Influenza Primer I

Influenza is the name of a syndrome or collection of clinical signs and symptoms, sometimes called ‘influenza-like illness’ (ILI). Since the 1930s we have known that one type of ILI, which we also call influenza, is caused by particular viruses (the influenza viruses). There are other viruses that also cause ILIs and it is sometimes difficult to distinguish them from the ILI caused by the influenza viruses without laboratory tests of varying degrees of sophistication and expense. Influenza caused by the influenza virus is a disease of the upper and lower respiratory tracts although it sometimes involves other organ systems.

Most people are familiar with the symptoms of ‘flu’: sudden fever, chills, headache, weakness, malaise, aches and pains and loss of appetite. The fever typically lasts a few days in adults, accompanied by sore throat and cough, painful eye movements, a runny nose, red eyes and tender lymph nodes (‘glands’) in the neck. As these acute symptoms begin to resolve, a dry hacking and protracted cough may remain. There is often an extended period of weakness and tiredness that can take weeks to get over.

While ‘stomach flu’ has nothing to do with this kind of flu (and of course has very different symptoms), many other infections start out just like influenza and a doctor may be unable to tell the different influenza-like illnesses apart without special laboratory tests. The reason for this is that in the early stages of an infection, even before it recognizes the nature of the invader, your body sounds a general alarm which results in the typical fever, muscle aches and pains and general malaise (all consequences of release of substances called cytokines involved in our body’s first response). These initial ‘flu-like’ symptoms are seen in infections as diverse as smallpox, anthrax, and of course, influenza (and other respiratory viruses). The syndrome could appropriately be called a general SOS response, but the term ‘flu like illness’ or ILI is now well-accepted. The difference the exact kind of microbe makes comes into play as the infection develops.

This is a good place to make an important point about infectious diseases and ‘disease organisms.’ Neither the ability to cause disease (which we call pathogenicity) nor the severity of the disease (virulence) is a property of the organism per se. Pathogenicity and virulence are properties of the relationship of the organism and the host it infects. All of us are home to a huge variety of micro-organisms, including viruses, bacteria and parasites. Most live peacefully with us and we are unaware of their presence, like roommates we see little of but with whom we share the rent. Some are beneficial, like paying tenants, such as bacteria whose metabolism supplies us with essential nutrients. Some are parasites, the ones that live at our expense, like the brother-in-law who won’t leave, eats our food, lies around drinking beer all day while watching our TV, always in the way, and generally making our lives miserable. Our brother-in-law by himself is harmless. It is only when he is in our house that there is a problem. And finally, just as the nicest person can arrive at your door at the wrong time, so too can a usually harmless micro-organism become a problem when arriving at the wrong time and the wrong place, as in the body of an HIV-infected person. An infectious disease (and the virulence with which it infects) is thus not solely a function of the invading organism, but the combination of the organism and the host at a particular time and place.

Disease, then, is the property of a relationship between host and parasite, and that relationship in different hosts and parasites will evolve differently. After the initial encounter with a parasite, a dance ensues, ranging from the delicate choreography of the ballet to the violent encounter of the French Apache dance. The host and parasite each make their moves and counter moves and just as in dance types, different host - parasite relationships have particular characteristics we identify as ‘diseases.’ The dance steps are dictated by the parasite’s biology and the host’s reactions, especially immune defenses.

Thus when the influenza virus takes up housekeeping in our respiratory tract there is the initial response, the sudden onset of the typical ILI (fever, chills, aches, etc., which we become aware of within about 2 days (with a range of 1 to 4 days) from exposure and infection. As the acute symptoms begin to resolve, a dry hacking and protracted cough may be left. In some people the airways become hyperactive (‘twitchy’) leading to paroxysms of coughing and breathing difficulties. This may last for weeks or months, even in previously healthy people. Eventually most people get back to normal health.

These symptoms of viral respiratory infections are caused by inflammation of the the upper and lower respiratory tract. Inflammations are local tissue reactions to some harm or injury (like an infection, but not limited to them). An inflammation is also dynamic in nature, that is, it is a process or response, not a specific condition. It is part of the body’s defensive reactions, designed to shorten the harm and promote healing, although on some occasions the inflammation itself may become harmful if the response is too vigorous.

To get a better picture of what is going on we should pause for a moment to sketch out the structure of the respiratory system.

You can think of the system (mouth, nose, throat, ‘wind pipe’, down into your chest and lungs) as an upside-down tree (root at the top, leaves at the bottom). We take in oxygen through our nose and mouth and it is ‘conducted’ down a tube (the trachea or ‘wind pipe’) which starts just below the back of our throat at our larynx (Adam’s apple or voice box), and then proceeds to branch into a series of pipes called bronchi (singular bronchus) in back of and spreading to either side of our breast bones. At the tips of the branches, just after a very fine level of tiny twig-like tubes, is a delicate sac called the alveolus, which comes into intimate contact with tiny blood vessels (capillaries) that allow oxygen to pass into the blood and waste carbon dioxide to be returned to the outside.

