CHAPTER 11

FUTURE DIRECTIONS

Following my gathering of source material over the years and writing this monograph, it became obvious to me that there are a whole host of unanswered research questions related to the structure and function of the ET system and its role in otitis media and related diseases and disorders. Thus, this second edition is still a work in progress that hopefully will be further updated as outcomes of future research become available. Immediately following the eighth quadrennial international symposia on otitis media—the first meeting was in 1975—David Lim and I, along with our other colleagues in the field from around the world, convened to review the progress in research in otitis media during the previous four years and to identify future research goals. The most recent research abstracts, prepared after the 18th International Symposium in 2015, were published on line by the International Society for Otitis Media (ISOM).¹ Those abstracts of panel reports cover various aspects of research in otitis media, such as immunology, microbiology, molecular biology, and vaccines, that are vitally important toward improving our knowledge base of middle-ear disease. It did address the ET, middle ear, and mastoid anatomy and physiology, pathophysiology, and pathogenesis discussed in this monograph. The report of that panel’s review of the previous four years of research and their recommendations for future research goals were published online by the International Society for Otitis Media.¹ From my perspective, the following are additional important research questions that need to be answered in the future.

Epidemiology

As described in Chapter 1, there are certain risk factors for development of otitis media that are related to the ET system, such as infants being more prone than older children and adults because their tubes are structurally and functionally immature, whereas other factors are not directly related, such as a lack of breastfeeding. Still others are most likely not related at all, such as boys having a higher incidence than girls. Some factors have convincing evidence of being a risk (genetic predisposition), whereas other risk factors are not evidence-based (gastroesophageal reflux). For certain racial groups, we are not certain why they present a risk of developing otitis media; thus, we need further study to enhance our knowledge of how these risk factors impact susceptibility for middle-ear disease. This, in turn, will increase our understanding of the pathogenesis of otitis media in general and impact our understanding and management of those individuals identified as being prone to this common disease.

Certain Racial Groups and Special Populations

Investigations into certain ethnic groups and special populations who are at higher risk of otitis media could help us understand more about the pathogenesis of the disease, which could lead to therapeutic interventions and methods of prevention. Studies of groups with a low risk of developing middle-ear disease could also be informative.

High Incidence of Otitis Media

Some special populations have an extraordinarily high incidence of middle-ear disease; thus, histologic studies of temporal bone specimens of Aborigines of Australia^2,3 and certain Native North Americans⁴ should be conducted. Also recommended is the assessment of the ET function in these special populations with high incidence of middle-ear disease and comparing these findings with function in individuals without the disease. Other target populations are Inuits of Greenland^5–7 and certain individuals who are natives of the South Pacific, such as those who live in the Solomon Islands^8–10 and Micronesia,^11,12 and the Maoris of New Zealand.^13,14 All of these groups have been identified as having high rates of not only otitis media but also chronic perforation of the tympanic membrane and chronic suppurative otitis media (see Pathology and also Chapter 10, “Role in Certain Complications and Sequelae of Middle-Ear Disease”).

Low Incidence of Otitis Media

At the other end of the spectrum are those populations that have a purportedly low risk of developing otitis media. Studies of their ET structure and function could shed light on why their rates are lower than other populations. A prevalence study of children in multiracial schools in Hong Kong found that Chinese children had a statistically lower prevalence rate of otitis media with effusion than their white schoolmates.¹⁵ But another study from Hong Kong from the same investigators reported that Chinese children had similar rates as reported from other countries.¹⁶

