Учебники / Otolaryngology - Basic Science and Clinical Review

TABLE 6-4 SURGICAL PROCEDURES FOR SNORING

AND OSAS

Nose and nasopharynx

Septoplasty

Turbinectomy

Adenoidectomy

Oral cavity and oropharynx

Tongue suspension suture

Tonsillectomy

UPPP

LAUP

Hypopharynx

Midline lingual glossectomy

Linguoplasty

Excision of lingual tonsil

Hyoid suspension

Partial epiglottectomy

Skeletal

Genioplasty

Genioglossus muscle advancement

Maxillomandibular advancement

Mandibular osteotomy

Other

Radiofrequency wave ablations

Tracheotomy

LAUP, laser-assisted uvulopalatoplasty; OSAS, obstructive sleep apnea syndrome; UPPP, uvulopalatopharyngoplasty

Other mechanical treatments include the use of nasal dilator splints and nasopharyngeal stenting, which bypasses the nose and palate.

SURGICAL TREATMENT

The numerous surgical procedures available for the treatment of snoring and OSAS (Table 6-4) underscore the difficulty in selecting the proper one. It is important to have a systematic approach when selecting the surgical procedures to be employed. Identifying the site or sites of soft tissue obstruction, skeletal deficiencies, and the severity of the disease in the spectrum of sleep-related disorders will help in selecting the most appropriate surgical procedures to be employed. An assessment of what is to be accomplished by the surgical procedure and the order in which it is approached should be thought out prior to embarking on this mode of therapy. Nasal and oropharyngeal surgery should be considered in the majority of cases because it usually correlates with the assessment prior to surgery. Skeletal surgery that mobilizes bone and soft tissue attached to it

should be used as a primary modality only in cases in which gross craniofacial and skeletal deficiencies exist. Otherwise it should be performed as a staged procedure after other primary soft tissue surgery has failed and in patients with AHI indexes of greater than 25, as proposed by Powell et al (1990).

The aim of the surgical techniques is to enlarge and stabilize the airway.The mechanisms in which these techniques attempt to reach their objectives are by reducing or displacing soft tissue volume. Skeletal surgery, particularly the maxillomandibular advancement, will have the largest impact on the RDI scores. Future surgical techniques may focus on improving the neuromuscular tone of the tongue and pharynx by attempting to pace the neuromuscular units with external pacers. Early work on this frontier has been performed by attempting to pace the hypoglossal nerve. This experimental work may be expanded in attempting to pace the dilator muscles of the pharynx.

Some frequent surgical techniques employed in the treatment of sleep disordered breathing, and some salient points will be outlined below. The reader is encouraged to consult other textbooks and articles that specifically describe the techniques in detail.

Tracheostomy

This is the most effective surgical technique that bypasses the upper aerodigestive tract. It is 100% effective in relieving obstruction and correcting oxygen desaturation, hemodynamic alterations, and symptoms. However, there is a low patient acceptance of this procedure because it requires chronic maintenance and carries with it long-term morbidity at the tracheal site. A tracheostomy is indicated in patients with severe sleep apnea that is not respondent to CPAP and in patients with the alveolar hypoventilation syndrome.

Uvulopalatopharyngoplasty

Uvulopalatopharyngoplasty (UPPP) is a procedure in which the uvula, part of the soft palate, and redundant pharyngeal tissue are removed.The procedure increases the pharyngeal air space and stiffens the pharyngeal wall, decreasing the collapsibility of the upper airway. UPPP is effective in eliminating snoring in 80% of patients, presumably by removing the tissues that vibrate. However, the surgery is not as effective in curing obstructive sleep apnea, achieving an overall success rate of 50%. More dramatic responses are noted in those patients in whom hypertrophied tonsils are removed at the same time. Patients with a UARS and mild apnea have a better and more sustained response

rate than those with moderate and severe sleep apnea syndrome, particularly if the patient is able to maintain or reduce his or her premorbid weight.

Serious complications from UPPP are infrequent, and postoperative bleeding will occur in less than 1% of the patients. Most of the complications are in relation to an overzealous attempt at removing excessive amounts of palatal tissue. Nasopharyngeal regurgitation of liquids will occur as a temporary symptom in a significant number of patients, particularly if drinking fast or leaning forward in the water fountain position. This symptom usually dissipates in a period of 3 months.Another sequela that the patient must be informed about is the sensation of oropharyngeal dryness, which in our experience occurs in one third of patients on a temporary basis, but in a few it will be present for extended periods of time. A rather frequent complication after UPPP, and to a lesser extent also after laser-assisted uvulopalatoplasty (LAUP), is swallowing dysfunction characterized by a loss of control of the bolus during the pharyngeal phase of swallowing. It is crucial that airways are closed when food is passing the hypopharynx, otherwise aspiration can occur. Only a few patients will actually have problems with aspiration after UPPP, but as many as 20% will have swallowing problems in that they have to concentrate very hard on swallowing to avoid aspiration when eating or drinking, which makes it impossible for them to talk while eating. There is evidence that this swallowing dysfunction may exist in snorers already before surgery, probably because of destroyed sensory nerve endings, but it may become overt after surgery. An infrequent but annoying complication is pharyngeal stenosis, where the patient complains of dysphagia, an inability to clear nasal secretions, and impaired breathing. Correction of this problem may require staged procedures with the use of lasers, stents, and pharyngeal flaps.