Thus the system is in two functional parts, a conducting system to get the gases from and to the place where gas exchange takes place, and the gas exchange part itself, the alveoli (the ‘leaves’ on the tree). Many of our respiratory reflexes (like coughing, choking, sputum production) are designed to keep the delicate alveoli clear of damaging substances. But cells in any part of the system, from the upper part (mouth, nose, throat) to the lower part (trachea, bronchi and alveoli) can be infected by a virus or other pathogen (disease-causing organism). Inflammation of specific tissues is indicated by appending the suffix -itis, as in laryngitis (inflammation of the larynx), bronchitis (inflammation of the bronchi), or sore throat, pharyngitis (inflammation of the pharynx or back of the throat). A prominent feature of viral respiratory infections is a tracheobronchitis, inflammation of the lower conducting system. Here is a picture I found at Patient-UK. The upper respiratory tract is the nose, throat larynx (Adam’s Apple or voicebox) and some of the trachea, the main wind pipe just below the larynx (the border between upper and lower respiratory tract is somewhat variable in usage). The lower respiratory tract usually includes the small bronchi (broncioles) and the alveoli, the little gas exchange units that are like leaves on the ends of the bronchiole twigs.

This upside down tree is made up of different kinds of cells and any or all of them can become infected by a virus. Infections by primary lung pathogens (of which there are a little more than half a dozen) are major causes of sickness and death and the leading cause of acute illness resulting in a visit to a health care provider. Although viruses are not susceptible to antibiotics, acute respiratory viral infections are also one of the major reasons for (inappropriate) antibiotic prescriptions in the US (Mainous, Hueston 1998). Most start out as upper respiratory infections (URIs) and are usually sudden in onset (‘acute’) and recovery is usually ‘spontaneous’ (i.e., you get better without special treatment). What sets the infection by influenza virus apart from most other virally caused URIs (like a bad cold) is the high fever, severity and protracted recovery.

People with influenza infections suffer to varying degrees, but even the sickest usually recover. Some people don’t even know they are infected or have only minor symptoms. But even though the percentage of really serious illness and death is quite small overall, in epidemic situations infection is so widespread that even if the percentage of people who die is small, it can add up to tens of thousands of people in an ordinary year and in a major pandemic it would likely be in the hundreds of thousands or even millions in the US and many tens of millions or even hundreds of millions worldwide. Influenza virus strains that cause pandemics also tend to be more virulent, so the mortality is higher still.

Among the most serious consequences of an influenza infection is a primary viral pneumonia. Pneumonias are inflammations of the lung tissue caused by infections (a pneumonia thus can also be called pneumonitis in keeping with the -itis naming convention) that cause an accumulation (consolidation) of fluids and dead cell debris in the tissues and spaces of the respiratory tract. They are visible on x-rays as cloudy patches (‘infiltrates’) in what would normally be clear lung. If not too severe and extensive the patient may remain ambulatory and even go to work or school (‘walking pneumonia’), but in normal flu seasons about 2% of of the pneumonia cases are serious, and during pandemics this figure may reach 20%. Influenza pneumonia usually starts as a typical flu but after a few days turns into wheezing, shortness of breath and pain when taking a breath. In very severe cases the patient may cough up blood or blood-tinged sputum and there is high mortality (Acute Respiratory Distress Syndrome or ARDS). Treatment is primarily supportive and often requires use of a ventilator (mechanical breathing help). Since ventilators are not plentiful (of the 100,000 estimated in the US, about 80,000 are in use at any one time), a shortage here will require rationing and triage in a pandemic setting.

Pneumonia in the setting of a viral infection of the lungs can also be caused by bacteria that take advantage of the damaged lung tissue (‘secondary infections’). These superimposed secondary infections can be treated with antibiotics if the bacteria are susceptible to them. Secondary infections are not uncommon, but in some instances can spread to other organs and lead to meningococcal infection or toxic shock syndrome (from secondary staph infection). Other rare complications include kidney failure, muscle destruction (rhabdomyolysis), massive clotting with subsequent hemorrhage (disseminated intravascular coagulation) and encephalitis, paralysis (Guillain-Barré) and Reye syndrome (sudden increased accumulation of fat in the liver, brain and other organs that can be rapidly fatal and affects children primarily recovering from a viral infection). These complications are ordinarily rare (<1%) but were prominent in the 1918 pandemic. The rate of complication and involvement of other organ systems is related to the specific strain of influenza virus. Exactly what are the factors that make one strain so much more virulent than another is only now being understood and for the most part we cannot predict ahead of time. The H5N1 bird flu virus now endemic in poultry in asia seems particularly virulent when it crosses over to humans, but whether a version of it that is easily passed from person to person will remain so virulent is unclear. Already the virus shows signs of changing its virulence characteristics to a less fatal form, but it remains exceedingly dangerous.

Clearly the virus itself damages the cells of the respiratory system, killing some of them outright and inducing others to kill themselves (i.e., initiate a ‘cell suicide’ program). But there is also good evidence that the vigorous immune response meant to protect us may paradoxically also play a big part in making us sicker. When lung system cells get infected they show fragments of viral protein on their surfaces. Immune system cells (‘T-cells’) can recognize these infected cells and are activated to produce soluble signals to call other cells to the site to help fight the infection. One or more of these soluble signaling chemicals (called chemokines or cytokines) may be responsible for producing even more lung damage or damage in other organs, as well as producing many of the symptoms like fever, loss of appetite and muscle aches and pains. Tumor Necrosis Factor-α is one of the cytokines implicated in this (Xu et al., J Immunol. 2004 Jul 15;173(2):721–5.). Some consider that an unregulated positive feedback might actually cause a Cytokine Storm, that is, an uncontrolled outpouring of cytokines that induce an overzealous reaction, but much work remains to be done to parse this complex process. Current research involves unraveling this immunopathologic response so as to intervene with drugs that prevent it.

«« Glossary · Science · Influenza Primer II »»