COVID-19 and influenza co-infection

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zaida Obeidat, M.D.[2]

Synonyms and keywords:

In December 2019, a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of an outbreak of acute respiratory illness in Wuhan, China. Since then, there has been a rapid spread of the virus, leading to a global pandemic of coronavirus disease 2019 (COVID-19). Influenza, commonly known as flu, is an infectious disease of birds and mammals caused by RNA viruses of the biological family Orthomyxoviridae (the influenza viruses). Coronavirus disease 2019 (COVID-19) and Influenza share many characteristics, common symptoms of the co-infection are fever, sore throat, dyspnea, myalgia, cough, headache, fatigue and malaise. ^{[1] [2] [3]}

• COVID-19, also called severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) originated in Wuhan, China in late December 2019.
• It has been declared a global pandemic by the WHO after being caused a significant morbidity and mortality worldwide.
• Influenza is a highly contagious respiratory virus, it causes an acute respiratory infection, occurs mainly during the winter, it causes significant morbidity and mortality worldwide.
• It can be mild or sever, which may result in hospitalization or death.
• People at high risk of serious complications are young children, elderly, and people with underlying medical conditions.
• The total number of morbidity and mortality has been declining significantly after the seasonal Influenza vaccine. ^[4]

• There is no established system for the classification of COVID-19 and Influenza co-infection.

• The exact pathogenesis of co-infection with SARS-CoV-2 and Influenza viruses is not fully understood.

• Coronavirus disease 2019 (COVID-19) and Influenza co-infection are caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza (A or B) virus.

• Influenza and COVID-19 are both contagious respiratory illnesses, but they are caused by different viruses.
• Influenza is caused by infection with influenza viruses and COVID-19 is caused by infection with the coronavirus2 (SARS-CoV-2).
• Testing may be needed to help confirm a diagnosis because some of the symptoms of flu and COVID-19 are similar.
• Influenza and COVID-19 share many characteristics, but there are some key differences between the two.

This table compares the Influenza and COVID-19: “Similarities and Differences between Flu and COVID-19 | CDC”.
	Similarities between Covid-19 and Influenza infection	Differences between Covid-19 and Influenza infection
Signs and symptoms	Signs and symptoms can vary from asymptotic (subclinical) to severe symptoms. Common symptoms include: Fever/chills, cough Shortness of breath Fatigue Sore throat Runny nose Muscle aches Headache Gastrointestinal symptoms (vomiting and diarrhea).	Change in or loss of taste or smell can be a specific sign of COVID-19.
Incubation Period	It takes one or more days for a person to get infected and develop symptoms after the exposure.	It takes longer to develop symptoms in COVID-19 than Influenza. The time range can be vary in COVID-19, symptoms can appear early in 2 days or late in 14 days. In Influenza, symptoms may develop 2 to 4 days after infection.
Period of Contagiousness	A person can spread the virus for 1 day before the appearance of any symptoms.	The period of contagiousness is longer in COVID-19, a person can spread the virus for about 2 days before having any symptoms and remain contagious for at least 10 days after experience any signs or symptoms. Asymptotic or after the symptoms disappeared, It can be contagious for 10 days after testing positive for COVID-19. In Influenza, it can be contagious for about 1 day before appearing any symptoms. Older children and adults can be most contagious during the first 3-4 days, but may remain contagious for 7 days of their illness. Infants and immunocompromised patients can be contagious for longer.
How does it spread	Both can spread from person-to-person, people in close contact (within 6 feet) with one another. Mainly by droplets from sick people when cough, sneeze, or talk. Physical contact or touching their own face, mouth, nose or eye after touching contaminated surfaces or objects. Asymptotic or people with very mild symptoms.	COVID-19 is very contagious among certain populations and age groups than Influenza. The SARS-CoV-2 virus can quickly and easily spread to a lot of people, COVID-19 has been observed to have more super spreading events than Influenza.
High risk groups	Highest risk groups to develop severe illness and complications in both COVID-19 and Influenza includes: – Elderly. – People with underlying medical conditions. – Pregnant[ women.	– School-aged children infected with COVID-19 are at higher risk of Multisystem Inflammatory Syndrome in Children (MIS-C) which is rare but sever complication. – The risk of complications in Influenza for young healthy children are higher compared to COVID-19. – Infants and children with underlying medical conditions are at the highest risk for both Influenza and COVID-19.
Complications	Complications in both can include: Pneumonia Respiratory failure Acute respiratory distress syndrome (ARDS) Sepsis – Heart attacks or myocardial infarction (MI) – Multiple organ failure (renal failure, respiratory failure, shock) Worsening of chronic medical conditions Heart, muscle, or brain tissues inflammations.	COVID-19 can associate with: Blood clots in the heart, lungs, or, brian blood vessels. Multisystem Inflammatory Syndrome in Children (MIS-C).
Treatment	– Supportive medical care to relieve symptoms and complications.	COVID-19: – The National Institute of Health (NIH) has developed guidance on treatment, which will be updated regularly as new evidence on safety and efficacy of drugs come out. – There are no drugs approved by the FDA to prevent or treat COVID-19. – Remdesivir (antiviral agent) is available under Emergency Use Authorization (EUA), and being explored as a treatment for COVID-19. Influenza: – Hospitalized patients with Influenza or high risk group are recommended to be treated with antiviral drugs.
Vaccine	– Vaccines for COVID-19 and Influenza must be approved by the FDA.	– There are multiple vaccines to protect against 3 or 4 viruses that cause the Influenza produced annually and approved by the FDA. – There is no Vaccine to COVID-19 yet but researchers and vaccine developers are working on developing a vaccine to prevent COVID-19.