Laser-Assisted Uvulopalatoplasty

LAUP, an office-based procedure, reduces soft palatal tissue, the amount determined according to the judgment of the individual surgeon.The technique employed by most surgeons removes a triangular section of tissue adjacent to each side of the root of the uvula, followed by a reduction of 50% of the distal uvula, thus shortening and elevating the size and position of the uvulopalatal complex. Both authors usually perform a sweeping technique in which the entire uvula and a portion of the soft palate are removed, leaving a surgical defect that looks like an arch, much like the defect left after a standard UPPP. LAUP is an effective modality in

treating snoring and the symptomatology of UARS and mild OSAS, but it has little effect in changing the AHI.

RadiofrequencyTissueVolume Reduction

The proponents of this technique claim that by inserting electrodes into various portions of the soft palate and applying thermal energy, the soft tissue will experience a definable “thermal lesion” that over a period of 6 weeks will contract and be replaced by fibrotic tissue that “stiffens and reduces” the targeted soft tissue. The vibratory capacity of the palatal tissue will diminish, and as a consequence snoring is reduced.This procedure can be repeated multiple times and in multiple target sites of the upper airway, including the tonsils and tongue base. To date few reports have documented the effectiveness of this experimental therapeutic modality.

Tongue Base and Hyoid Bone Suspension

This is a recent technique in which a biocompatible screw with two nylon sutures attached to it is drilled into the lingual cortex of the symphysis of the mandible.The nylon attachments are then submucosally sutured, wrapped around the tongue base, and tied to each other in the floor of the mouth with a certain degree of tension. The proponents of this technique claim that the tongue base is contained from “dropping back” and narrowing the posterior airway space (PAS) during sleep.A similar technique is performed in which the attachment of the biocompatible screw to the mandible is the same; however, the free nylon edges are tunneled subcutaneously to the anterior portion of the neck and wrapped around the hyoid bone and tied under tension. This causes anterior and superior displacement of the hyoid bone, resulting in enlargement of the PAS. These techniques are performed on their own or simultaneously, and they can also be combined with other known procedures in the treatment of OSAS. To date fewer than 100 cases have been reported. Because the procedure is usually combined with other known surgical procedures in the treatment of OSAS, it is difficult to assess the amount of change in snoring and RDI scores by this technique. Furthermore, these “ingenious” novel techniques have yet to stand the scrutiny of time.

Maxillofacial (Skeletal) Surgery

Included in the category of skeletal surgical procedures are the inferior sagittal myotomy with hyoid bone suspension and maxillomandibular advancements. Maxillofacial

surgeries increase the size of the upper airway by moving the base of the tongue away from the posterior hypopharyngeal and oropharyngeal walls, decreasing the collapsibility of the airway. The sleep apnea center at Stanford University (Powell et al, 1990) is one of the few to report findings using this surgical approach. Patients there are selected on the basis of the severity of their apnea (moderate to severe), presence of craniofacial abnormalities, such as micrognathia or retrognathia, or failure to respond to other therapy or as staged treatment in a surgical algorithm that performs this kind of surgery after having had prior nasal and oropharyngeal surgery. In Powell et al’s series, maxillomandibular advancements combined with sagittal mandibular advancements have the greatest affect on OSAS. Unfortunately, their good to excellent results have not been matched by other centers performing the same kind of surgery.

Complications include those seen in other surgeries such as pain, bleeding, and wound infection. Problems specific to these procedures include dental nerve anesthesia, mandibular stress fracture, and esophageal reflux from decreased upper esophageal sphincter tone.

GOALS OF TREATMENT

Improvement of symptoms of daytime somnolence, fatigue, snoring, reduction in AHI, and nocturnal hypoxia are the ultimate goals of treatment. The physician and patient must understand the limitations of the various surgical procedures to be selected. Procedures like palatal somnoplasty and LAUP are aimed at reducing the amount of snoring, whereas UPPP and skeletal procedures are aimed at reducing the apnea/hypopnea index. More often than not UPPP does not significantly reduce the AHI scores; however, a good percentage of patients, for reasons that are not clear, will report improvement in their energy level and decrease in symptoms of fatigue and daytime somnolence. This is also true in patients undergoing an LAUP after having undergone a previous tonsillectomy or when the tonsils do not appear to be obstructing the airway. Also, patients with UARS respond well to the modalities mentioned.