Another potential special population for further study is those who have cystic fibrosis as they apparently have a lower rate of recurrent and chronic middle-ear disease than children without the disease.¹⁷ Further investigation into the prevalence, incidence, and natural history of middle-ear disease should be conducted to confirm this report. Also, if these children do have a lower rate, they should also be studied. Assessment of temporal bone pneumatization, similar to the study reported by Todd and Martin,¹⁸ could shed light on why these children have chronic sinusitis as an almost universal disease but have an unusually low rate of chronic otitis media with effusion. Unfortunately, these children do not have a long survival rate; thus, histopathologic studies of their temporal bones could potentially render new insights into this dilemma. Evaluation of ET function could also help, but because these children rarely need tympanostomy tube placement, direct measurements of ET function would not be feasible. Sonotubometry, Bluestone’s nine-step tympanometry test, or testing in a pressure chamber could be used when the tympanic membrane is intact and the middle ear is without effusion (see Chapter 8, “Diagnosis and Tests of Function”).

In my 50 years at the Children’s Hospital of Pittsburgh, which has a very large clinic devoted to infants and children who have cystic fibrosis, I have inserted tympanostomy tubes into only two siblings. In my experience, middle-ear disease is almost nonexistent in these children. A recent hypothesis is that it is related to chloride channels, but this remains to be proven.

Pacifier Use and Position in Infants

A former research panel reported on epidemiology, natural history, and risk factors and identified the risk of use of a pacifier for otitis media as being a future goal for research.¹⁹ It is my opinion, not based on any clinical study, that the pacifier may cause abnormally high negative pressure to develop in the nasopharynx when there is nasal obstruction (the Toynbee phenomenon), such as can occur during periods of a viral upper respiratory tract infection. This is a hypothesis that should be tested by assessing open- and closed-nose nasopharyngeal and middle-ear pressures and ET function when an infant pacifier is in place.

The observation that the prone sleeping position in the infant is a risk factor for otitis media is another avenue for investigation in which several theories have been postulated, but none have been tested and reported on. One hypothesis could be differences in the function of the tube when in the prone position compared with the supine position. Similar testing of pressures in the nasopharynx and middle ear during open- and closed-nose conditions, as suggested previously, when a pacifier is in an infant’s mouth might prove revealing. I would also recommend including nasal rhinometry testing because there may be a difference in nasal-airway resistance in infants related to position.

Genetic Predisposition

There is now ample evidence, primarily from studies in twins, that there is a genetic susceptibility for otitis media.^20,21 There are certain high-risk ethnic populations in which there is some evidence of structural and functional abnormalities in the ET; there may be genes controlling the tubal system (e.g., craniofacial skeletal differences) in the pathogenesis. Similar to my suggestion to investigate possible protective genes in individuals with cystic fibrosis, targeting genetic research toward high-risk ethnic populations, including a search for a genetic association with the ET system, is a future goal.

Anatomy

I recommend studies to determine the normal anatomy of the lymphatic system of the tubal system for future research. But, other aspects of the system’s anatomy could be investigated that might lead to better understanding of the pathogenesis of middle-ear disease.

Human Temporal Bones

Chapter 3, “Anatomy,” describes several studies from the laboratory at the University of Pittsburgh by the late Ismu Sando, MD, that involved human temporal bone specimens in which the normal anatomy of the ET system was defined, but other potential investigations could prove enlightening. Studies involving temporal bone specimens of individuals who have evidence of middle-ear disease (acute otitis media and chronic suppurative otitis media, cholesteatoma) could be compared with normal anatomic structures (specimens from individuals without middle-ear disease). It is possible that there may be abnormalities similar to those identified in specimens that had a cleft palate, especially since tubal manometric function tests in the child with a cleft palate and the child without a cleft palate with chronic otitis media with effusion had similar outcomes (failure of tubal opening and tubal constriction).²²