• Coronavirus disease 2019 (COVID-19) and Influenza co-infection, must be differentiated from other diseases that may cause fever, cough, shortness of breath and tachypnea. The table below, summarizes the differential diagnosis:

Diseases	Past medical history	Symptoms							Physical Examination			Diagnostic tests		Other Findings
		Headache	Chest pain	Wheezing	Dyspnea	Chest Tenderness	Cough	Hemoptysis	Fever	Tachypnea	Tachycardia	CT/MRI	Chest X-ray
COVID-19 and Influenza co-infection	Possible exposure to infected individuals.	+/-	+/-	–	+	+/-	+	+/-	+	+	+	Chest CT findings: bilateral ground glass consolidations.	Chest X-ray: consolidation, peripheral ground glass opacity.
Pneumonia	Ill contact Travel Smoke Diabetic Recent hospitalization COPD	+/-	+	–	+	–	+	–	+	+	+	Chest CT findings: Consolidation (alveolar/lobar pneumonia), Peribronchial nodules (bronchopneumonia) Ground-glass opacity	Chest X-ray: Consolidation (alveolar/lobar pneumonia), Peribronchial nodules (bronchopneumonia, Ground-glass opacity, Abscess, Pleural effusion
Chronic obstructive pulmonary disease (COPD)	Smoking Alpha-1 antitrypsin deficiency Increased sputum production (chronic bronchitis) Cough	–	–	+	+	–	+	–	–	+	+	Chest CT findings: Chronic bronchitis may show bronchial wall thickening, scarring with bronchovascular irregularity, fibrosis Emphysema may show alveolar septal destruction and airspace enlargement (Centrilobular– upper lobe, panlobular– lower lobe) Giant bubbles On MRI: Increased diameter of pulmonary arteries, Peripheral pulmonary vasculature attentuation, Loss of retrosternal airspace due to right ventricular enlargement Hyperpolarized Helium MRI may show progressively poor ventilation and destruction of lung	Chest X-ray: Enlarged lung shadows (emphysema), Flattening of diaphragm (emphysema)	Alpha 1 antitrypsin deficiency may be associated with hepatomegaly
Tuberculosis	Immunocompromised host e.g. HIV infection malnutrition smoking diabetes alcohol abuse indoor air pollution [5]	+	+	–	+	–	+	+	+	+	+	CT scan findings: Primary tuberculousis: lobar consolidation (well defined, dense, homogenous, and confined to a segment or lobe), middle or lower lobe involvement is very common, small cavities, with mediastinal or hilar adenopathy. Reactivation tuberculosis: most commonly involved segments are the upper posterior segment of upper lobe and the superior segment of the lower lobe. Cavitation is associated with bronchogenic spread of the disease. seen in more than 50% of cases, usually multiple and involves thick walls without an air fluid level (seen as multiple ill-defined 5- to 10-mm nodules that usually involve the dependent lung zone). [6]	Chest X-ray: lobular infiltrate with bilateral hilar adenopathy. [6]	Fever usually develops during sleep, accompanied with night sweats. Malaise, irritability, weakness, unusual fatigue, and weight loss, may be present. Chest pain may be localized and pleuritic. [6]

• Patients of all age groups may develop COVID-19 and influenza co-infection.
• The countries that got affected by the pandemic are:
  • China
  • Italy
  • India
  • The United States
  • Brazil

• Common risk factors in the development of COVID-19 and influenza infection include:
  • Immunocompromised ( e.g. chronic infections or cancer patients).
  • It’s more common among the workers who works in close contact.
  • It’s common among the population who doesn’t maintain proper social distancing.
• To view the COVID-19 risk factors, click here.