SUMMARY

Although OSAS is very common within the American and European populations, this syndrome as an entity has only been known for 4 decades, first described by Gastaut in 1966. Treatment with CPAP and the UPPP operation both started in 1981, before which the only possible treatment was tracheotomy. Today we know a

lot more of the serious effects of this syndrome, and there are more treatment modalities available, but this is still a “new” disease with many questions to be answered. One important question is what mechanisms underlie the pattern of progression from snoring to OSAS.

When taking care of the individual patient, the complexity of the syndrome must be kept in mind. Each patient, and if possible also his or her bed partner, has to be thoroughly questioned about both night and day symptoms, and the physical examination has to include an ear, nose, and throat examination as well as an examination of the heart and lungs. Before treatment such as CPAP, surgery, or dental appliance is started, an overnight sleep recording that will give an AHI is mandatory. The different possibilities of treatment have to be discussed with the patient, who also should be given information of possible side effects. Whatever treatment modality is chosen, each patient also has to be informed of the necessity of not gaining weight. After treatment, the effect of the treatment has to be controlled regarding the patient’s symptoms and the outcome measured by the change of AHI.

The doctor treating patients with OSAS should have good knowledge of the complexity of this syndrome as well as of the whole spectrum of treatment modalities that are available. It seems preferable if the surgeon, the physician, and the dentist work together to optimize the best treatment for each individual patient suffering from heavy snoring and OSAS.

SUGGESTED READINGS

American Electroencephalographic Society Guidelines: guideline for polygraphic assessment of sleep-related disorders (polysomnography). J Clin Neurophysiol 1994;11:116–124 American Sleep Disorder Association. Intrinsic sleep disorders. In: Thorpy MJ, ed. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. Lawrence, KS:

Allen Press; 1990:52–61

Bålfors EM, Franklin KA. Impairment of cerebral perfusion during obstructive sleep apneas. Am J Respir Crit Care Med 1994;150:1587–1591

Findley L, Unverzagt M, Guchu R, et al.Vigilance and automobile accidents in patients with sleep apnea or narcolepsy. Chest 1995;108:619–624

Franklin KA, Nilsson J, Sahlin C, Näslund U. Sleep apnea and nocturnal angina. Lancet 1995;345:1085–1087

Friberg D, Ansved T, Borg K, et al. Histological indications of progressive snorers disease in an upper airway muscle. Am J Respir Crit Care Med 1998;157:589–593

Fujita S, Conway W, Zorick F, et al. Surgical correction of anatomic abnormalities in obstructive sleep apnea syndrome: uvulopalatopharyngoplasty. Otolaryngol Head Neck Surg 1981;89:923–934

Gastaut H,Tassinari C, Duron B. Polygraphic study of the episodic diurnal and nocturnal (hypnic and respiratory) manifestations of the Pickwick syndrome. Brain Res 1966;2:167–186

Gislason T, Benediktsdottir B, Bjornsson JK, et al. Snoring, hypertension, and the sleep apnea syndrome: an epidemiologic survey of middle-aged women. Chest 1993;103:1147–1151 Guilleminault C, Tilkian A, Dement WC. The sleep apnea

syndromes. Am Annu Rev Med 1976;27:465–484 Haraldsson P-O, Carenfeldt C, Lysdahl M, Tingvall C. Does

uvulopalatopharyngoplasty inhibit automobile accidents? Laryngoscope 1995;105:657–661

Hung J, Whitford E, Parson R. Association of sleep apnea with myocardial infarction. Lancet 1990;336:261–264

Jung R, Kuhlo W. Neurophysiological studies of abnormal night sleep and the pickwickian syndrome. Prog Brain Res 1965;18:140–159

Keenan Bornstein S. Respiratory monitoring during sleep: polysomnography. In: Guilleminault C, ed. Sleeping and Waking Disorders: Indications and Techniques. Menlo Park, CA:Addison Wesley; 1982:183–212

SELF-TEST QUESTIONS

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

1.Below are listed some medical and surgical treatment modalities. These treatment modalities are usually performed for other reasons than affecting obstructive sleep apnea syndrome (OSAS). Four of them probably will have a beneficial effect on a person with OSAS, whereas one probably will worsen OSAS.Which treatment modality probably will worsen OSAS?

A.Gastric banding

B.Treatment of hypothyreosis

C.Nasal corticosteroids.

D.Pharyngeal flap as part of cleft palate repair

E.Evulsion of nasal polyps

2.Which of the following statements is false?

A.OSAS has no effect on intellectual performance.

B.OSAS is more common in males than females.