Imaging the ET System

The normal structure of the tubal system has been studied in postmortem temporal bone specimens, but there is a need to assess anatomy in vivo in both individuals without otitis media and with middle-ear diseases and disorders. Even though radiographic studies have been conducted in the past in individuals with and without otitis media,²³ these methods were invasive, given the amount of radiation in fluoroscopy. This inhibits use in children, especially when serial examinations could be advantageous. A potential avenue of research would be to use the latest imaging methodology, possibly with contrast, to show the anatomy of the system, and as recommended by the 2015 research panel, the mastoid gas-cell system. It might be possible to insufflate the newer contrast materials into the tube to visualize the tubal system. If noninvasive methods using magnetic resonance imaging (MRI) were to be successful in individuals without middle-ear disease, such as in adult volunteers, these outcomes could be compared with the outcomes of imaging in patients with the disease. These studies could also be combined with assessments of function of the ET in the same subject; thus, studies of structure and function related to physiology and pathophysiology could be forthcoming. Ideally, with advances in imaging technology, dynamic images could permit imaging of both function and structure.

Physiology

The panel also recommended research goals related to the physiology of the ET system that included studying ion and fluid transport in the system’s mucosa, developing experimental and computational tools (also, included in the 2015 report) to assess the system’s structure–function relationships, and determining the relative contributions of tubal gas transfer and middle-ear mucosa in the maintenance of middle-ear gas composition and pressure. (The 2015 panel stressed the need for these assessments for the mastoid gas-cell system.) These are excellent goals to achieve through future research because the pressure regulation function is the most important of the three functions; however, there are other research directions to achieve because there are two other major physiologic functions of the ET system: protection and clearance.

Pressure-Regulation Function

One of the panel’s goals was to assess the ET system (and as recommended by the 2015 panel, the mastoid gas-cell system) in modulating partial pressures of gas in the middle ear. However, the analysis of middle-ear gas composition in humans and animals is based on an invasive methodology. If the gas composition of the middle ear–mastoid gas-cell system could be determined by noninvasive methods, then the assessments would be more physiologic. Ideally, a noninvasive probe in the ear canal could identify the individual gases and the partial pressures in the middle ear; thus, physiologic changes in the middle-ear gas composition and pressure could be better evaluated in different age groups, during alterations in body position and sleep, and when there are common potential pathologic challenges to the system, such as viral upper respiratory tract infections.

Protective Function

A limited number of studies have assessed the protective function of the ET system, and they have been relatively invasive using fluoroscopic radiographic methodology and contrast material to determine if the media instilled in the nasopharynx entered the middle ear.^22,23 The invasive nature of radiography notwithstanding, contrast material is not a physiologic or pathophysiologic secretion; thus, if dynamic imaging could be developed in which one of the newer contrast agents, or one to be developed in the future, could target secretions, the protective function could be evaluated in a more physiologic manner than the relatively crude methods employed in the past.

Clearance Function

The panel did target clearance function of the tubal system as a future goal but only as it relates to possible therapeutic interventions. Honjo and colleagues elucidated some of the physiologic aspects of middle-ear clearance, especially the pumping action of the tube during opening and closing, but these investigations were conducted using potentially invasive radiographs and nonphysiologic contrast material.^24,25 If new noninvasive methods with more physiologic contrast agents could be developed, clearance function would be better understood. Contrast agents that target secretory cells of the middle-ear cleft that could be visualized using imaging would be an advance, especially if the imaging could be dynamic to show function.

Pathophysiology

The panel recommended an attempt to identify the structural properties of the tube that govern its function in an effort to target treatment; however, the report did not specify which properties might be candidates for investigation related to the pathophysiology of the ET system that are probably involved in the pathogenesis of middle-ear diseases and disorders.

Failure of Pressure-Regulation Function

Several abnormalities of the human tube system (some of which have been replicated in animal models) prevent physiologic regulation of middle-ear pressure in humans who have middle-ear diseases and disorders and are candidates for investigation that could lead to corrective action in the future.

Constriction of Tubal Lumen

As documented in Chapter 5, “Pathophysiology,” constriction of the tube appears to be a common pathophysiologic finding in humans who have recurrent otitis media and chronic otitis media, as well as in certain animal models of middle-ear disease.²⁶ Determining the etiology of constriction is an important future direction so that corrective action can be developed. Focus would be directed at the paratubal muscles, that is, tensor veli palatini and levator palatini.

