How extra-esophageal reflux arises. Arrows show path of reflux out of the stomach.
UES=upper esophageal sphincter and
LES = lower esophageal sphincter.
Intermittent reflux of stomach contents into the esophagus is a normal physiological process. It occurs because of transient relaxation of the sphincter located where the esophagus connects to the stomach. Gastroesophageal reflux is considered to be abnormal or pathologic if it produces symptoms, and is then referred to as gastroesophageal reflux disease (GERD).
GERD is a well-documented and common occurrence among adults, but during the last twenty years, it has been increasingly recognized as a clinical entity among children and infants. GERD most commonly results in vomiting, abdominal or chest pain, heartburn, arousal from sleep, and regurgitation (spitting up).
If gastric reflux reaches the level of the pharynx (throat) by moving past both the lower and upper esophageal sphincters (Figure 1), it is termed extra-esophageal reflux (EER). Evidence is accumulating that EER can be a factor in disorders of the upper and lower airway in both adults and children (reviewed in 1, 2).
Infants may be especially predisposed to reflux-related problems because they have relatively more reflux events than adults. In a survey of 948 infants, it was found that nearly 50% of babies less than 3 months old had reflux events that resulted in regurgitation or spitting up at least once a day (3). The number increased to a maximum of 67% of 4-month-olds. By 1 year of age, percent of infants with daily regurgitation events was less than 5%.
Although symptoms of GERD are fairly easy to diagnose, extra-esophageal reflux is a more difficult diagnosis. “Silent reflux” or atypical reflux in which the patient has no gastrointestinal symptoms is very common in children with upper and lower airway complaints. Determining the involvement of EER requires verifying its presence by some diagnostic methodology.
A methodology commonly used to determine whether a person has gastroesophageal reflux is to measure acidity by means of a pH-detecting “probe” placed at the lower esophageal sphincter (LES, Figure 1). However, traditional pH probes placed to detect acid reflux at the LES can easily overlook EER in the child. A significant percentage of children who have EER show normal pH data from probes placed at the LES (4, 5). Therefore, a better approach to EER diagnosis is to monitor pH in the pharynx or upper esophagus. Although pharyngeal probes provide excellent measures of EER, they are uncomfortable for some children because the procedure involves insertion of rubber tubing through the nose. Parents also shy away, especially once they learn the tubing must stay in the nose for 24 hours.
An innovative alternative for diagnosing EER is the Bravo pH capsule. This capsule is wireless, and is placed in the upper esophagus just behind the upper esophageal sphincter (6). The Bravo system has been a very good way to measure upper esophageal reflux without any tubing.
In this chapter we focus on how EER results in damage to cells and tissues of the larynx and upper respiratory tract. We also discuss a number of ear, nose, throat, and laryngeal disorders commonly encountered in pediatric patients and examine evidence for the role of EER in causing or exacerbating these conditions.
How Reflux Affects the Airway
The larynx, or voice box, acts as a two-way valve to prevent aspiration of food and liquids into the lungs during swallowing. During breathing, the larynx is open, allowing air to move in and out of the lungs via the trachea, but during swallowing, the larynx closes off the airway.
Even so, the proximity of the airway to the esophageal entrance makes the potential for reflux to enter the airway very high in certain situations. When a person is lying flat, refluxing gastric contents can readily flow into the esophagus to the level of the larynx and throat. Babies are especially prone to EER because their lower esophageal sphincter doesn’t reach maturity until 18 months and therefore doesn’t always function fully to keep gastric contents in the stomach.
Acid and the digestive enzyme pepsin are responsible for the damaging effects of reflux. Stomach tissue is most protected against their damaging effects, but even so, erosions and ulcers can develop. While not nearly as resistant to the effects of acid and pepsin as the stomach tissue, the esophagus is adapted to handle some acid exposure that occurs due to intermittent physiological reflux. Peristalsis, which is rhythmic, wavelike movement of the esophagus, helps push reflux back into the stomach (Figure 2A). The esophagus secretes mucus that forms a protective barrier against the corrosive effects of the reflux. The esophagus is also lined by a specialized layer of cells called stratified squamous epithelium that secretes bicarbonate ions, which can neutralize the acid (Figure 2B and C). Even these protective mechanisms in place, acid may still penetrate the epithelial layers and irritate nerve endings, which results in the sensation of “heartburn.”
