Учебники / Otolaryngology - Basic Science and Clinical Review

often requiring the reduced pH and oxygen (O2) tension characteristic of tissue necrosis, decreased blood supply, and obstructed cavities to grow. The combination of anaerobes and facultative aerobes may give rise to virulence synergy too complicated to dissect, but resulting in further tissue-destructive relationships.

These combinations of organisms are isolated from multiple infections of tonsils, sinuses, middle ear, and deep neck, as well as from oropharyngeal Vincent’s angina and necrotizing ulcerative gingivitis. They may induce inflammation resulting in a host component to the pathology; may directly destroy tissues; facilitate spread of aerobes to the neck, brain, or lung; and prevent antibiotic effects because of the high frequency of-lactamase production by this group. Together, they represent a significant pathogenic potential of the normal flora of the oropharynx, resulting frequently in postsurgical infected wounds, infected wounds of malignancies of the head and neck, and infectious complications due to mechanical trauma to the oronasopharynx. Infections are usually polymicrobial and require antibiotics against both aerobic and anaerobic species for their cure.

HOST RESISTANCE TO

VIRAL INFECTIONS

The same innate and acquired immune defense systems that protect against bacterial infections also protect against viruses. Successful infection requires specific attachment of proteins on the viral surface to receptors on the target cell, followed by penetration into the cell. The receptor for a given virus can be limited to a specific cell type or tissue in one species of animal, providing highly restricted host specificity, or can be broadly represented on many cell types. The presence of a mucous barrier in the respiratory tract limits and reduces the likelihood of successful viral infection by blocking access to the receptors.

The interferon system can also be considered a part of the innate system of protection because it is not specific for antigens of a given virus. Synthesis of double-stranded RNA (dsRNA), usually late in the viral replication cycle, induces synthesis of type I interferons (interferon from infected lymphocytes and interferon from fibroblasts). Binding of type I interferons to uninfected cells then induces an antiviral state that limits successful spread of the viral infection (Fig. 7-1). Destruction of messenger RNA (mRNA) and phosphorylation of the translation factor F-2 inhibit both viral and host protein synthesis in the cell. In some cases, the inhibition simply reduces the ability of newly infected cells to produce more virus; in other cases, it kills the newly infected cells, thereby

Figure 7-1 Induction of interferon and establishment of an antiviral state in uninfected cells.

halting spread of infection. Patients who are unable to generate interferons suffer from severe disseminated infections. They can be treated by injections of purified interferon. However, the side effects of interferon (fever, malaise, hair loss) have limited its use as a therapeutic agent to severe infections such as hepatitis B and C.

Those viruses that kill cells slowly and generate large amounts of dsRNA during infection are strong inducers of interferon, whereas viruses that rapidly kill the host cell, prevent synthesis of host proteins, or do not generate dsRNA as part of their life cycle are generally poor inducers. Moreover, not all viruses are susceptible to inhibition by interferon. Adenovirus, one of the viruses associated with respiratory infections, is resistant to interferon, while other respiratory viruses such as rhinovirus and influenza virus are susceptible.

Antigen-specific acquired immune defenses, described earlier in this chapter, are key to preventing and managing most viral infections. Specific antibodies reduce viral load and infectivity, and antibody-based immunization has successfully limited or eliminated many viral scourges including smallpox, polio, and measles. However, antibodies are not essential to manage viral infections. Children with agammaglobulinemia primarily

suffer from bacterial rather than viral infections.Antigenspecific cell-mediated immunity, on the other hand, appears essential to control viral infections. Patients with DiGeorge’s syndrome, characterized by congenital thymic aplasia, suffer from severe and frequent viral infections. Measles, for example, is often fatal in these patients. Some viruses have evolved ways to evade the immune system, permitting long-term persistent or latent infections. For example, adenoviruses and herpesviruses produce proteins that block presentation of major histocompatibility complex (MHC) class I molecules on the cell surface, preventing effective cytotoxic T-cell destruction of the infected cell.