Because constriction is common in the patient with a cleft palate and in the cleft palate animal model, this deformity at the proximal end of the tubal system could be a promising candidate for study in both humans and animals. Also related to the patient with a cleft palate, determining the cause of high tubal resistance is a desired goal (see Dysfunction Related to Cleft Palate).

Functional Obstruction Owing to Increased Tubal Compliance

Constriction of the tube is a functional obstruction, but there is evidence that the tube can be functionally obstructed in certain humans with middle-ear disease in whom constriction does not appear to play a role, in that the tube fails to dilate (open) during swallowing. In the monkey model of functional obstruction, surgical transection and expunging the tensor veli palatini muscle resulted in constriction.²⁷ Inoculation of botulinum toxin into the muscle resulted in functional obstruction (and middle-ear effusion), but constriction did not occur.²⁸ Functional obstruction may be due to abnormalities of paratubal muscle function, related to defective tubal cartilage, or to other defects yet unknown. The tube appears to be too compliant (floppy). The etiology of functional obstruction is an important future direction. Developing and testing tubal compliance with the methodology recently reported by Ghadiali and colleagues are avenues for future investigation.²⁹

Toynbee Phenomenon

As suggested earlier, in targeting for research the mechanisms related to pacifier use in the infant causing otitis media, abnormal pressures generated in the nasopharynx during closed-nose swallowing are postulated to be a possible pathophysiologic condition. I have termed this the Toynbee phenomenon. This hypothesis has not been adequately investigated in humans and animal models. Despite the findings of abnormal middle-ear pressures documented in the ferret with bilateral nasal obstruction by Buchman and colleagues,³⁰ the nasopharyngeal pressures have not been documented. Also, related to nasopharyngeal obstruction owing to space-occupying masses in the nasopharynx (adenoids or post–nasal packing), the hypothetical effect of a smaller volume of nasal pharyngeal space related to the pressures generated could increase the magnitude of the abnormal pressures developed during swallowing. This is related to Boyle’s law. These hypotheses are testable in the animal model with the aid of a pressure transducer in the nasopharynx positioned at the pharyngeal orifice of the ET and another in the middle ear. Tympanometry could also be used to monitor middle-ear pressure, or a transducer could be placed in one ear, with tympanometric recordings obtained in the contralateral ear.

Another potential mechanism associated with the Toynbee phenomenon is closed-nose thumb sucking.³¹ This is another pressure-related abnormal mechanism that can be investigated to shed light on nasal obstruction related to the ET system.

Other Causes of Abnormal Pressures at the Nasopharyngeal End of the Tubal System

A possible mechanism involved in a defective pressure regulation system is when abnormally high negative pressure develops in the face of a tube that fails to completely close passively during habitual sniffing.^32,33 Sniffing can result in negative pressure that inhibits tubal opening, or the abnormal pressures can be transmitted to the middle ear with resultant middle-ear underpressures. Even though this mechanism is uncommon in infants and young children—the age group at highest risk of otitis media—habitual sniffing is not uncommon in adults. The pathophysiology of this condition should continue to be a research goal in adults.

Abnormal nasopharyngeal pressures may also develop when an infant sucks on an unventilated milk bottle. This should be investigated in the future to confirm the observations by Brown and Magnuson³⁴ and to develop bottles that would not create unphysiologic delivery of milk to the baby. We did not evolve as a species sucking on a bottle of milk because the breast is physiologic and bottles are not.

Loss of Protective Function of the System

There are four major abnormalities that can impair the protective function of the tubal system (described in Chapter 5):

       1.  The tubal lumen is abnormally patent (too open).

       2.  The tube is too short.

       3.  Abnormal gas pressures develop at either end of the tubal system.

       4.  The middle ear is not intact, that is, the system is too open at its distal end.

Related to a tube that is too short, which is universal in infants and young children, growth and development should correct the problem; if they do not (cleft palate, Down syndrome), there is little that can be done to lengthen the tube. However, research into other anatomic and functional abnormalities may improve the tubal system in those who have lifelong problems.