Acid-protective mechanisms of the esophagus
A. Peristalsis pushes gastric contents back into the stomach.
B. Cross-section of esophageal epithelium shows glands that secrete a protective layer of mucus.
C. Closeup shows layers of stratified squamous epithelial cells, which secrete acid-neutralizing bicarbonate ions.
Unlike the stomach and esophagus, the respiratory tract is extremely sensitive to the damaging effects of gastric fluids. The respiratory tract is lined by a cell layer called pseudo-stratified, ciliated columnar epithelium, which is very different in structure from the epithelium in the esophagus (Figure 3). Respiratory epithelia possess tiny hairs called cilia that perform a protective function. The sweeping action of the cilia keeps the airway clear by removing mucus from the respiratory tract. The cilia also help eliminate infectious and allergenic materials from the body because any bacteria, viruses, dust, pollen or mold that float onto the cilia also are swept out of the airway.
When repeatedly exposed to reflux, the respiratory columnar epithelium sometimes will change into stratified squamous epithelium like that found in the esophagus (Figure 3). Although more resistant to the damaging effects of reflux, squamous cells do not possess cilia. By causing the loss of cilia, EER compromises an essential cleansing process in the respiratory tract.
Cellular structure of the upper respiratory tract.
A. Cross-section of respiratory epithelium.
B. Closeup of respiratory tract showing transformation of ciliated epithelial cells to unciliated squamous cells in response to EER.
Sometimes when explaining to patients the difference between the ability of the esophagus and the airway to tolerate reflux, we use the analogy of the esophagus being a rubber hose and the airway being tissue paper. While not entirely accurate, it does paint a picture of the relative sensitivities of the two.
Although direct irritation of the respiratory tract by acid and pepsin can bring about the signs and symptoms of airway disease, reflux can also have an indirect, or referred, effect on the airway even if it never leaves the esophagus. This indirect effect comes about because the esophagus and airway are connected to a common central nerve called the vagus. When acid refluxing into the lower esophagus interacts with special structures called receptors, nerve impulses can arc backwards along the vagus to cause spastic closure of the larynx (laryngospasm). This reflexive response of the airway to reflux is yet another way in which the body protects itself from aspiration.
A number of ear, nose and throat disorders commonly encountered in children and infants have been found to be associated with EER. For some disorders, the association is likely causative, that is, the acid and pepsin in reflux are directly responsible for the signs and symptoms associated with the condition. For other disorders, EER is not necessarily causative, but the presence of reflux can make the signs and symptoms much worse. In a few cases, it has been speculated that worsening of symptoms is because the condition increases the likelihood that reflux can escape the esophagus and get into the airway. In other words, rather than EER causing the condition, the condition causes EER. This section provides an overview of the signs and symptoms of laryngeal and upper airway disorders commonly encountered in pediatric practice and how EER can bring about or aggravate these disorders. The role of anti-reflux therapy in treating these conditions is also discussed.
Effects of EER on the larynx, or voice box
The larynx is anatomically just in front of the esophagus and therefore is very susceptible to the effects of EER. Multiple sites of the larynx can be irritated and cause a number of different signs and symptoms. Some of these include: chronic cough, hoarseness with or without vocal cord nodules, laryngeal ulcers, and vocal cord dysfunction.
Cough is one symptom commonly associated with irritation of the larynx. Cough is a protective reflex that removes irritants or infectious organisms such as those causing pneumonia. Irritants are detected by “cough receptors,” which are nerve endings located in the larynx and other parts of the respiratory tree. Receptors are also located in the naso- and oro-pharynx (throat), the sinuses, and the ears (7). Through coughing, the airway tries to relieve itself of its acid load as best as it can. However, persistent cough can itself further irritate the airway. EER is an important agent in chronic cough, that is, coughing that continues for 3-8 weeks. Excluding infectious diseases, EER is third most common cause of chronic cough in children and the most common cause in infants 0-18 months old (8).