Levring Jäghagen E, Berggren D, Isberg A. Swallowing dysfunction related to snoring: a videographic study. Acta Otolaryngol 2000;120:438–443

Marklund M, Franklin KA, Sahlin C, Lundgren R. The effect of a mandibular advancement device in patients with obstructive sleep apnea. Chest 1998;113:707–713

Newman J, Clerk A, Moore M, et al. Recognition and surgical management of the upper airway resistance syndrome. Laryngoscope 1996;106:1089–1093

Powell NB, Riley RW, Guilleminault C. Maxillofacial surgery for obstructive sleep apnea. In: Guilleminault C, Partinen M, eds. Obstructive Sleep Apnea Syndrome: Clinical Research and Treatment. New York: Raven Press; 1990: 153–182

Riley RW, Powell NB, Li KK, Troell RJ, Guilleminault C. Surgery and obstructive sleep apnea: long-term clinical outcome. Otolaryngol Head Neck Surg 2000;122:415–421

Sullivan CE, Issa FQ, Berthom-Jones M, et al. Reversal of sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1981;1:862–865

C.OSAS is associated with increased incidence of myocardial infarction and stroke.

D.Diminished pharyngeal muscle tone will aggravate symptoms of snoring and sleep apnea.

E.The most frequently occurring daytime symptom of OSAS is sleepiness.

3.Which of the following statements is true?

A.Laser-assisted uvulopalatoplasty is recommended as treatment for a person with OSAS and an apnea/hypopnea index (AHI) of 46.

B.Hypertrophic tonsils occasionally may be the single contributing factor causing OSAS.

C.Obesity is not a major risk factor for development of OSAS.

D.Uvulopalatopharynoplasty is more effective in the treatment of sleep apnea than in the treatment of snoring.

E.Continuous positive airway pressure is not recommended for patients with a body mass index higher than normal.

The respiratory system represents the largest surface area of the human body in contact with the external environment. This epithelial cell–lined structure is directly exposed to the environment, and thus in contact with a myriad of microbes as part of normal respiration. The nose, nasopharynx, and mouth normally are colonized with bacteria. However, the sinus structures, middle ear, and lungs are normally sterile. Because inhalation results in the deposition of

microorganisms on the surface of the respiratory tract, a complex system of defense mechanisms has been defined that explains, to a great extent, the sterility of these sites. These defense mechanisms protect the human host. In this chapter, we will focus on the bacteria that cause infection of the upper respiratory tree—the posterior nasal cavity, nasopharynx, oropharynx, and sinuses—and, to a lesser extent, the middle ear.

SYSTEMS OF PROTECTION

AGAINST BACTERIA

There are two systems that control bacterial colonization and infection of the upper respiratory tract. One is the innate defense system, the other the acquired immune defense system. The innate defenses are nonspecific mechanisms that are constitutively present.The posterior two thirds of the nasal cavity, the nasopharynx, and the sinuses are primarily lined by ciliated, pseudostratified epithelial cells. The epithelial linings also contain mucus-secreting goblet cells, found at high density in the nasal passages and to a lesser extent in the sinuses. Seromucous glandular cells are abundant in the nose but relatively rare in the sinuses. Mucus and fluid produced by the goblet cells and seromucous glandular cells, together with secretions from the submucosal vascular bed, form a blanket that is transported by the concerted action of the ciliated epithelium from the nasal passages and sinus cavities to the oropharynx. Microorganisms trapped in the mucous layer are thus delivered to the oropharynx and swallowed.The mucous layer, which travels at 4.6 to 12.3 mm per minute, and which is replaced by newly produced mucus 2 or 3 times each hour, efficiently cleanses these cavities mechanically and helps to ensure sterility of the nasal sinuses. Other constituents of the nasal secretions, including plasma proteins in the mucin layer, inflammatory mediators, and antibodies or cells of the immune system, may also play a role in maintaining nasal sinus sterility. The volume and composition of the human nasal secretions thus binds microbes mechanically, exerts antimicrobial action, and prevents binding of microbes to cells of the upper respiratory tract. These functions are similar to those that protect the lower respiratory tree from invading pathogens. All act in concert as a primary host defense to protect the mucosal lining.

If the innate defense mechanism is compromised, infection can occur.Acquired mucociliary abnormalities have been shown in children with acute viral respiratory infections such as influenza and adenovirus type 1, and many bacterial infections of the respiratory tract and middle ear follow viral infection. Primary acute alcohol ingestion and smoke inhalation, ciliary dyskinesia, Young’s syndrome, and cystic fibrosis all cause alteration of mucociliary transport that appear to play a role in decreasing host resistance to bacterial infection of the upper airway.