The most severe form of abnormal patency of the ET is a chronic patulous tube. The causes of the tube being abnormally patent have not been adequately assessed. Using newer methods (such as imaging) to assess the structure and function of the tubal system in these patients may yield information that would shed light on this pathophysiologic abnormality.

Because closed-nose swallowing (the Toynbee phenomenon) can result in either positive or negative pressure (or both) in the nasopharynx being transmitted to the tubal system, positive pressure could insufflate nasopharyngeal secretions into the middle ear. This is in addition to the possibility of negative pressure causing impaired pressure regulation. Indeed, in the ferret model of bilateral nasal obstruction by Buchman and colleagues, persistent abnormal positive pressures were recorded in the middle ears of the animals.³⁹ Related to fluid dynamics through a collapsible tube, a liquid flows more readily than a gas. The possibility of secretions being driven into the middle ear should be added to the research goals suggested earlier when the Toynbee phenomenon is being investigated.

The most common cause of abnormal middle-ear negative pressure is secondary to ET obstruction, either anatomic (mechanical) or functional or both, that occurs during a viral upper respiratory tract infection.⁴⁰ Abnormal middle-ear negative pressure resulting from extreme changes in ambient pressure (airplane flying, scuba diving, pressure chamber) occurs, but not as frequently as during the onset of a common cold. Politzer’s hydrops ex vacuo theory is related to the pathogenesis of middle-ear effusion (see Politzer’s Hydrops Ex Vacuo Theory, Viruses, and Bacterial Pathogens in the following section), but underpressures in the middle ear could also potentially aspirate unwanted nasopharyngeal secretions into the middle ear. Except for unpublished experimental data in our laboratory, this mechanism remains hypothetical and should be investigated in an animal model to confirm or reject the hypothesis. In addition to creating middle-ear underpressures (botulinum inoculation into the tensor veli palatini) when the nasopharynx has colonized pathogenic bacteria to determine if a middle-ear infection occurs, histologic studies of the temporal bones and ET to assess the tubal mucosa are a possible laboratory investigation for the future.

Impairment of Clearance Function of the System

As suggested earlier for future goals related to physiology, a more physiologic method to assess clearance would enhance our knowledge of normal function and would also aid in studying factors that impair clearance (see Table 5–4).

MRI that could be dynamic and using contrast agents that target mucociliary cells would be an option. Also, most of the current reports of studies that have examined the role of impaired clearance in the pathogenesis of middle-ear disease have concluded that in otherwise healthy individuals who have otitis media, abnormal clearance is not involved in the initial cause but contributes to persistent middle-ear effusion. This remains a hypothesis to be tested: what is the role of impaired clearance in the middle-ear cleft in the pathogenesis of otitis media?

Dysfunction Related to Cleft Palate

As described in the appropriate chapters in this text, there are documented abnormalities of the anatomy of the ET in temporal bone specimens from individuals who had a cleft palate. The proximal end of the system is open (an open cleft) in cleft palate cases. This is a pathophysiologic defect that has not been assessed in terms of nasopharyngeal pressures during open- and closed-nose swallowing compared with subjects whose palates are normal. Similar studies in the same patient following palate repair (and type of repair) could be enlightening. Improved methods of assessing function that are more physiologic than are currently available would be useful in determining the role of the unrepaired and repaired palate in the pathogenesis of otitis media in this high-risk special population. Because tubal constriction during swallowing has been identified in these patients, the etiology of this phenomenon should be included as a specific aim.

Pathogenesis

Related posts:

Introduction and Overview Pathology Role in Certain Complications and Sequelae of Middle-Ear Disease Physiology Anatomy Diagnosis and Tests of Function

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