OVERVIEW OF VIRAL STRUCTURE AND REPLICATION

Viruses have a much simpler structure than bacteria, consisting of nucleic acid, usually complexed to one or more proteins, enclosed within a protein coat or capsid to form a nucleocapsid. Subsets of viruses are surrounded by a lipid envelope derived from cellular membranes. The structure of the nucleic acid varies among viruses and is a major factor in determining classification. The genome can be either DNA or RNA, linear or circular, in one piece or several, double or single stranded. The capsid protects the nucleic acid from the environment and mediates entry into the host cell. It is normally composed of several subunits or capsomeres, each made of one or more proteins that are assembled to provide a specific shape to the viral particle. Most capsids are either icosahedral (20 sided) or helical.A few viruses (e.g., poxviruses) have complex multilayered protein coats surrounding the nucleic acid, rather than a simple capsid. The lipid envelope is derived from cellular

membranes.The envelope is studded with virally coded glycoproteins, some of which interact with cell-surface receptors, and matrix proteins that link the envelope to the nucleocapsid. Presence of a lipid envelope increases the sensitivity of the virus to solvents such as ether.

Virus infection is a multistep process (Fig. 7-2). A successful infection requires that the virus enters a host cell and subverts that cell to producing viral proteins and nucleic acids, assembling new virus, and releasing that virus to repeat the cycle. An abortive infection, for example, would occur if the virus bound to a cell that could not support viral replication. There are several steps in the cycle where the process can be blocked.Antiviral approaches that inhibit binding (such as soluble receptors that “soak up” virus or small peptides that bind to cell-surface receptors and compete for virus binding) are attractive preventive strategies currently being developed. Once a virus has penetrated, antibodies and agents that inhibit binding are no longer effective. Replication is dependent on a combination of viral and host enzymes. Expression of viral proteins required for replication can be inhibited by interferon (see above). In the small DNA viruses, nearly all of the host DNA replication machinery is used, and a small number of virally encoded proteins provide enhanced viral DNA replication over cellular replication. In the poxviruses and herpesviruses, which are very large, the viruses code for many replication enzymes, and dependence on host enzymes is reduced. Retroviruses, such as HIV, code for an RNA-dependent DNA polymerase (reverse transcriptase) that copies the viral RNA into copy DNA (cDNA)—the opposite of the normal transcription, where DNA is transcribed into RNA.The viral cDNA is inserted into the host cell chromosome and then transcribed by host RNA polymerases to make many copies

of viral RNA. Other RNA viruses either code for their own RNA polymerase or alter the cellular polymerase by addition of viral subunits. These are all targets for antiviral therapy.

The previous process describes the infectious cycle of viruses. Some viruses establish latent infections, where the virus binds, penetrates, is uncoated, and then fails to replicate for a protracted period of time. The herpesviruses are the best-studied examples of latency. Herpes simplex initially infects epithelial cells of the oral mucosa or genital tract and establishes a small localized active infection.The virus then travels along nerve fibers to the dorsal root ganglia, where it can persist for the life of the patient. In the ganglia, only a few latent-specific RNAs are expressed, and there is no viral replication. If local trauma or inflammation of the epithelium occurs, some of the viral DNA travels back down the nerve fiber to the epithelium, reenters the epithelial cells, and enters the full replication cycle.

Another variant of the life cycle is a persistent infection, with virus being produced at very low levels for a protracted period of time (often years). Many viruses can cause persistent infection, including measles, mumps, HIV, and Epstein-Barr virus. This type of infection is characteristic of the “slow viruses” that are associated with some neurologic diseases and is suspected of playing a role in multiple sclerosis.

PATHOGENESIS OF

VIRAL INFECTIONS

Multiple factors influence the outcome of a viral infection.These include the patient’s age and nutritional and immune status, as well as the specific type of virus.

TABLE 7-1 ANTIVIRAL DRUGS

Some viruses cause asymptomatic or minor illness in young children but severe illness in adults. For example, poliovirus infection is usually asymptomatic in infants, especially in populations where the virus is endemic and most adults have antibodies that partially protect infants. The advent of better hygiene and delayed infection resulted in the polio epidemics of the 1940s and 1950s, which were especially severe in middleclass populations. Other viruses cause only minor illness in older children and adults but severe illness in infants (e.g., respiratory syncytial virus). The characteristic pathogenic processes of viruses commonly associated with diseases of the head and neck are discussed below with the individual viruses.

