The purpose of this article is to familiare the reader with evidence that supports a putative connection between the upper and lower airways. In doing so, the author has relied heavily on previous reviews of this subject.15 To limit this article to 20 references, it has been necessary to refer to these reviews as reference sources rather than cite each individual article. It is also important for the reader to be aware that this article deals mainly with studies that support upper and lower airway links. There are data in the literature to the contrary, but these are not discussed in detail. Finally, this discussion is limited only to studies involving the purported mechanisms that underlie the putative link between the upper and lower airways.
THEORIES REGARDING THE MECHANISMS UNDERLYING CONNECTIONS BETWEEN THE UPPER AND LOWER AIRWAYS
The theories underlying the mechanisms of the link between upper and lower airway disease can be conveniently divided into three categories: (1) reflex mechanisms; (2) loss of nasal air conditioning functions; and (3) dissemination mechanisms (drainage, aspiration, or systemic dissemination through the circulation).
The idea that there is a reflex connection between the upper airway and the lower airway is ancient, and may have been first proposed by Galen.15 Investigations surrounding such a reflex were initiated in the late 1800s and involved animal models. In 1870, Kratschner used cat and rabbit models to study the effect of chemical irritation of the nasal mucosa on the lower airway. He found that such irritation could produce apnea, laryngeal closure, bronchoconstriction, and bradycardia.2
Subsequently, other authors have demonstrated such effects from a number of different stimuli, including smoke, sulfur dioxide, and the instillation of cold or hot water into the nasal cavity. Early on, it was demonstrated that the afferent limb of this reflex was carried through the trigeminal nerve and could be interrupted by the application of a local anesthetic to the nasal mucosa. The efferent limb was determined to be via the vagus nerve and could be blocked by atropine administered prior to stimulation. These observations in animal models were later extended to humans.
In 1929, Allen showed that a strong odor stimulating the human maxillary nerve could suppress respiration and that this suppression could be prevented by anesthetic blockade of the trigeminal nerve or local anesthesia to the nasal mucosa.2 Hallmark studies were performed by Kaufman et al.6-7 These investigators applied silica particles to the noses of individuals who did not have asthma and demonstrated increases in lower airway resistance. This response could be prevented by atropine. Similar results were obtained with sulfur dioxide, packing of the nose, and cold air. One year later/ these investigators studied the effect of silica application to the nasal passage in patients who had previously undergone unilateral trigeminal nerve resection. Increases in the airway resistance were limited to the side with the intact neural pathway.
In 1982, Yan and Salome found that the application of histamine to the noses of patients with stable asthma resulted in small, dose-dependent decreases in forced expiratory volume 1 second (FEV1) in 8 of 12 patients.8 However, in the late 1980s and early 1990s, other investigators were unable to confirm these results, and the existence of a clinically important upper and lower airway reflex was questioned and fell out of favor.1 More recent studies, however, have revived this concept.
