SARS-CoV-2 and influenza in the respiratory tract
SARS-CoV-2 and influenza A virus produce similar respiratory illness by different molecular routes. Each enters and leaves a cell in its own way and takes hold where the airway carries the molecules it binds. In both, infection and the immune response to it can lead to acute respiratory distress, which starves the blood of oxygen. The two viruses also differ in how deadly they are and in how they spread.
The two viruses and their surface proteins
Influenza viruses come in four types, A to D. Types A and B cause seasonal outbreaks in humans, and influenza A virus (IAV) is responsible for pandemics and for most annual outbreaks.
The SARS-CoV-2 genome is one long RNA molecule, and its coat displays several proteins, among them the spike (S) protein. The IAV genome is eight RNA molecules, and two of its surface proteins are hemagglutinin (HA) and neuraminidase (NA). HA, NA and S are vital to the two viruses' life cycles. The H and N numbers in the name of an IAV subtype give the types of HA and NA on the viral envelope, as in the recent avian strain H5N1 and the human subtypes H1N1 and H3N2.
How each virus gets into a cell and out again
Both viruses pass through the same stages: recognition of and attachment to the host cell, fusion of the viral and host membranes and entry of the genetic material, synthesis of new genomes and proteins, packaging, and release. They differ in the specific mechanisms by which they do so.
Recognition, the first stage, is a protein-protein interaction. The S protein of SARS-CoV-2 binds angiotensin-converting enzyme type 2 (ACE2), and the HA of IAV binds modified proteins called sialic acid glycoproteins. These come in at least two varieties, α2,3 and α2,6, named for a linkage within the molecule. Avian IAVs, those that jumped from birds to humans, prefer the α2,3 form, and human IAVs the α2,6 form.
Once S has latched onto ACE2, proteases cut it, with transmembrane protease serine 2 (TMPRSS2) a key one, and the cell then takes the virus in within a vesicle called an endosome. Some scientists suggest that these events may also occur in reverse order: the virus is internalised in an endosome first, and a protease in the endosomal membrane then clips S and promotes membrane fusion. Once the viral and host membranes fuse, the genome is released into the cytoplasm, where the cell's transcription and translation machinery makes many copies of the genome and of the viral proteins. New virions are assembled in the Golgi network, and vesicles carrying them pinch off, travel to the cell membrane and release them by exocytosis.
IAV takes a different route through the same stages. Binding of HA to sialic acid glycoproteins triggers internalisation in an endosome, and a change in endosomal pH starts the fusion of the viral and endosomal membranes. As for SARS-CoV-2, protease activity may be required for these steps, and human airway trypsin-like protease and TMPRSS2 are two candidates. Fusion releases the genetic material into the cell. Unlike the RNA of SARS-CoV-2, the IAV RNA strands travel to the nucleus, where the host's tools and a few viral enzymes copy the genetic material and make templates for protein production. The proteins themselves, HA and NA among them, are made in the cytoplasm. Assembly and release differ too. The new RNA strands and proteins move to the host's plasma membrane and gather at lipid rafts, with the RNA tethered to the inside of the raft and HA and NA extending outside. Release is by budding: NA cuts HA free of the sialic acid glycoproteins, and the new virions leave the cell like bubbles from a child's bubble wand.
Where in the airway each virus can take hold
Epithelium lines the respiratory tract from the nasal cavity to the alveoli, and each of its cell types carries its own combination of surface proteins. That combination decides which areas are susceptible: cells carrying ACE2 together with the TMPRSS2 protease are prime targets for SARS-CoV-2, and cells carrying sialic acid glycoproteins for IAV. The expression profile suggests that SARS-CoV-2 preferentially targets the nasal passages and the alveoli. IAV also interacts strongly there, but its reach likely extends to the throat and the airways of the lower respiratory tract as well.
How infection and the defence against it produce the symptoms
COVID-19's symptoms range from mild or none to severe and deadly, and some of them, especially those of the respiratory system, are similar to those of influenza. The symptoms of both arise because respiratory cells become infected with SARS-CoV-2 or the influenza virus. Most SARS-CoV-2 and seasonal IAV infections do not cause severe illness, and for both about 80% of cases result in mild or unnoticeable symptoms.