ANTIVIRAL THERAPIES

Historically, the best approach to control virus infections has been preventive—vaccines and better hygiene to provide safe food and water. More recently, several specific therapies have been developed to treat viral infections after they begin (Table 7-1). In addition, nonspecific treatments such as interferon are used for some types of severe infections. The basic philosophy behind most antiviral drugs is to inhibit an enzyme or process in the viral life cycle that is not shared by the host cell. For some viruses, this would appear relatively easy. Viruses that encode unique enzymes (e.g., RNA viruses that use reverse transcriptase to convert their nucleic acid to DNA) should be treated effectively by drugs that target the enzyme. However, most viruses use host enzymes for transcription and replication.Any drug that interferes with these processes will also interfere with normal host functions, causing significant side

effects. Moreover, the reverse transcriptase mentioned above is an error-prone enzyme. This means that the mutation rate for these viruses is very high, and treatment with antiviral drugs selects for those mutant viruses that are more resistant to the drug.This has been and continues to be a major problem for therapies for HIV infection. Despite these limitations, several effective antiviral therapies have now been developed.

RESPIRATORY VIRAL INFECTIONS

Several viruses cause respiratory infections in infants, children, and adults. Though usually self-limiting, these infections resulting in a large amount of absenteeism from school and work. Often, they are associated with secondary bacterial infections like those discussed earlier in this chapter. These infections can involve the sinuses, the middle ear, and the lower respiratory tract. Thus viral respiratory infections have a significant impact on the health care costs of the nation.

RHINOVIRUSES

Rhinoviruses are the cause of the common cold. They are small, nonenveloped single-stranded RNA viruses, closely related to poliovirus.There are over 100 different serotypes of rhinovirus, and antibodies against one type are usually not protective against another. The average adult will get one or two rhinovirus infections per year, and young children get six to eight. Rhinoviruses infect the ciliated epithelium of the nose, with virus replicating and shed for 3 to 5 days. The viruses are temperaturesensitive, unable to replicate at 37°C, which limits the infection to the nasal passages, which are slightly cooler than the rest of the respiratory tract. Rhinoviruses are highly infectious.Transmission usually occurs by transfer from contaminated hands touching mucous membranes of the eyes or nose. Symptoms are caused by the host inflammatory immune response, rather than by any significant damage to the mucosa itself.

CORONAVIRUSES

Coronaviruses are a common cause of colds occurring in the late winter and spring, causing 10 to 25% of upper respiratory infections. They are also single-stranded RNA viruses, but unlike the rhinoviruses they are enveloped. These viruses are primarily associated with infections in adults rather than children.Transmission is normally by a fecal–oral route, rather than airborne droplets or from hands to nose.The pathophysiology of disease symptoms is very similar to rhinoviruses.

INFLUENZA VIRUSES

Influenza viruses are quite different from either rhinoviruses or coronaviruses. The virus genome is composed of eight separate segments of RNA. Replication of this RNA virus, unlike many other RNA viruses, occurs in the nucleus. Replication is mediated by an RNAdependent RNA polymerase coded for by the virus.

Influenza virus enters the nasopharynx, invades the mucous layer, and infects the ciliated respiratory epithelium. Infection causes necrosis and desquamation of the epithelium, resulting in a loss of the protective mucous layer. Many of the systemic symptoms of influenza are caused by release of cellular contents, including interferons, during necrosis. Because the protective ciliary action on the mucous layer is lost, the respiratory tract is highly vulnerable to secondary infections. Approximately 10% of acute influenza virus infections subsequently lead to pneumonia.

Immunization is a very effective preventive of infection, if the vaccine is against the same virus types and subtype currently in circulation. The influenza virus is surrounded by a lipid envelope with multiple protein spikes embedded in it.The virus is very unstable, with a high mutation rate. Mutation of the spike proteins causes a new subtype of virus, partially limiting effectiveness of antibodies from earlier influenza infection or immunization. Multiple infection of a single cell by two or more different types can generate a new mix of RNA segments. This results in a new viral type—the cause of worldwide epidemics with few people resistant due to prior infection with other types. Many of these new types originate in China. Both ducks and pigs harbor influenza viruses that can infect humans. Ducks and pigs are grown together in China, facilitating mixing of infections from one to another. One of the major problems in influenza vaccine development is predicting, a year in advance, which subtypes or new types that have appeared are likely to spread through the population.

