopharyngeal swab specimen	Improved
		26	F	Cough, malaise, and sore throat	Peribronchial infiltration and GGO at right lower lobe anterior segment	1.84	RT-PCR of a nasopharyngeal swab specimen	B	DFA of a nasopharyngeal swab specimen	Improved

• Abbreviations: BALF, bronchoalveolar lavage fluid; COVID-19: coronavirus disease 2019; CT, computed tomography; DFA, direct fluorescent antibody; F, female; GGO: ground-glass opacity; M, male; mNGS: metagenomic next-generation sequencing; ND, not defined; RSV, respiratory syncytial virus; RT-PCR, reverse transcription-polymerase chain reaction.
• a Zhu et al¹⁵ reported coinfection with influenza A (n = 2) and influenza B (n = 5), both detected by PCR, without giving specific characteristics of the patients.
• b Patients’ characteristic were not provided.²¹

4 DISCUSSION

Use of advanced technologies including PCR and rapid antigen detection kits increased recognition of viral respiratory infections.²² During COVID-19 pandemics, RT-PCR of nasopharyngeal swab specimen was commonly used. Since the COVID-19 pandemic coincided with the season of influenza, COVID-19 and influenza was seen in some patients. Since we used influenza test to routinely screen every patient with a presumed diagnosis of COVID-19, we detected relatively much patients. Another screening study¹⁵ reported the highest number of coinfection (n = 7) suggesting that this coinfection is underestimated.

There are concerns about the risk of increased severity of coinfections. Viral respiratory coinfection or pneumonia generally has been a severe disease of immunosuppressive patients. Coinfections with respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) caused more severe infection than either virus alone with longer hospitalization and oxygen requirement in children younger than 3 years of age.²³ The rate of patients with dual respiratory viral infections who are hospitalized was found greater than that of patients with single viral respiratory, suggesting possible increased morbidity associated with coinfection.²⁴ In a study including 284 patients with viral pneumonia, 84 patients (29.6%) were found to have a respiratory coinfection.²⁵ Viral respiratory coinfections (with adenovirus, coronavirus, influenza, hMPV, parainfluenza, rhinovirus/enterovirus, and RSV) were detected in 28 patients (33.3%) with herpes simplex virus, cytomegalovirus, or both. While many patients needed mechanical ventilation (54%) and vasopressor support (36%), overall in-hospital mortality was high (23.2%). Readmissions were common within 30 (21.1%) and 90 days (36.7%) of discharge.

During pandemic 2009 to 2010 influenza A H1N1, 617 patients with a single virus and 49 patients with two viruses (ie, coinfection) were reported among the hospitalized patients with respiratory viral infection.²⁶ Influenza-rhinovirus and adenovirus-rhinovirus coinfections were in majority. The likelihood of death, length of stay, and requirement for intensive care unit level of care were comparable in both monoinfected and coinfected patients, but coinfected patients were more likely to experience complications, particularly treatment for a secondary bacterial pneumonia.

Patients with COVID-19 coinfected with other respiratory pathogens are increasingly reported: with mycoplasma,^{13, 27} legionella,²⁸ CMV,^{13, 29} parainfluenza,^{30, 31} RSV,^{13, 31} Epstein-Barr virus (EBV),¹³ hMPV,^{31, 32} rhinovirus,³¹ and other coronaviruses.^{31, 33}

In a retrospective study, 257 laboratory-confirmed patients with COVID-19 in Jiangsu Province, China, 242 (94.2%) patients were found coinfected with one or more pathogens.¹⁵ Bacterial coinfections were dominant in all patients with COVID-19 and 81 patients (31.5%) had viral coinfection. EBV, rhinovirus, and adenovirus were the most common coinfected viruses, while they described five patients with influenza B and two with influenza A. The highest rates of coinfections were found in patients aged 15 to 44 years and the rates of coinfections were the highest in severe/critical category suggesting that microbial coinfection increases the risk of disease severity.¹⁵

The radiology an important role in clinical decision making in patients with suspected COVID-19.³⁴ Combining with previous experience of influenza imaging, thoracic radiology made it possible to differentiate findings of influenza to those of COVID-19.^{11, 35} In our case series, we noted that one of our patients (case 6) had characteristics of influenza radiology other than that of COVID-19 including single lesion, central location, inferior lobe involvement, and cluster-like GGO, while other five (cases 1-5) showed CT findings of COVID-19.

Our influenza-COVID-19 coinfected cases were mild to moderate in severity. Four out of six of our patients were diagnosed as influenza B. The mild-to-moderate severity of the patients may be attributed to influenza B. None needed ventilatory support and all improved without any complication. The reported cases in the literature, however, included patients died (n = 2) and those living ventilator dependent or under mechanical ventilation, mostly those coinfected with influenza A. The prognosis of some reported cases is unknown since the information comes from laboratory-based studies.

In the diagnosis of influenza, viral culture, antigen detection, and nucleic acid testing methods are used.³⁶ Viral culture has high sensitivity (close to 100%) and specificity. However, it takes 3 to 10 days to give the result which is not useful in clinical decision making. It is labor- and time-intensive. RT-PCR has also sensitivity close to 100% and high specificity and is widely used for the identification of influenza viruses in most diagnostic labs around the world. It is considered a gold standard assay for influenza diagnosis. It is expensive, however, and requires specialized equipment and personnel. It also carries the potential for cross-contamination.³⁶

Rapid antigen detection methods are either immunochromatogenic assay or DFA. Immunochromatogenic assay has a short turnaround time (<30 minutes), needs no specialized equipment or technical skill. However, it is the least sensitive method (59%-93%). The DFA test is an antigen-based test routinely used for diagnosis of influenza virus infections. It involves direct staining of respiratory epithelial cells obtained by nasopharyngeal swabs or nasopharyngeal aspirates with fluorescently labeled influenza virus-specific antibodies. For seasonal influenza viruses, this test has showed sensitivities of 60% to 80% compared to the traditional viral isolation procedures.^{36, 37} Serological tests of influenza are available, however they are not recommended in clinical decision-making. They can be useful in clinical studies and outbreak investigations.^{36, 38}

The pitfall of the study is that we used DFA test for the detection of influenza virus which has relatively lower sensitivity for detection of influenza virus.^{33, 34}

The second pitfall of our cases and other reported ones is that we detected two viruses generally on admission and do not know the viral dynamics, shedding, clinical features of individual virus and also their interactions. A novel design is required for differential analysis of the either virus for better understanding the coinfection dynamics.

COVID-19 and influenza coinfection is rare. Screening studies report more cases, suggesting that unless screening patients with COVID-19, the coinfection remains undiagnosed and underestimated. Increasing experience in thoracic radiology may contribute to diagnose the responsible virus(es) from the clinical illness. Influenza vaccine for larger population groups can be recommended to simplify clinicians' work, for the foreseen second wave of COVID-19, which is expected to evolve in September/October, the start date of influenza season.

ACKNOWLEDGMENT

The authors would like to dedicate this paper to loving memories of health care workers who died during the fight against coronavirus disease 2019.