Up to 58% of patients with human immunodeficiency virus (HIV) infection experience recurrent sinus infections. Recent studies of these patients have

shown impaired mucociliary transport due to increased viscosity of the mucus. However, defects in the innate defense system are not the only reason for increased infections in this population. Early in the course of HIV-induced disease, impaired resistance may reflect altered immunoglobulin synthesis as part of polyclonal B cell activation. Late in infection, severe immunoincompetence of both immunoglobulin and cell-mediated immune defenses are more common.The most common pathogens of immunocompetent hosts are also the most common in HIV-associated sinus infections. The less common gram-negative bacterial infections seen in these patients, including Pseudomonas aeruginosa and Mycobacterium kansasii, as well as opportunistic fungi such as Aspergillus fumigatus and Candida albicans, probably reflect a combination of altered clearance and altered immunity, as well as frequent use of antibiotics.

Finally, nosocomial sinusitis linked to nasotracheal obstruction is found in critical care settings.These infections are often due to gram-negative bacteria, selected for by antibiotic therapy, depressed consciousness, and steroid therapy so common in acute critical care situations.

The acquired immune defenses do not act constitutively. Rather, this system involves the antigen-specific responses of immunoglobulins and cell-mediated immunity that are induced in response to invading microbes.As a part of the innate defense system, and in response to signals of inflammation generated by the lymphoid system, granulocytes are mobilized and chemotactically attracted to the upper respiratory tract to act as phagocytes against many bacterial and/or fungal pathogens. By active phagocytic action, the cells ingest and, after phagolysosomal fusion, kill microbes. This is accomplished by a series of intracellular myeloperoxidases and amines that form powerful antimicrobial compounds that function together with granulocyte defensins, proteases, and hydrolases to destroy microorganisms that penetrate the mucosal barrier.

The chemoattraction of these cells, plus the increase in secretion of antimicrobial factors, and finally the stimulation of immunocytes to respond with antibodies, complement, and so on, in upper respiratory tract secretions, may be amplified and orchestrated by cytokines. These substances, produced by many cell types, play an active role in the secretion of innate factors of inflammation such as tumor necrosis factor (TNF- ), the interleukins (ILs) 8,10, and 12, interferon , and granulocyte-macrophage colony–stimulating factor (GM-CSF).The details of the interaction of these molecules, the mechanisms of their function, and their potential role in the pathogenesis of viral and bacterial infections of the upper respiratory tract are beyond the

scope of this chapter. However, cytokines appear to play an important role as an intrinsic part of both viral and secondary bacterial pathogenesis of sinus and middle ear infections.

SPECIFIC BACTERIAL INFECTIONS

The nonsterile areas of the upper respiratory tract are colonized by bacteria that are the indigenous flora of the adult nose. Staphylococcus aureus is found in the nasal vestibule of 25 to 40% of adults. The posterior nasopharynx of adults harbors Streptococcus pneumoniae (15–25% of people), Haemophilus influenzae (6–40%),

Streptococcus pyogenes (6%), and other Staphylococcus species (12%).These are also the major pathogens found in infected sinuses of adults. Moraxella (Branhamella) catarrhalis is a frequent etiologic agent of acute infections in children, and gram-negative bacterial infections are often seen in adults. Many infections are negative for bacteria when cultured by routine methods. Most of these are undoubtedly due to virus infections, but Chlamydia pneumoniae, Mycoplasma pneumoniae, and

Legionella are suspect organisms as well. Fungi are occasional causes of upper respiratory infections, especially in cases of diabetes mellitus or immunosuppression by either disease or medical intervention. In the next sections we will discuss some of these organisms in more detail.

STREPTOCOCCUS PNEUMONIAE

This gram-positive aerobe is of overwhelming importance in infections of the upper respiratory tract. For this reason, it has been studied intensively. In fact, the study of the pneumococci has played an important role in the development of the field of molecular biology, as well as elucidating much of our understanding of the virulence of microbes. Studies of pneumococcus provided the first clear evidence that deoxyribonucleic acid (DNA) was the genetic material. Experiments showed that DNA was able to transfer the information required for capsular synthesis from encapsulated to noncapsulated strains. Research into understanding of serological types has clarified much of the epidemiology of this pathogen.Work on the mechanism of antibiotics elucidated the molecular target of penicillin, as well as concepts of tolerance to cell wall antibiotics. More recently, studies of the virulence of pneumococcus have led to new concepts regarding the role of the external capsule, the binding of the organism to human cells, and the role of the bacterial cell wall as a factor in human disease. The knowledge gained from study of this

bacterium overshadows our understanding of other human pathogens and has pointed the way toward a greater comprehension of bacterial virulence in general.

The process of colonization and pathogenesis will be described in some detail for the pneumococci. Specific information on other common organisms that cause respiratory tract infections, as well as ways they differ from the pneumococci, will then be discussed.

Colonization

We now know that, for pneumococcus, as well as for many other microbes, binding to a human cell is the initial requirement for disease. Studies of the pneumococci have revealed that they may exist in two major phase variation types as distinguished by colony appearance: transparent and opaque.These variants possess different affinities for nasopharyngeal epithelial cells. The transparent colony types bind to host-cell sugar residues with between 102- and 106-fold more efficiency than the opaque types. There is strong evidence that glycoconjugate molecules on the membrane of the host cell serve as receptors because disaccharides can compete experimentally for binding to the cell surface.The primary site of binding of pneumococcus is the nasopharynx. In both children and adults, colonization may last up to several months without symptoms. It has been estimated that up to 90% of children may serve as carriers in the first 2 years of life.