PARAINFLUENZA VIRUSES

Despite its name, this virus is not related to influenza virus. Parainfluenza viruses are single-stranded RNA viruses most closely related to the mumps virus. The virus replicates in the cytoplasm and buds through the cell membrane without killing the host cell. However, infected cells lose ciliated function, some cells are lost, and some fuse to form giant multinucleated cells. Parainfluenza virus types 1 and 2 cause laryngotracheobronchitis, and type 3 causes bronchiolitis and pneumonia.Transmission is by both aerosol and hand.

The infection is usually subclinical in adults but acute in children.

RESPIRATORY SYNCYTIAL VIRUS

This single-stranded RNA virus is the most frequent cause of upper respiratory infection in babies. Approximately 1% of infants with clinical disease will require hospitalization. Respiratory syncytial virus (RSV) is transmitted by hand contact from adult carriers and is a common nosocomial infection. It has been estimated that 25 to 30% of the staff in a newborn nursery carry RSV. Adults with compromised immune systems are also at risk for RSV infection. Infection initially occurs in the upper respiratory tract, where it kills the infected epithelial cells, but in babies infection can spread to the lower tract, causing multiple symptoms, including croup, bronchitis, bronchiolitis, and pneumonia. T-cell response to infection is critical for control but can also contribute to the pathology, with a delayed hypersensitivity reaction in the lungs.

RSV is a rather fragile virus and not too easily infectious.The initial vaccine against RSV, tested several years ago, actually proved to exacerbate disease. Antibodies bound to the virus enhanced uptake by macrophages by binding to receptors on the cell surface. Recently, a new vaccine has been developed that should protect infants against RSV infection.

ADENOVIRUS

The last of the viruses that commonly cause respiratory infections is the adenovirus. Unlike all those listed above, this virus contains DNA as its nucleic acid, with one moderately large double-stranded molecule containing 35,000 to 38,000 base pairs. (For comparison, papillomavirus DNA is only 8000 base pairs, whereas Epstein-Barr virus is 171,000 base pairs).The viral DNA replicates in the host cell nucleus, using host enzymes in combination with virally coded enzymes. Adenoviruses are nonenveloped, with fiber spikes projecting from the icosahedral capsid at each apex. These fibers determine the hemagglutination properties of the virus.

Adenoviruses are very stable, maintaining infectivity for several weeks at 4°C, and several months at 20°C. They are grouped into seven subgroups, subdivided into 40 serotypes. The pathogenesis of adenovirus infection varies, depending on the serotype. The most common otolaryngological disease manifestations are acute respiratory disease restricted to new military recruits (types 4 and 7), pharyngoconjunctival fever and pharyngitis (type 3), conjunctivitis (types 3 and 7), and epidemic keratoconjunctivitis (types 8 and 19). Several fatal cases

of nonbacterial pneumonia in infants have been ascribed to types 3 and 7.Transmission is from person to person through respiratory and ocular secretions. Infection of epithelial cells causes a complete halt to cellular DNA and RNA synthesis, as the host machinery is subverted to synthesis of viral components, but the infected cells do not usually die.The viral material is only inefficiently assembled into new viral particles, and most accumulates in the nucleus as large inclusion bodies that identify the infected cells. Most adenovirus infections are subclinical, and most people are infected with one or more serotypes before the age of 15.Adenoviruses often establish latent infections in the tonsils. Infection with one serotype is generally protective against subsequent infection with the same serotype, and neutralizing antibodies persist for many years.The persistent elevated titers probably reflect occasional low-level activation of the latent tonsil infection, which serves to restimulate the immune system. Activation of latent infection can be a problem in immunosuppressed patients.

VIRUSES ASSOCIATED WITH OTOLOGIC DISORDERS

In addition to contributing to bacterial middle ear infections secondary to viral respiratory infections that cause swelling of the nasopharyngeal mucosa and obstruction of the eustachian tube, viruses are also directly associated with otologic disorders. These can result in permanent hearing loss.