In a series of investigations. Bucea et al.4'9 studied relationships between the upper and the lower airways. They found that patients with sinusitis and asthma or sinusitis alone had extrathoracic airway obstruction, as measured by declines in the maximal inspiratory flow rate at 50% of vital capacity, and intrathoracic obstruction, as measured by slowing of expiratory air flow with stimulation of the airways by histamine inhalation. When both extrathoracic and intrathoracic obstruction occurred in an individual, they were well correlated. These investigators also studied 106 patients experiencing an acute exacerbation of sinusitis as documented by signs, symptoms, and radiographic changes. These patients had no asthma and normal lung functions. When in the acute phase of the infection, 76 of these 106 patients had a positive response to the inhalation of Mstamine. All 76 also had slowing of inspiration, whereas 46 had slowing of expiratory flow as well. Bronchial hyperresponsiveness also occurred and its degree was closely correlated to reductions in expiratory flow rate. Pharyngitis was a strong predictor for hyperresponsiveness. Treatment of these patients with antibiotics and nasal corticosteroids reduced both extrathoracic and intrathoracic hyperresponsiveness to histamine. Pharyngeal biopsy specimens from patients with chronic sinusitis and extrathoracic hyperresponsiveness to histamine demonstrated increased nerve fiber density. From these studies, the investigators postulated that both extrathoracic and intrathoracic airway obstruction can result from oral-pharyngeal reflexes.9
In keeping with these observations, Fontanari et al. used nasal provocations with high-flow bursts of cold, dry air to evaluate the nasal pulmonary reflex in patients with asthma. They included healthy control subjects and found that both groups demonstrated increased lower airway resistance during challenge. When warm air was used, no such change occurred. To evaluate the mechanism of the increase in airway resistance, they delivered cold air to the nose and the mouth. Pretreated patients received cold air challenge to the nose with intranasal lidocaine and intrapulmonary inhalation of atropine. Cold air delivered to the mouth produced no change in airway resistance in the pretreated group, whereas an increase in lower airway resistance occurred in untreated patients. In addition, pretreatment with lidocaine to the nasal cavity and atropine to the lungs reduced the effect of nasal cold air challenge.10
Another form of nasal challenge supporting a nasal-bronchial reflex was devised by Togias et al.4 They applied capsaicin by aerosolization to the nasal cavity in a manner that prevented pulmonary penetration. Approximately 10% of their patients with active rhinitis and asthma showed immediate reductions in FEV1 and forced vital capacity (FVC) within 30 seconds after such challenge. A return to baseline lung functions occurred within 60 seconds.
Sato5 made an attempt to identify the point of origin of the putative upper airway and lower airway reflex. He insufflated powdered pepper into the noses of patients who had undergone total laryngectomies and into the noses of normal control subjects. Airway resistance increased in the normal control subjects, but not in those who had undergone laryngectomies. He thus concluded that deposition of the powder on the larynx was responsible for the increase in lower airway resistance, and that the larynx could serve as a point of origin of the reflex.
A number of authors have approached this subject using models more closely rnimicking natural exposures, such as associated with an infection. Lemanske et al.11 inserted rhinovirus into the noses of 10 adults with allergic rhinitis due to ragweed. Preinfection measurements of airway reactivity to histamine and ragweed challenge (bronchial inhalation) were performed, and the patients were observed for immediate and late asthmatic reactions. One month after these baseline studies, rhinovirus was inoculated intranasally. Baseline FEV1 levels remained stable throughout the study. However, during acute rhinoviral illness, there was a significant increase in airway reactivity to both histamine and ragweed. Before rhinovirus inoculation, only 1 of the 10 patients had a late asthmatic response after ragweed challenge. However, during the acute viral illness, 8 of 10 patients had late asthmatic responses. The authors concluded that rhinovirus infection of the upper respiratory tract enhances airway reactivity and predisposes the allergic patient to late asthmatic responses after allergen inhalation. However, the authors did not delineate the mechanism of production of this phenomenon. It could only be assumed that the results might be related to a nasal-bronchial reflex.
In another benchmark investigation. Corren et al. evaluated 10 patients with seasonal respiratory allergy who had worsening exacerbations of asthma during hay fever symptoms.12 Nasal provocation with allergen significantly increased the bronchial responsiveness to the pulmonary inhalation of methacholine. This increase occurred 30 minutes after nasal challenge and persisted for 4 hours. There were no changes, however, in specific airway conductance or spirometry measured at these time intervals. Because radionuclide studies demonstrated no evidence of allergen deposition in the lungs, the authors attributed the increase in methacholine responsiveness to a possible neural mechanism.