Once bound, the colonizing organism may multiply locally to establish a stable colony. In the case of a capsulated strain, the organism is able to avoid ingestion by polymorphonuclear (PMN) cells that are attracted toward it for elimination.The capsule, although necessary for bacterial survival at this phase, does little to incite an inflammatory response by the host.

Pneumococci can also penetrate deeper into host tissues. Whether such penetration occurs by passage through the epithelial cells by endocytosis or between cells is unknown, but either mechanism may be operative as shown by studies of other pathogens. Antibody response to bacterial capsular polysaccharide occurs with colonization or asymptomatic invasion and is protective, maintaining colonization without evidence of disease. Exposure to a new serotype, or inflammation caused by a viral upper respiratory infection, may alter the host–parasite relationship and lead to acute infection.

Inflammation and Pathogenesis

In vitro, activation of epithelial cells by cytokines IL-1 or TNF- (two of the cytokines produced during inflammation) alters host-cell surface molecules. These

cytokines increase the density of platelet activating factor (PAF), which facilitates the binding of the bacterium, thus furthering colonization and increasing the likelihood for penetrating to deeper host tissues. This series of events is especially true for pneumococcal pneumonia, and presumed true for systemic bacteremia as well.

The cell wall, a macromolecule composed of several glycopeptides, has potent biological inflammatory activity. Isolated and purified pneumococcal cell wall is capable of eliciting an inflammatory response in the lung, the cerebrospinal fluid, and the middle ear. By analogy, initiation of inflammation of the paranasal sinus by pneumococcal cell wall constituents would also appear likely.

Initially, cell wall–induced inflammation causes separation of epithelial and vascular endothelial cell–cell connections.This results in vascular engorgement, leakage of serous fluid, attraction of PMNs, and induction of the inflammatory cytokines TNFand IL-1, all manifestations of acute bacterial-induced inflammation. It also activates complement by both classic and alternate pathways. Bacterial viability is unnecessary to induce these events. Killed encapsulated strains are capable of eliciting the full inflammatory response. Pneumolysin, a 53 kD bacterial toxin, is released as the host inflammatory response lyses the bacteria, resulting in further activation of inflammation, further toxicity to host cells, and amplification of the effects of the bacterial infection. Indeed, the concept that modulating the host response to pneumococcus-induced inflammation with corticosteriods, to minimize the effects of the infection, has now been incorporated into clinical treatment of pneumococcal meningitis in children.

In summary, the pneumococcus, once having achieved a successful colonization, is capable of being trapped in the closed spaces of the nasopharyngeal sinuses or the middle ear. This could be caused by inflammatory swelling of the osteomeatal complex or the eustachian tube, perhaps following a viral infection. Once there, release of cell wall substances results in additional inflammation, further perpetuating the damage done by host response mechanisms. The organisms may be localized by the host to the tissues involved initially, or may extend to the lung or the blood stream in a potentially fatal infection.

HAEMOPHILUS INFLUENZAE

First identified as a pathogen by Koch, this facultative gram-negative, often pleomorphic, bacillus has long been identified as an important human pathogen. Generally described as an encapsulated bacterium, serotyping has

identified six types of H. influenzae based on capsule antigenicity. The most important type clinically is type B. It causes most invasive diseases, including meningitis, pneumonia, cellulitis, sepsis, arthritis, and osteomyelitis. However, nonencapsulated strains are of great importance in infections of the ear, nose, and throat, particularly otitis media, sinusitis, epiglottitis, and conjunctivitis. Nonencapsulated strains also can cause chronic bronchitis and pneumonia.

Primarily found as a colonizing agent of the human respiratory tract, the nonencapsulated organism is carried asymptomatically for months at a time in the throats of 60 to 90% of infants and young children. In contrast, carriage of the encapsulated type B strain is less than 5%. Rates of colonization are lower for older children and adults.

Children under age 6 months have passively acquired maternal antibodies to type B, and only after age 2 does a child’s immune system produce protective antibodies against the H. influenzae capsule. The period between ages 6 months and 2 years constitutes the time of greatest incidence of type B–induced disease. Recently, vaccination with capsular type B polysaccharide conjugated to a protein carrier has successfully immunized children in this age group.This has resulted in a major reduction of serious Haemophilus type B–induced disease as well as colonization in children.