Hoarseness is another symptom that can be associated with the deleterious effects of reflux on the larynx. Hoarseness is a general term for any abnormal voice quality, but voice quality can be further described as breathy or harsh, husky or rough, strident, or coarse. Though voice intensity varies with the amount of a air pressure against vocal cord resistance, voice quality is primarily determined by length, tension, strength of movement, mass, or position of the vocal chords (9). Any aberration of length or tension of the vibrating segment, mass, posture, or strength of the vocal cords may result in hoarseness. In a study of children aged 2-12 years old who had chronic hoarseness for more than 6 months, 70% of them were found to also have GERD (10). When researchers directly examined the vocal cords of these children, one child’s vocal cords looked normal, but the remainder had a variety of abnormalities that included cord swelling, nodules (Figure 4), and evidence of healing ulcerations.
Top and side views of the larynx afflicted with EER-associated conditions compared to a normal larynx. Top views are what an ENT physician would see looking down a child’s throat using a laryngoscope.
Arrows point to affected regions:
Vocal nodules, swellings on the vocal cords;
Laryngomalacia, collapse of the entrance to the larynx upon inhaling;
Subglottic stenosis, narrowing of the area below the vocal cords.
Furthermore, ear infections can be closely tied to food reactions. If your child is experiencing chronic ear infections and/or reflux, it’s time to examine diet as well as addressing medication!
Rhinosinusitis (nose and sinus infection)
Reflux may be a factor in inflammation of the nose and sinuses. Called rhino-sinusitis, this inflammation is caused by obstruction of the final common pathway of the maxillary, ethmoid, and frontal sinus tracts (Figure 6). Although infection is often present, it is not typically the primary underlying factorfor rhinosinusitis. Rather, infection occurs secondarily because the impaired drainage due to swelling, or edema, of sinus and nasal tissues creates an ideal environment for the growth of bacteria. Anything irritating the sinus and nasal tissues can result in swelling of tissues: Allergies, cigarette smoke, recurrent viral infections, and EER. Edema from EER is a common cause of sinus obstruction (22). People with chronic sinus problems often have corrective surgery. However, Bothwell et al. (23) found that 89% of children who underwent reflux therapy in addition to maximal medical management of allergy and other irritants could avoid sinus surgery.
Front and side views of the sinuses, which are cavities located in the bones of the face. They are connected to the nasal cavity by narrow passages. EER can cause inflammation of the sinuses. Infection is often a secondary complication.
Otitis media (middle ear infection)
Like the sinuses, the ear has natural openings that must remain functional to prevent problems. As in rhinosinusitis, the development of middle ear infections (otitis media) is a secondary complication that results from impaired function of the eustachian tube. Studies using animal models have shown that exposure of the middle ear and the eustachian tube to acid and pepsin results in failure of the eustachian tube to perform its dual function of sweeping out secretions and modulating pressure within the ear (24, 25). In a study examining patients who had chronic ear problems, treatment with the anti-reflux medication omeprazole resulted in complete resolution of symptoms (26).
Eustachian Tube Dysfunction
The change that occur to the eustachian tube that lead to ear infection is called Eustachian Tube Dysfunction.
Proximal esophageal reflux: acid gets into the eustachian tube and causes inflammation with histamine release which causes the itching and desire to eat things, chew hands, ear itching.
Acid reflux into the proximalesophagus and airways leads to a number of “so-called” extra-esophageal manifestations” of GERD. The eustachian tubes are hit with acid and they swell with edema/inflammation that blocks the outflow of secretions from the middle ear and allows bacteria to colonize the middle ear. The bacteria increase in number and there is an ear infection.
EER is a topic to be investigated along with other important causes of ENT problems such as allergy, immune deficiency, smoke exposure, and other yet-to-be defined factors. EER sometimes is a difficult diagnosis to make and is even more difficult if not suspected. However, if EER is discovered to be an underlying or contributing problem, instituting reflux therapy often can control or even eliminate symptoms altogether.