Non-Allergic Perennial Rhinitis: A Family of Disorders
Michael Groves, M.D.
September 25, 2008
Disclaimer: The information contained within the Grand Rounds Archive is intended for use by physicians and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No warranties, either express or implied, are made with respect to accuracy, completeness or timeliness of this material. This material does not necessarily reflect the current or past opinions of the faculty of Baylor College of Medicine and should not be used as a basis for diagnosis or treatment, and is not a substitute for professional consultation and/or peer-reviewed medical literature.
Today we will be talking more specifically about non-allergic perennial rhinitis, but we will begin with a brief discussion of rhinitis in general. It is a global medical problem. Some estimate between 10% and 25% of the world population suffers from rhinitis symptoms. That is roughly the population of the United States and China combined. Strictly speaking, rhinitis is defined as inflammation of the nasal mucosa, which can be incited by numerous entities. However, multiple rhinitis syndromes are not the direct result of inflammation at all. Therefore, in common usage, rhinitis is defined mainly by the symptoms that it causes including rhinorrhea, nasal obstruction, sneezing, nasal pruritis, and in some patients, ocular symptoms such as itching and watering eyes.
These may sound like trivial things, but for most patients it can cause a significant impact on their quality of life. Treatment tends to be expensive to our health care system. It is estimated in 2002 that allergic rhinitis alone accounted for 11 billion dollars in indirect and direct medical costs (indirect cost meaning lost productivity at work or missed days at school). When you add in the non-allergic rhinitides, that number continues to grow. Rhinitis is also a particular problem because patients can be misdiagnosed and mismanaged by primary care providers, costing much more to the system in lost days of work for ineffective treatment and continued discomfort to the patient. So, it is important to treat these patients properly in order to decrease the associated costs.
Rhinitis can be divided into several broad categories. First is the acute infectious rhinitides, including viral, bacterial, and fungal rhinitis. Acute viral rhinitis is the most common and easily diagnosed due to its episodic nature and self-limiting course. Allergic rhinitis, on the other hand, is chronic and often seasonal. It is IgE-mediated, with mast cells releasing histamine to produce an inflammatory response in the nasal mucosa. Finally, non-allergic rhinitis is a catch-all term for a lot of other diseases that produce rhinitis symptoms, but are not infectious or IgE-mediated. In terms of patients with non-infectious rhinitides, there is a 3:1 ratio of allergic and non-allergic etiologies; however, many patients do not have a pure allergic or non-allergic cause of their symptoms. Some estimate that between 44% and 80% of patients will have some sort of mixed allergic/non-allergic picture.
So, what types of rhinitis fall into the “non-allergic rhinitis” category? Vasomotor or idiopathic rhinitis is a rhinitis caused by environmental irritants such a tobacco smoke, perfume, chemical fumes. There is cold air rhinitis, exercise-induced rhinitis and idiopathic, where the inciting factor is simply unknown and can produce symptoms of both rhinorrhea and nasal obstruction. Gustatory rhinitis is caused by ingestion of various food products, and drug-induced rhinitis is caused by different medications and multiple different pathways. A more recently defined syndrome is non-allergic rhinitis with eosinophilia syndrome (NARES), thought to be related to vasomotor rhinitis. Hormonal rhinitis can be caused by pregnancy; and some believe thyroid dysfunction can also cause some rhinitis symptoms. In occupational rhinitis, the exposure is in the work place. Atrophic rhinitis and systemic diseases can also cause rhinitis symptoms. We will discuss each of these in a little bit more detail shortly.
Before that, let’s review normal nasal physiology. Obviously the nose’s most important function is to provide an airway and, while air is passing through the nose, the nasal mucosa warms, filters, and humidifies it. The nose also provides a resonant chamber for the voice. One of the nose’s most important features is that it provides protection to the lower airways from noxious stimuli in the environment. That protection is mediated by modulation of airflow. As we know, the turbinates have the ability to swell and shrink, thus modifying airflow from laminar to very turbulent. Turbulent air will spend more time in the nose as it passes through being filtered, humidified and warmed. This process requires the proper function of multiple systems, including the mucosal vasculature, autonomic nerves and sensory nerves. The vasculature is made up of a series of resistance vessels, which are connected to capacitance vessels. The resistance vessels are the small arteries and arterioles, which provide inflow into the superficial capillary network, arteriovenous anastomoses and glandular capillaries. Blood flow then travels to valveless veins and venous sinusoids, which are particularly abundant in the mucosa of the turbinates. Blood pooling in the venous structures of the mucosa tends to swell the turbinate mucosa. This process is controlled mainly by the autonomic nervous system. This has two components: parasympathetic and sympathetic. The parasympathetic input originates in or around the facial nucleus, travels on the nervus intermedius to the greater superficial petrosal nerve, through the vidian canal to the sphenopalatine ganglion, where it synapses. Post-ganglionic fibers will travel with various sensory nerves to reach their targets in the nasal mucosa, specifically the glands and some of the blood vessels. The sympathetic system takes a different route. It originates in the thoracic spinal cord, traveling up the sympathetic chain to the superior cervical ganglion where they then synapse and pass onto the internal and external carotid plexus before traveling with various other nerves to reach their targets. Parasympathetic activation will cause increased glandular secretion and some vasodilation of the arteries and arterioles, while sympathetic input causes vasoconstriction of these resistance vessels, decreased blood flow to the mucosa and shrinking of the nasal erectile tissue.