Microbial transmission occurs from an infected (colonized) patient to the nasopharyngeal mucosa of a nonimmune individual. Several modes of binding have been identified. Specific sugars can mediate binding of H. influenzae fimbriae (specific bacterial cell surface organelles) to the mucous layer. However, nonfimbriated bacteria can also bind to the mucous layer. Haemophilus also binds directly to the surface of epithelial cells by mechanisms that have not yet been determined. Both capsulated and noncapsulated strains bind efficiently.

Once binding has occurred, the capsule appears to be of major importance in maintenance of colonization. H. influenzae is protected from secreted antibodies by bacterial IgA-specific proteases, and the capsule provides resistance to host polymorphonuclear leukocytes. The capsule is also important for invasion. Experimental studies of translocation across respiratory epithelium show that organisms whose capsule contains polyribosylribotol phosphate have pathogenic properties lacking in those with capsules of other serotypes or noncapsulated strains. It is this process of binding, followed by local invasion of the nasopharynx, that results in infection of the uvula and epiglottis. If the invading Haemophilus reaches the bloodstream, capsule-mediated resistance to

phagocytosis allows bloodstream survival, high-grade bacteremia, and invasion of other tissues.

As with other microbes that predominantly attack by the respiratory route, effective mucociliary clearance is of major protection. Therefore, diseases that affect cilia, as well as environmental influences such as passive smoking, reduce this protection.As with the pneumococci, mucosal edema and impaired mucociliary clearance caused by viral infections result in trapping of Haemophilus in sinus and middle ear cavities, in turn resulting in bacterial sinusitis and otitis media.

Like other gram-negative organisms, all strains of Haemophilus express lipopolysaccharide (endotoxin). Along with other cell wall components, endotoxin induces an inflammatory response that both impairs ciliary function and disrupts the respiratory epithelium. It is in these areas of damaged epithelium that invasion appears to occur, resulting in both local inflammation and bacterial seeding of other host tissues.

In summary, Haemophilus organisms, both capsulated and noncapsulated, are able to bind to upper respiratory tract mucus and epithelium. If mucociliary clearance is compromised, or if the epithelium is damaged, the bacteria survive and successfully colonize the mucosa, further preventing successful mucociliary clearance by phagocytic host defenses. Invasion of the respiratory epithelium may be facilitated by a host inflammatory response to virus infection or by immune deficiency, as with acquired immunodeficiency syndrome (AIDS). Transport to lung tissue, especially in patients with chronic obstructive pulmonary disease (COPD), allows access to anatomically altered pulmonary tissue. This successful human pathogen thus has evolved to invade sterile tissue, by overcoming both static and acquired host defenses, to result in several well-recognized pathological consequences in both children and adults.

MORAXELLA (BRANHAMELLA) CATARRHALIS

This gram-negative coccus resembles Neisseria species and was classified as Neisseria catarrhalis for many years. However, DNA studies showed a lack of genetic relatedness, and it has now been classified as a separate genus (Moraxella) within the family Neisseriaceae.The genus is now split into two subgenuses: Branhamella (coccal organisms) and Moraxella (more rod shaped).

These organisms are so common in the human oral flora that they have been considered normal commensals. However, they clearly can be etiologic agents of sinusitis, otitis media, mastoiditis, and pneumonia. Colonization of the nasopharynx occurs in up to 7.4% of adults and is increased in winter months. In contrast, 50% of

children between 3 and 12 years of age carry Moraxella. This value is slightly higher (63%) in children with otitis media.

Transmission occurs from patients with upper respiratory infections to colonize the susceptible (nonimmune) individual.An increase in susceptibility to M. catarrhalis infection is apparent in disorders of humoral immunity. However, most adults have both immunoglobulin (Ig) G and IgA Moraxella-reactive antibodies that correlate with protective immunity. A rise in both serum and local antibody levels to bacterial outer membrane proteins (OMPs) is detectable with M. catarrhalis–documented otitis media. However, complete protection may not occur in otitis-prone children because colonization is so frequent in this group.

Moraxella, like other gram-negative organisms, possess lipopolysaccharide (endotoxin), which induces inflammation. Localized diseases, such as otitis media and sinusitis, are common with this bacterium, but disseminated disease is rare. This implies either that humoral immune resistance is sufficient to curtail most invasive infections or that the reduced frequency of invasion is due to lack of the virulence factors seen in Pneumococcus and Haemophilus. However, tracheobronchitis and pneumonia do occur, especially in older adults with COPD.This would suggest that Moraxella does have at least some potential for virulence.

OTHER BACTERIA

S. pneumonia, H. influenzae, and M. catarrhalis are the most frequent community-acquired infections causing bacterial sinusitis and otitis media. However, there are several other bacteria that are human pathogens of the upper respiratory tract.These less often encountered organisms are usually found in chronic upper respiratory tract infections, infections of immunocompromised hosts, and nosocomial infections.They usually are found as polymicrobial infections, not necessarily preceded by viral upper respiratory infections (URI), and complicated by prior use of multiple antibiotics, immunocompromising drugs, and/or mechanical obstruction by nasotracheal or nasogastric intubation. In all of these circumstances, comorbidity of disease and other medications is common, and the ability to respond with innate as well as acquired host defenses is diminished. We will briefly discuss a few of these organisms in the next section.