Togias et al. studied 15 patients with chronic allergic airway disease who were not selected for any particular characteristic other man the presence of allergy to ragweed or grass.4 They performed nasal allergen and bronchial allergen challenges. Bronchial methacholine inhalations were performed at 5, 12, and 22 hours after nasal challenge, and at 22 hours after bronchial allergen challenge. Twenty-five percent to 30% of the patients demonstrated increases in airway responsiveness following nasal allergen provocation. Those patients who had increased airway responsiveness to methacholine after nasal challenge also had reductions in lung function. There was a correlation between changes in airway responsiveness and these reductions. In addition, the patients with asthma whose airway responsiveness and lung function were affected by nasal challenge were also those who experienced similar changes when allergen was administered directly to the lower airway.
Subsequently, Togias et al. questioned whether patients with asthma who experienced changes in methacholine responsiveness and airway function following allergen challenge did so regardless of whether the allergen was administered to the upper or the lower airway.4 Ten patients with asthma with significant increase in methacholine sensitivity after bronchial allergen inhalation received nasal provocation with allergen. Six hours after challenge, there was a significant increase in airway responsiveness to methacholine. There was no change in lung function postchallenge compared with baseline.
A third trial by Togias et al. studied the effect of nasal challenge on lung function and airway responsiveness to methacholine in patients with asthma who had an inflammatory infiltrate in nasal lavage after allergen challenge. Thirty percent experienced a marked increase in responsiveness and a decline in FEV1 and FVC 6 hours after nasal allergen challenge. This effect could be reduced by pretreatment with cetirizine.4
Togias concluded that the observations from his group, together with those of Corren's studies, indicate that perhaps 20% to 30% of patients with chronic allergic airway disease demonstrate an interaction between the upper and the lower airways. This interaction consists of a reduction in airway caliber, an increase in airway responsiveness, or both after nasal allergen challenge. He also concluded that there is evidence to support the fact that the effects demonstrated after nasal challenge are more prominent in patients who also respond to pulmonary inhalation of allergen.4
Consistent with these experimental results are the much older observations of Gerblich et al. They found that patients with allergic rhinitis had subclinical airway constriction as measured by specific airway conduction during the pollen season. However, these patients did not have potentiated sensitivity to methacholine during this period.13
These studies, taken as a whole, give strong support to the existence of a reflex between the upper and the lower airways. Apparently, this reflex can be generated at any position ranging from the nose to the larynx. The afferent limb is carried by sensory nerve fibers (in the nose, the trigeminal nerve) to the brain, from which the effector response is mediated through the vagus nerve. The clinical importance of this reflex has not been quantitated and needs better definition.
Loss of Nasal Air Conditioning Functions
The nose is a magnificent air conditioner. The shape of the nose induces air turbulence, thus facilitating filtration. The nose is surprisingly efficient in this regard. Even particles with low mass diameter can be effectively filtered. Fifteen percent to 20% of particles with a 2-^m diameter are deposited in the nose when breathing at a rate of 25 L /minute; 45% are filtered at 50 L /min, and 60% at 75 L /min.14 In addition, the nose heats the air rapidly. Air at -18°C at the entrance to the nasal cavity can be warmed to +200C by the time it reaches the segmental bronchi. Additionally, the nose humidifies inspired air. This may be its most important function. A normal adult inspires 1,400 L of air in 24 hours. The air can contain 680 g of water after inspiration. This is approximately 20% of the normal total water intake and 50% of the daily urinary output. If most air is exhaled through the nose, approximately one-third of water can be extracted from the air.14 While at rest, approximately 33% of the water and heat contents are preserved when passing through the nasal cavity, possibly increasing to 50% in colder conditions.14
Nasal obstruction, resulting in mouth breathing and hyperventilation of dry air, can reduce water vapor enough to cause mucosal shrinkage and produce morphologic changes in respiratory epithelium.14 Thus, nasal breathing can be crucial to the proper functioning of the lower airway.
Clinically, the effect of nasal breathing on lower airway function has been evaluated using models of exercise-induced asthma and the inhalation of cold, dry air. Forced mouth breathing in individuals with asthma during exercise increases the degree of bronchospasm compared with nasal breathing.15 The same holds true for the inhalation of cold air through the nose versus the mouth.16 Thus, chronic nasal obstruction necessitating mouth breathing may be another mechanism linking upper airway disease to the worsening of asthma.
