The symptoms of uncomplicated rhinotracheitis usually peak by days 3 to 5, and patients are asymptomatic by days 7 to 10. Some of the symptomatology is readily understood by examination of electron micrographs of mouse trachea following influenza virus infection (Figure 2).
On scanning electron microscopy of the normal respiratory tract epithelium, two cell types - ciliated and serous - predominate. Transmission electron microscopy shows that serous cells have short microvilli and mucous granules. Ciliated cells have longer microvilli interspersed between cilia. There are "watertight" seals between ciliated and serous cells, formed by tight junctions and belt desmosomes. A third cell type, the basal cell, is also present. Basal cells normally cover about one third of the basement membrane. Normally, the mucous film produced by serous cells lining the airways traps bacteria, soot, and other particles, including virus, and cilia push the film and its entrapped debris into the posterior pharynx, where it is swallowed. This is called the tracheal toilet.
Three days after influenza infection, serous and ciliated cells are desquamated, and the basal cells have now spread out to cover the entire basement membrane. There are, however, gaping holes between basal cells, allowing extracellular fluid to escape. This explains the nonviscous rhinorrhea, or "runny nose," characteristic of this phase of infection with the virus.
By day 5, basal cells are progressively differentiating into serous and ciliated cells, which are readily distinguishable by differences in the length of their microvilli. By day 10, serous cells again contain mucous granules, but ciliated cells are not quite back to normal. These observations help explain the viscous secretions that can be bothersome during the recovery phase. Mucus is produced, but ciliated cells are unable to move it adequately, so that patients must snort and blow the nose to clear the sinuses and cough to clear the trachea. By day 14 in the mouse model, the epithelium has returned to normal. It should be pointed out that the course described is for a primary infection. If a person (or experimental animal) has had a prior type A influenza infection, as is almost always the case in human adults, recovery occurs a few days earlier because of heterotypic immunity induced by prior infection.
A frequently asked question is, Why doesn't the virus destroy basal cells? If basal cells were susceptible to influenza infection, it seems likely that the infection would irreversibly destroy the epithelium and probably be uniformly fatal. According to studies by Catherine Meitin in the University of Florida labs, it appears that basal cells lack receptors for influenza virus. Using gold-labeled antibody against influenza virus and scanning electron microscopy, Meitin detected virus adhering to intact serous and ciliated cells. However, no detectable virus adhered to basal cells exposed by influenza- or acid-induced desquamation of serous and ciliated cells. By about day 7 of infection, as basal cells differentiated into ciliated and serous cells, virus receptors were again detectable.
In influenza, the goal of treatment is to restrict the infection to the upper respiratory tract. The symptomatic approach passed on by many generations of mothers and grandmothers - rest, keep warm, drink lots of fluids - accomplishes this.
Rest reduces oxygen requirement and thus airflow, thereby decreasing the chance of spreading the virus from the upper to the lower respiratory tract. Keeping warm helps maintain lower respiratory tract epithelium at core body temperature (37 degrees Celsius, or higher if the patient is febrile), thereby inhibiting virus replication, which is optimal at 35 degrees Celsius. (This also suggests that drugs such as acetaminophen should not be given to control mild fever but only for pain, high fever, or both. Aspirin should generally be avoided because of its association with Reye syndrome.) Finally, drinking lots of fluids ensures that mucus secretion and tracheal toilet will not be further compromised by dehydration.
Upper respiratory tract infection predisposes to otitis media. Although this complication occurs in less than 5% of patients with flu or a common cold. more than 90% of patients with otitis media have a recent history of an upper respiratory viral infection. Studies of experimental influenza in the ferret have shown that, as in the trachea, ciliated epithelium of the eustachian tube is destroyed by the virus, setting the stage for bacterial infection.
Normally, ciliated cells lining the trough in the bottom of the middle ear and in the eustachian tube function as a one-way conveyor belt, transporting any bacteria and debris that get into the middle ear to the posterior pharynx for harmless disposal by swallowing. When ciliated epithelium of the human ear is denuded by an upper respiratory viral infection, bacteria forced into the middle ear (e.g., by sneezing or nose blowing) are not removed. They remain in the middle ear's warm, moist environment, an excellent culture medium.
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