Staphylococcus Aureus

This aerobic gram-positive coccus normally colonizes the mucosa of the anterior nares, but it can spread from

there past the mucous membranes to contaminate other areas of the body. It binds to nasal mucus, facilitating its colonization and resulting in high rates of colonization (up to 30%), which may be either intermittent or prolonged. It does not bind to nasal mucosal cells, but rather to endothelial cells of the vascular system.

S.aureus is particularly common in patients with surgical or traumatic breaks in mucosa or skin, or decreases in polymorphonuclear leukocytes. These infections are often local, with a tendency toward abscess formation, but can become systemic with invasive and “metastatic” potential to bone, muscle, and heart. The organism possesses a capsule and secretes a variety of enzymes (coagulase, hyaluronidase, protease, nucleases) and toxins (hemolysins, toxic shock, toxin, and epidermonecrolysin) that are associated with systemic syndromes. Added to these virulence factors, the recent development of several forms of antibiotic resistance, along with the occurrence of S. aureus in compromised hosts due to intravascular and prosthetic devices, results in both severe local and systemic disease. Not clearly understood is its ability to establish chronic infections. This is presumably the result of multiple depressed local host defenses as well as its ability to persist in host phagocytes.

Acute ear, nose, and throat infections are rarely seen. Chronic infections, especially of nasal sinuses and middle and external ear, are more common. Infections are frequently mixed with anaerobic and gram-negative organisms that are also part of the normal flora of the mouth. However, S. aureus is usually the sole pathogen in acute parotid gland infection, especially in the elderly.

Pseudomonas Aeruginosa

This aerobic gram-negative bacillus is not normally a part of the endogenous flora of the human host. It has gained notoriety as an opportunistic pathogen, adhering through pili to gangliosides on human mucosa and other cell surfaces. A ubiquitous organism associated with warm, moist environments, it also possesses multiple virulence characteristics that facilitate human infection. Endotoxin, common to all gram-negative bacterial cell walls, can induce destructive host inflammation. In addition to endotoxin, it possesses a series of exotoxins. Exotoxin A affects protein synthesis of human cells through adenosine diphosphate (ADP)-ribosylation of elongation factor 2, in precisely the manner found for

Corynebacterium diphtheriae. This toxin causes local cell death. In synergy with its co-cytotoxin, a pore-forming toxin of human cells, exotoxin A impairs host PMN function.These toxins, and the proteases and hemolysins secreted by this organism, facilitate invasion.

Commonly associated with plastic catheters, and selected for by surgical tissue breakage, P. aeruginosa is a frequent nosocomial organism. It causes local infections of paranasal sinuses of noncompromised hosts and severe infections in patients compromised by the obstruction of nasotracheal tubes, impaired mucous membrane clearance, and neutropenia.These infections have become more difficult to treat because of the selection for antibiotic resistance in hospitalized patients. Classic infections of the ears, especially malignant external otitis, are seen in elderly diabetic patients, again in those with decreased normal host defenses. Simple external otitis, auricular perichondritis, and chronic infections of nasal sinuses or otitis media are also well described.

Klebsiella Species

Other facultative gram-negative bacilli share virulence factors of capsules, endotoxins, exotoxins, and invasiveness. Most Klebsiella infections are due to K. pneumoniae; however, of particular note is K. rhinoscleromatis, of which little is known about specific virulence factors. This organism is capable of chronic infections of the pharyngeal mucosa, perhaps associated with its large antiphagocytic capsule and its intrinsic resistance to intracellular killing. Often seen in immunocompromised hosts, it causes an indolent, chronic, granulomatous process that appears in upper respiratory tissue as a scarring, obstructing lesion, often resistant to prolonged antibiotics, and often requiring surgical removal. K.ozaenae causes atrophic rhinitis, a disease seen more in underdeveloped countries, particularly of Southeast Asia.

Anaerobes of the Oropharynx

Most bacteria in the normal flora of the human oropharynx are anaerobes, numbering between 10and 100-fold more abundant than aerobes. These grampositive and -negative organisms are associated with a variety of chronic infections of the ear and sinuses and of dental infections. They also cause complications by spreading to the lung and the brain.These infections are usually polymicrobial, also including many of the aerobes already described.

The organisms express several virulence factors that lend to their extension from the mouth. Many possess antiphagocytic capsules, endotoxins, toxins that attack host defenses, and exoenzymes capable of tissue destruction. The list of organisms, present in all standard treatises on oral microbes, includes Peptostreptococci, Fusobacteria, and Prevotella (previously called Bacteroides melaninogenesis).This collection is variously aerotolerant,