ACE2 is found on lung cells, but also on some other cell types, such as those of the gut, and to a lesser extent in parts of the brain, which might explain why some patients have neurological symptoms such as a transient loss of smell and taste. In May 2020 the symptoms of SARS-CoV-2 infection were reported to vary, and part of that variation could stem from the presence of ACE2 in different tissues.
The airway epithelium is not defenceless. Mucus secreted by its goblet cells forms a physical barrier over the host cells, and one type of mucus contains a chemical resembling sialic acid that likely lures IAV to the mucus rather than to the cell. Viral entry triggers further defences: the immune system is activated, cytokines flood the area, resident immune cells fight the pathogen and recruit others, inflammation increases, and interferons start antiviral events inside host cells. SARS-CoV-2 may suppress this interferon production. These immune reactions, together with the damage viral replication does to host cells, produce some of the symptoms the two diseases share.
Influenza and COVID-19 share the respiratory-related symptoms of cough, stuffy nose and fatigue and, in advanced cases, acute respiratory distress syndrome (ARDS). These symptoms make sense given the expression of ACE2, TMPRSS2 and sialic acid glycoproteins, which occurs predominantly in the nasal cavity and lungs. Both viruses enter the body in droplets inhaled into the nasal cavity, where ACE2 and sialic acid glycoproteins on the host cells are welcome mats for them. In most cases the immune system confines the infection to the upper respiratory tract. A greater viral load makes spread to the lower tract more likely, because the cells of the alveoli also carry the proteins that tether the viruses. In the alveoli, viral attack, the body's counterattack and excess cytokine production cause ARDS.
ARDS developed in at least 15% of patients hospitalised with COVID-19 and in 25% or more of those hospitalised with pandemic influenza strains. These figures are cohort-specific, and some of the influenza figures may reflect coincident pneumonia, so the two must be compared carefully.
SARS-CoV-2 kills through viral pneumonia. Infection of the alveolar cells provokes an immune response, which leads to inflammation and so to fluid buildup. As the alveoli fill with liquid, diffusion slows and oxygen struggles to reach the capillaries, and scar tissue can form and make the situation worse.
Why ARDS starves the blood of oxygen
Patients with ARDS have substantial difficulty getting enough oxygen into their bodies. In a healthy lung, unobstructed airways carry oxygen to the alveoli and carbon dioxide away from them. The alveoli are lined with a single layer of flat cells, the type I pneumocytes, interspersed with cuboidal cells, the type II pneumocytes. The gases diffuse across the type I pneumocytes between the alveoli and the adjacent capillaries, and the cells' flat shape minimises the distance they travel. Type II pneumocytes secrete surfactant, a chemical that reduces surface tension and prevents the alveolar walls from collapsing.
Normal levels of oxygen and carbon dioxide depend on three conditions: easy air flow into and out of the lungs, properly distended alveoli, and a short distance between the alveoli and the capillaries. These conditions contribute to a diagnostic tool, the ratio of the partial pressure of oxygen in systemic arteries to the fraction of oxygen in inspired air, written PaO2/FiO2. With a normal PaO2 of 100 mmHg and an FiO2 of about 20%, or 0.2, healthy lungs give a ratio of 500.
Infection and the immune response compromise these conditions. Thickened lung walls or fluid around the lungs limit expansion and so air flow. Cardiac complications of SARS-CoV-2 infection, such as heart failure, may make these pulmonary conditions worse. The surface available for gas exchange shrinks directly when viral or immune destruction kills type I pneumocytes. It shrinks indirectly when infected type II pneumocytes make less surfactant, so that alveoli may collapse and block air entry. This impaired gas exchange drops oxygen in the pulmonary veins and systemic arteries below 100 mmHg and produces hypoxaemia. PaO2 also falls because the distance between alveoli and capillaries grows, for at least two reasons. The alveolar walls thicken as they gather protein and other debris from the immune system's fight against the viruses, and oxygen and carbon dioxide cannot easily diffuse across this barrier. Fluid also accumulates, partly as a by-product of immune activity and partly because the immune system makes blood vessels leakier to let more immune cells reach the area, so that fluid escapes into the space between alveoli and capillaries, and gases cannot diffuse efficiently across this widened distance.