RUBELLA VIRUS

This virus was associated with epidemics in the past that resulted in large numbers of congenitally deaf children. Fortunately, a vaccine against rubella has now been developed. Rubella is an enveloped, single-stranded RNA virus that is a member of the Togaviridae family. It is the only member of the family that exclusively infects vertebrates, while the other viruses in the family infect and replicate in insects for at least part of their life cycle. Rubella virus RNA replicates in the cytoplasm, viral proteins are inserted into the outer cell membrane, and the virus buds through this membrane for a prolonged period of time. Although the virus is cytoplasmic, cultured cells infected with rubella frequently show multiple chromosomal breaks and damage.

Infection normally occurs in the respiratory tract, transmitted by nasal secretions, but then causes a hematogenously spread viremia.The infection is generally self-limiting in children and adults, and normally causes little pathology in the host beyond a rash that may

appear 14 to 25 days after infection. In fact, most young adults with rubella infection are asymptomatic. However, during the viremia that precedes the rash, rubella can cross the placenta and infect a developing fetus. If infection occurs during the first trimester of pregnancy, multiple congenital developmental abnormalities, including deafness, cataracts, cardiac abnormalities, and motor deficits, occur in 30% of patients. Damage to the fetus is caused by rapid death of some fetal cells, coupled with persistent infection and chromosomal breaks and abnormal mitoses in other cells. Babies born with congenital rubella infection are infectious and can shed virus for up to 2 years.

MEASLES VIRUS

Measles virus can cause otitis media and mastoiditis. Measles is a member of the paramyxoviruses, related to parainfluenza virus, RSV, and mumps, with a single strand of RNA and a viral envelope. Like the other paramyxoviruses, the viral particle contains an RNA-dependent RNA polymerase that initiates viral replication. It is the most infectious known virus, with successful infection established by as little as one viral particle. The virus is transmitted by respiratory secretions, enters the upper respiratory tract, and replicates in respiratory epithelium and regional lymph nodes. This phase of infection can be characterized by conjunctivitis, dry cough, sore throat, headache, low-grade fever, and tiny red patches with central white specks on the buccal mucosa (Koplik’s spots). The localized infection then spreads to more distant lymph nodes and skin by hematogenous dissemination, resulting in the characteristic rash. Multinucleated giant cells can be detected in nasal secretions and sputum from infected patients prior to rash appearance. The most frequent complications of measles infection are bronchopneumonia and otitis media. However, the most serious complications are neurological— encephalomyelitis and subacute sclerosing panencephalitis (SSPE). SSPE is a chronic, progressive fatal disorder due to persistent low-level infection.

MUMPS VIRUS

The mumps virus, another paramyxovirus, can also cause otologic disease. The virus is transmitted by saliva and respiratory secretions, infects the respiratory tract, and replicates initially in respiratory epithelium and cervical lymph nodes. The virus then spreads to the salivary glands, the primary target organs, through a hematogenous viremia. This viremia occurs several days prior to clinical mumps symptoms, during which time the patient is infectious. Although disease is usually limited to the

salivary glands, multiple other organs can be involved causing orchitis, meningitis, meningoencephalitis, and deafness. Mumps can cause deafness in the absence of other central nervous system symptoms, through destruction of the organ of Corti. Deafness is often preceded by a sense of “fullness” and tinnitus, and is bilateral in 20% of affected patients.

HUMAN IMMUNODEFICIENCY VIRUS

This virus, more commonly associated with its immunodestructive functions, can also cause otologic symptoms. HIV is a lentivirus, an enveloped retrovirus containing two identical copies of RNA. Other lentiviruses cause slowly developing diseases in sheep and horses. It has recently been nearly conclusively proven that HIV infections were transmitted from chimpanzees to humans, and probably occurred multiple times, generating different HIV strains in the human population. HIV infects T cells, macrophages, astrocytes, and neurons. The initial infection is latent, and activation requires both cellular and viral factors. HIV is characterized by a high rate of mutation, which has limited effectiveness of antiviral drugs and further complicated development of a successful vaccine.