It has been postulated that inflammatory mediators or cells from the nose might be disseminated to the lung via nasal drainage or the systemic circulation. Theoretically, such dissemination might cause or worsen asthma.
Early studies attempted to discern whether upper airway material could be aspirated via postnasal drainage. Huxley et al. studied pharyngeal aspiration during sleep in normal individuals and patients with decreased consciousness. When intermittent boluses of a radionuclide tracer were delivered into the nasal pharynx, almost half of the subjects showed pulmonary aspiration.5
Results to the contrary, however, were found by Bardin et al.,5 who evaluated 13 patients with chronic sinusitis and 9 with asthma by injecting a radionuclide tracer into the maxillary sinus. Twenty-four hours later, tracer was noted in the sinuses, esophagus, and nasal pharynx, but none was detected in the lungs.
Brugman et al. used a rabbit model of sinusitis to evaluate whether secretions from the sinuses could gain access to the lower airway.17 They induced a sterile sinusitis by the injection of C5a des arg (a complement chemotactic factor) into the maxillary sinuses. The development of sinusitis was associated with lower airway hyperresponsiveness. This hyperresponsiveness could be eliminated by positioning the rabbits in a way that gravity would not drain secretions into the lung. In addition, lower airway hyperresponsiveness was abrogated by eliminating upper-lower airway communication using an inflated endotracheal tube cuff. Finally, airway hyperresponsiveness was not induced in this model by injection of C5a des arg into a knee joint. The authors concluded that the change in lower airway hyperresponsiveness must be due to drainage of sinus secretions into the lungs rather than via the systemic circulation.17
Although, as noted above, there is some supportive evidence that drainage from the upper airway can exacerbate lung disease, little evidence exists to support the contention that systemic communication could be responsible for this phenomenon. Nonetheless, such circulatory communication could occur via either the traffic of cells or soluble molecules. It is clear that nasal allergen challenge significantly increases peripheral eosinophilia, and, theoretically, these cells could seed the lung. Of course, inflammatory molecules such as histamine and leukotrienes, as well as cytokines produced locally in the nose, could gain access to the systemic circulation.
Of interest in this regard is a study by Bufe et al.18 These investigators examined how nasal secretions affect the cutaneous reactivity to allergens in patients with allergic rhinitis. Nasal secretions from healthy individuals and from those with allergic rhinitis significantly enhanced the skin test reactivity to Timothy grass allergen. Thus, on a theoretical basis, should the substances contained in these secretions reach the lungs in significant quantities, one could imagine a similar reaction occurring within the bronchial tree.
The access of the products of sinus secretions to the systemic circulation has been proposed to account for the relationship between chronic sinusitis and asthma. This theory is based on Szentivanyi's19 animal model of asthma in rodents. These rodents developed a syndrome similar to human asthma when injected with live or killed Bordetella pertussis organisms. The syndrome consisted of increased bronchial hyperresponsiveness, eosinophilia, decreased response to beta-adrenergic stimulus (beta-adrenergic blockade), and enhanced allergic antibody production. Szentivanyi coined the term beta-adrenergic blockade to refer to these abnormalities.19 Some experimental support for this observation has been offered by Friedman et al.,20 who demonstrated that treatment of sinusitis enhanced the response to beta-adrenergic agonists in patients with asthma.
Strong evidence exists to support a link between the upper and the lower airways. Most compelling is the evidence for a neurogenic reflex that exacerbates the severity of asthma. There is also strong indication that lower airway disease is worsened by chronic mouth breathing due to nasal obstruction. There is less evidence to support the contention that the transmission of cells or molecules from the upper airway to the lower airway via nasal drainage or the systemic circulation can exacerbate lower airway disease. The observations noted herein have important clinical bearing on the treatment of lower airway disease, which is discussed elsewhere in this issue.
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