ARDS is a symptom rather than a disease. Its conceptual definition was endorsed by European and American clinical societies in 2012. The definition's parameters are inflammation leading to increased pulmonary vascular permeability and loss of aerated lung tissue; hypoxaemia; signs of fluid; a mixture of oxygenated and deoxygenated blood leaving the pulmonary capillaries; increased physiological dead space, meaning destroyed alveolar surface; decreased respiratory system compliance, meaning the lungs' ability to expand; and lung oedema. It also sets the PaO2/FiO2 ratio at 300 or below in the presence of positive pressure ventilation. Positive pressure ventilation forces air into compromised lungs and itself raises both PaO2 and FiO2.
How mechanical ventilation helps patients with ARDS
Mechanical ventilation saves the lives of many patients with COVID-19 who present with ARDS. It delivers regulated levels of oxygen by positive pressure. The increased oxygen delivery to the alveoli treats the patient's hypoxaemia, because higher oxygen levels in the alveoli enhance oxygen diffusion into the blood, and the raised PaO2 then improves the PaO2/FiO2 ratio. Where fluid in the alveoli slows diffusion, ventilators help because the much higher pressure they produce can force oxygen through, if only temporarily. The positive pressure also opens airways and alveoli and forces fluid back out of the lungs, reclaiming space for oxygen-rich air.
How many each virus infects and kills
As of 8 September 2020, SARS-CoV-2 had infected 27 million people worldwide and nearly 900,000 had died, a mortality rate of 3% to 4%. In the United States at least 6.2 million people had been infected and 188,000 had died, a rate of 3.3%. The 1918 influenza pandemic infected at least 500 million people, nearly a third of the world's population, and killed an estimated 50 million, a rate approaching 10%. In nonpandemic years influenza infections stay numerous, but mortality falls drastically. The Centers for Disease Control and Prevention reported between 9 million and 45 million seasonal influenza cases a year in the United States in recent nonpandemic years, with 12,000 to 61,000 deaths, a rate of 0.1% to 0.2%. Worldwide, nearly a billion people catch influenza each year, and 290,000 to 650,000 of them die, a rate below 0.1%.
As of September 2020, the incidence of SARS-CoV-2 infection was at first glance lower than the annual incidence of seasonal influenza. However, SARS-CoV-2's mortality rate was much higher, its numbers were still rising, isolation and masking were likely keeping them down, and no vaccine had kept its spread in check.
In May 2020 the mortality of SARS-CoV-2 infection stood at around 2%. The true figure was likely lower, because the percentage counted only people who had been tested, but it still appeared higher than influenza's.
How the two spread
The spread of SARS-CoV-2 and IAV depends on the viruses' infectivity, the host's anatomy and physiology, and people's practices. It is described by parameters that include the incubation period, the transmissibility period and the reproduction number. The incubation period, from exposure to symptom onset, is typically 5 to 6 days for SARS-CoV-2 and 1 to 4 days for IAV, so IAV spreads more quickly. However, people infected with SARS-CoV-2 stay contagious longer, for an average of 10 days against 3 to 4 days for IAV. Coughs, sneezes, speech and ordinary exhalation all eject particles from the sites of viral replication in the respiratory tract, and people transmit the virus whether their symptoms are unnoticeable or severe. The reproduction number, the number of people one infected person infects, is nearly twice as high for SARS-CoV-2, at 2 to 2.5, as for IAV, at 1.1 to 1.8.
SARS-CoV-2 is more contagious than the original SARS virus partly because the interaction between its S protein and ACE2 is about twice as strong. In May 2020 its incubation period was reported to range from as little as two days to several weeks, and this long period is another reason it is more contagious than the original SARS virus.
As the colder months of 2020 approached, the seasonal influenza season was expected to join the COVID-19 pandemic. People's vigilance and proactivity were expected to be important to controlling the viruses' spread, in addition to immune system activity and medical treatment.