HIV RNA has been found in outer hair cells and supporting cells of the cochlea and is associated with progressive high-frequency sensorineural hearing loss in 20 to 25% of AIDS patients. Active infection causes cell damage or loss through induction of apoptosis (programmed cell death), and adjacent uninfected cells can be killed by a bystander effect. Neuronal damage can be mediated through release of excitotoxins from infected macrophages and supporting cells.These toxins include nitrous oxide, arachidonic acid, and quinolinate. Moreover, there is some evidence that zidovudine (AZT), one of the primary drugs used to treat HIV infection, is itself ototoxic.

CYTOMEGALOVIRUS

Cytomegalovirus (CMV) is a herpesvirus, one of the family that also includes herpes zoster and herpes simplex. Herpesviruses are very large, enveloped viruses that contain one linear double-stranded molecule of DNA.These viruses enter the cytoplasm, where they are uncoated, and the DNA then moves to the nucleus. Herpesviruses replicate and are assembled into new virus particles in the host cell nucleus, with replication dependent on a virally coded polymerase that is a target for antiviral therapy, and acquire their envelope as they bud through the nuclear membrane. The enveloped viruses then transit the cytoplasm and exit the cell.

Herpesviruses can cause both acute and latent infections. Infection with CMV is widespread, but disease associated with infection of adults or children is rare. However, congenital CMV infection, acquired in utero, has a different outcome.Twenty percent of infants with congenital CMV infection will display severe symptoms (primarily neurological), and 25% of these infections are fatal. Five to 20% of “nonsymptomatic” infants will have significant sensorineural hearing loss due to cochleitis and auditory neuritis.

TUMOR VIRUSES

A subset of head and neck tumors is caused by viruses, although the vast majority of tumors are caused by environmental factors, primarily tobacco and alcohol use. A viral etiology holds out the hope that appropriate antiviral therapies might eventually be useful for the treatment of some tumors. Unlike most of the viruses causing respiratory and otologic disease, which are RNA viruses, the two viruses that cause head and neck tumors are DNA viruses.They are Epstein-Barr virus (EBV) and papillomavirus. Both viruses cause acute and persisting latent infections, and only a rare subset of infections results in tumors. Tumorigenicity is multifactorial, involving the virus and other cofactors.These cofactors include environmental agents that can cause cellular mutations or damage and host factors such as immune response to the viral infection.

EPSTEIN-BARR VIRUS

EBV is also a member of the herpesvirus family, with the same mode of replication and nuclear budding as CMV. Unlike the other herpesviruses, however, EBV establishes its latent infection in B cells and respiratory epithelium rather than in neurons. This latent infection is often located in tonsils, and tonsillar tissue will yield infectious EBV if cultured in the laboratory. The initial infection is usually asymptomatic, especially in young children. In teenagers and adults, initial infection is often manifested as infectious mononucleosis.

Nasopharyngeal carcinomas (NPCs) are caused by EBV. The virus infects the epithelium, establishes a latent infection, and expresses a subset of viral proteins including Epstein-Barr nuclear antigen 1 (EBNA-1) and EBNA-2. Detection of these proteins is diagnostic for latent EBV infection. Activation of the virus by cofactor(s) can then lead to induction of the cancer.The role of EBV in NPC was first recognized in China, where the southeast region (primarily Canton) has a very high rate

of NPC.This geographic region coincides with the area where the population has a high rate of exposure to croton oil.We now know that both croton oil and tung oil can promote EBV-induced NPC. More recently, scientists have realized that NPC in other parts of the world, including the United States, is also caused by EBV. The low incidence of NPC in the West probably reflects the low exposure to cocarcinogens that specifically promote the tumors, rather than lower prevalence of latent EBV infection. The cocarcinogens responsible for NPC in the United States and Europe have not been defined.

PAPILLOMAVIRUSES

Human papillomaviruses (HPVs) are a family of 100 closely related, very small nonenveloped DNA viruses that infect stratified squamous epithelium, including skin, respiratory, digestive, and genital mucosa.Viral type is based on DNA sequence homology, because there is no good serological test for HPV infection at this time. HPVs code for only eight to 10 proteins, including the two capsid proteins. The viral DNA replicates in the nucleus of infected cells, using the cell replication enzymes.Thus it is very difficult to prevent viral replication without significant toxicity to uninfected cells.The virus codes for one replication protein that enhances viral DNA replication, but to date there has been no successful antiviral therapy that targets this enzyme. Papillomaviruses are transmitted by contact with squamae shed from the surface of infectious lesions. The infection remains local, with no evidence for systemic spread.