• There is insufficient evidence to recommend routine screening for COVID-19 and Influenza co-infection.
• For the prevention and control of infection, on January 24th 2020 Taiwan Centers for Disease Control started testing of SARS-CoV-2 for people suspected with COVID-19. Until February 28th, 2015 cases were screened and 34 of them were diagnosed of COVID-19. During this time, 43 flu-like symptomatic patients were screened in China Medical University Hospital and 2 of them were confirmed to be positive for SARS-CoV-2. ^[7]
• To establish the diagnostic protocol for the co-infection of COVID-19 and other respiratory infections like Influenza A and B, they comparatively analyzed the clinical presentations, laboratory data, radiologic findings, and travel and exposure contact histories, of COVID-19 patients who suspected to have other respiratory infections.
• SARS-CoV-2 detection by real-time reverse transcription polymerase chain reaction (rRT-PCR) and Respiratory pathogens detection by FilmArray™ Respiratory Panel were used for screening.

• SARS-CoV-2 and Influenza co-infection has a wide range of clinical presentation, most of the symptoms are similar, the symptoms can be vary from asymptomatic to severe disease (ARDS) which require the ICU admission.

• The main complications for the patients according to a study conducted in Wuhan, China, were acute respiratory distress syndrome, acute liver injury, and diarrhea. ^[8]

• SARS-CoV-2 and Influenza co-infection did not significantly worsen the symptoms and outcomes. ^[9]

• The diagnosis of COVID-19 and Influenza co-infection can be established by the following investigations: ^[9]
  • SARS-CoV-2 detection by real-time reverse transcription polymerase chain reaction (rRT-PCR) from nasopharyngeal swab sample or bronchoalveolar lavage fluid.
  • Respiratory pathogens detection by FilmArray™ Respiratory Panel. ^[10]
  • Rapid nucleic acid amplification test for influenza A and B.^[11]
  • Chest Tomography images showing peripheral and bilateral multiple plaques or nodular ground-glass opacities.^[12]

• According to a study conducted in Wuhan, China, common symptoms at onset of illness included: ^{[8] [13] [14]}
  • Fever
  • Cough
  • Shortness of breath
  • Sore throat
  • Myalgia
  • Fatigue
  • Headache
  • Expectoration

• Common physical examination findings of the co-infection with COVID-19 and Influenza include: fever, dry cough, tachypnea, and tachycardia.
• Decrease in oxygen saturation SpO2(< 93%), the first manifestation of deterioration of inflammatory lung injury.

Common laboratory findings associated with covid-19 and influenza coinfection are:

• Lymphocytopenia (80% of patients)
• Thrombocytopenia
• Elevated liver functions AST, ALT (40%)
• Elevated CRP (80%)
• Elevated ESR (30%)
• Elevated BUN (30%)
• Elevated Creatinine (70%)
• Elevated ferritin (70%)
• Elevated fibrinogen
• Elevated D-dimer
• Elevated interleukin-6
• Elevated lactic acid
• Elevated LDH
• Elevated creatine kinase ^{[8] [4] [9] [13]}

• Chest X-ray images showing bilateral/peripheral opacities with lower lobes predominant.

• Chest Tomography images showing peripheral and bilateral ground-glass consolidation peripherally. ^{[13] [14] [3] [15]}

• There is no treatment available for COVID-19, the mainstay of therapy is supportive care.
• Hydroxychloroquine, azithromycin, Interferon-l, glucocorticoids, interleukin antagonists, Ulinastatin, intravenous immunoglobulins, and plasmapheresis are already used in clinical practice for COVID-19 and showed initial positive outcomes. ^[8]
• The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend Remdesivir for hospitalised patients with severe COVID-19. ^[16]
• Severe disease require intubation and mechanical ventilation.
• Dexamthasone is helpful in hospitalized and oxygen dependent patients with COVID-19.
• Antiviral agents (Oseltamivir, Zanamivir, Peramivir, and Baloxavir) are recommended by the CDC for all hospitalized and high risk patients with Influenza.

• Surgical intervention is not recommended for the management of COVID-19 and Influenza co-infection.

• The CDC recommends getting the Influenza vaccine, there are multiple FDA-licensed influenza vaccines produced annually to protect against the 3 or 4 influenza viruses.
• There is currently no vaccine to prevent COVID-19. The best way to prevent infection is to avoid being exposed to the virus by:
  • Washing hands regularly with soap and water for at least 20 seconds or using a hand sanitizer with 60% alcohol.
  • Wearing a cloth face mask and avoid touching eyes, nose, and mouth with unwashed hands.
  • Covering mouth and nose when cough or sneeze.
  • Maintaining 6 feet distance from other people and avoiding close contact.
  • Refraining smoking and other activities that weaken the lungs.
  • Clean and disinfect frequently touched surfaces and objects.

• There are no secondary prevention measures of COVID-19 and Influenza co-infection.
• The secondary prevention measures of COVID-19 include measures to make sure that an infected individual does not transfer the disease to others.
• WHO recommends for patients with suspected or confirmed COVID-19 with mild symptoms to stay home and self isolation from other family members at home.
• To read more about COVID-19 secondary prevention, Click here.