The majority of infections are subclinical or latent. For example, 5% of the population has latent respiratory tract infection, 30% of young adults have genital tract infection, and most people have latent skin infections. The most common manifestation of active HPV infection is a benign tumor, or papilloma. Eight to 10 HPV types are associated with papillomas in the oral cavity, oropharynx, nasopharynx, and larynx. Recurrent respiratory papillomatosis, caused by HPVs type 6 and 11, is the most serious benign disease caused by HPV infection.The disease is characterized by recurrent lesions that can be removed surgically but frequently recur. Recurrence is due to activation of latent infection, widespread in the respiratory tract of these patients, by some unknown process.Though unusual, the disease can involve not only the larynx but also the trachea, bronchi, and lung. Lung involvement is usually fatal. There is no effective medical treatment for respiratory papillomas and no cure. Interferon controls the disease in many patients, but the papillomas recur as soon

as treatment stops. Most patients are unwilling to undergo years of interferon therapy because of its side effects.

Malignant conversion of benign HPV-induced lesions also requires cofactors. Radiation is a known cofactor, and is thus contraindicated in the treatment of respiratory papillomas. Other cofactors are unknown, but any agent that can cause DNA damage is likely to be able to induce malignant conversion. Because HPV infection (primarily with types 16 and 18) is the cause of more than 90% of cervical cancers, many investigators have sought a role for HPVs in head and neck cancers. These investigations have had contradictory results, most probably confounded by the presence of latent HPV infection in oral and respiratory mucosa. There is, however, mounting evidence that tonsillar cancer is caused by HPV, usually HPV 16. More than half of all tonsil cancers contain HPV 16, and the two viral oncogenes, E6 and E7, are expressed at high levels. These two viral genes are not expressed in latent infection. The restriction of HPVinduced head and neck cancer to tonsils raises the possibility that HPV and EBV might interact in the pathogenic process. This is currently under investigation by several research groups.

SUMMARY

Clearly, a large number of bacteria and viruses cause otolaryngological diseases and disorders. However, one must always remember that these disorders do not necessarily exist as monomicrobial infections. Humans are colonized with large numbers of bacteria, most of which do not cause disease even if pathogenic types,

SELF-TEST QUESTIONS

For each question select the correct answer from the lettered alternatives that follow.To check your answers, see Answers to Self-Tests on page 715.

1.Which one of the following answers is correct? Penicillin resistance is primarily due to

A.Intrinsic high mutation rate of Streptococcus pneumoniae

B.Selection of resistance in hospitalized adults

C.Childhood pharyngeal colonization

D.Frequent use of oral antibiotics for viral upper respiratory infections (URI) in children

E.Potential for inadequate drug level in childhood otitis media

and carry many latent or persistent viruses. Mere presence of an organism does not necessarily define etiology of a disease. As our ability to detect smaller and smaller numbers of organisms increases, we risk overinterpreting results. Moreover, an active infection with one organism can directly contribute to a second pathogenic infection. This is most clearly seen in cases where an initial viral infection, for example, with influenza virus, leads to a secondary bacterial infection of the respiratory tract. It is the complex interactions of multiple factors, including the status of the host, that determine outcome of bacterial and viral infections.

SUGGESTED READINGS

Dulbecco R, Ginsberg HS, eds. Virology. 2nd ed. Philadelphia: JB. Lippincott; 1990

Fauci AS, Brounwald E, Isselbacher KJ, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. NewYork: McGrawHill; 1998

Field BN, Knipe KM, Howley PM, eds. Fields Virology. 3rd ed. Vols 1 and 2. Philadelphia: Lippincott-Raven; 1996

Gwaltney JM. Acute community-acquired sinusitis. Clin Infect Dis 1996;23:1209–1225

Johnson JJ, Yu VL, eds. Infectious Diseases and Antimicrobial Therapy of the Ears, Nose and Throat. Philadelphia: WB Saunders; 1997

Joklik WK,Willett HP, Amos DB,Wilfert CM, eds. Zinsser Microbiology. Norwalk, CT:Appleton and Lange; 1992

Kaliner MA. Human nasal respiratory secretions and host defense. Am Rev Respir Dis 1991;144:S52–S56

Steinberg BM. The role of human papillomaviruses in benign and malignant lesions. In: Hong WK, Weber RS, eds. Head and Neck Cancer. Norwalk, CT: Kluwer Academic; 1995:1–16

2.Pathogens causing acute community acquired bacterial sinusitis usually include all but one of the following:

A.Alpha-hemolytic streptococci

B.Haemophilus influenzae

C.Moraxella catarrhalis

D.Staphylococcus epidermidis

E.Mixtures of anaerobic bacteria

3.The differential diagnosis of acute viral versus acute bacterial sinusitis is difficult because

A.The conditions usually occur simultaneously.

B.The signs and symptoms of the two conditions have considerable overlap.

C.In the absence of an air–fluid level, sinus x-rays or computed tomography (CT) examinations cannot reliable distinguish between the two conditions.

D.A therapeutic trial of antibiotics does not result in rapid clearing of sinus abnormalities on x-ray or CT examination.

E.All of the above

4.Viral respiratory infections are difficult to treat because

A.Most viral infections are not diagnosed early enough in the viral life cycle to initiate effective drug therapy.

B.Most viruses use host enzymes for replication, and thus there is a limited therapeutic index for antiviral drugs.

C.The high mutation rate of viruses causes them to be resistant to most antiviral drugs.

D.The overlapping symptoms of adenoviruses, rhinoviruses, and influenza virus infections preclude accurate diagnosis and thus choice of the proper antiviral drug.

E.Most people do not generate sufficient interferon titers.

5.Pathogenic outcome of viral infection is multifactorial, due to the following:

A.Host expression of interferon, causing systemic effects, is induced by only some viruses.

B.The age of the patient at the time of infection can alter symptoms.

C.Some viruses primarily cause latent or lowgrade persistent infection.

D.Previous exposure to a virus can induce production of neutralizing antibodies that prevent or limit infection.

E.All of the above

PHARMACOKINETICS

DISTRIBUTION

BIOTRANSFORMATION

EXCRETION

PHARMACOKINETICS AS IT RELATES TO PREGNANCY

SUMMARY OF PHARMACOKINETICS

GASTROESOPHAGEAL REFLUX DISEASE: TREATMENT OF

THE OTOLARYNGOLOGICAL MANIFESTATIONS

H2 RECEPTOR BLOCKING AGENTS

PROTON PUMP INHIBITORS

PROKINETIC DRUGS

TREATMENT STRATEGY

GLUCOCORTICOIDS AND THEIR

USE IN OTOLARYNGOLOGY

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

THE PHARMACOLOGY OF ANALGESICS

MORPHINE

CODEINE

MEPERIDINE

AGONIST–ANTAGONIST ANALGESICS

OPIOID ANTAGONISTS

ANESTHETIC ANALGESICS

SUMMARY OF ANALGESICS

THE PHARMACOLOGY OF LOCAL ANESTHETICS

CHEMISTRY

PHYSIOLOGY OF NERVE TRANSMISSION

COMMONLY USED LOCAL ANESTHETICS

CLINICAL CONSIDERATIONS

TOXICITY

SUMMARY OF LOCAL ANESTHETICS

ANTIBIOTICS

SULFONAMIDES AND TRIMETHOPRIM

PENICILLINS

CEPHALOSPORINS

CARBAPENEMS

MONOBACTAMS

GLYCOPEPTIDES

AMINOGLYCOSIDES

SPECTINOMYCIN

TETRACYCLINES

CHLORAMPHENICOL

ERYTHROMYCINS (MACROLIDES)

KETOLIDES

LINCOSAMIDES

METRONIDAZOLE

OXAZOLIDINONES

QUINOLONES

ANTIFUNGALS

SUGGESTED READINGS

SELF-TEST QUESTIONS