Sensory nerves of the nasal mucosa are also important. They are able to detect temperature, pressure, pain, itch and are exquisitely sensitive to airflow traveling through the nose. They come in all different varieties, but one of the most important is the small, unmyelinated C fiber, which many believe are most important to initiating some of these rhinitis syndromes. They are responsible for transmitting painful stimuli. They are sensitive to capsaicin, which I will discuss a little bit later. They are meant to respond to irritative stimuli in the environment. They are also important in that they can secrete vasoactive inflammatory neuropeptides, which can further modulate the response of the nasal mucosa to various neuro- and immunologic inputs.
Armed with this understanding of nasal physiology, we can discuss the specific entities of non-allergic rhinitis in more detail. Vasomotor rhinitis, or idiopathic rhinitis as it is alternately called in the literature, is thought by many to be the result of a hyperactive response to external stimuli. Most people have some sort of nasal response to irritating stimuli in the environment, such as tobacco smoke, however, patients with vasomotor rhinitis have much more frequent and severe symptoms.
This hyperactive response can be caused by multiple things. Some believe that it is an autonomic imbalance – either an overly aggressive parasympathetic nervous system or a weak sympathetic nervous system leading to increased glandular secretion and nasal obstruction. Some attribute this to central hyper-responsiveness, meaning that the central nervous system is simply interpreting normal stimuli as being stronger than they actually are. This may be the result of inappropriate C-Fiber neuropeptide release in the CNS. This could increase transmission of action potentials from the periphery, allowing the central nervous system to be bombarded by an increased intensity of sensory input and producing an exaggerated parasympathetic response.
Others believe that vasomotor rhinitis may be caused by a process called neurogenic inflammation. This phenomenon known to happen in laboratory animals, however, its presence in humans is still debatable. In lab animals, the sensory C-Fibers of the nose can be antidromically stimulated, meaning a stimulus originating somewhere around nerve’s terminal end in the CNS can travel in a retrograde fashion to the cell body and dendrites, where neuropeptides are released in the nasal mucosa. These neuropeptides can cause the nasal mucosa to have increased vascular permeability leading to leakage of plasma into the nasal cavity, increased glandular secretion and recruitment, differentiation, and activation of many immune cells, including mast cells.
Others feel that vasomotor rhinitis actually is a local-IgE mediated disease, meaning that although the patient’s skin test is negative and they cannot be diagnosed with atopy, they will have a local allergic response to various allergens. The term entopy has been coined to describe “local allergy.” It is thought that IgE-producing plasma cells can exist strictly within the nasal mucosa. These IgEs combine with the allergens in the nose, causing mast cells to release their histamine and then start the inflammatory cascade.
Gustatory rhinitis is most often a problem related to ingestion of spicy foods containing capsaicin, which is the pungent compound in many peppers and directly stimulates C-fibers. It can be initiated by many other food particles such as sugars and starches. In many patients, the inciting agent cannot be identified. Nasal symptoms caused directly by food allergies are uncommon without other dermatologic or gastrointestinal manifestations. So, gustatory rhinitis is not truly an allergic reaction. It is most likely a neurally-mediated response to some chemical in the food, stimulating fibers within the nose or the palate.
Drug-induced rhinitis comes in many forms. In aspirin-sensitive patients, symptoms of nasal obstruction are quite common. Aspirin inhibits cyclooxygenases, causing arachidonic acid metabolism to be shunted towards leukotriene synthesis. These leukotrienes are known to cause mucosal inflammation and increase the survival of eosinophils in the mucosa, extending the inflammatory response. Rhinitis medicamentosa is a disease caused by down regulation of the alpha-adrenergic receptors in response to constant stimulation by topical vasoconstricting agents such as oxymetazoline. When the patient suddenly stops using these medications, the body’s own catecholamine production cannot counteract the resultant vasodilation and loss of sympathetic tone. The patients are stuck with a very stuffy nose and uncomfortable nasal symptoms.Other causes of drug-induced rhinitis can include beta-blockers, ACE inhibitors and chlorpromazine.
NARES is the acronym for non-allergic rhinitis with eosinophilia. On nasal smear you will find 5% to 20% of cells are eosinophils. The pathophysiology is very poorly understood at this time. Some people believe that it is an early form of aspirin sensitivity. Others think that it is akin to the local allergic reaction seen in vasomotor rhinitis. Biopsy specimens of the nasal mucosa in these patients can show mass cells with bound IgE.
Nasal congestion is common in pregnancy and in some points of the menstrual cycle in some women. This is thought to be related to the high levels of progesterone, causing vascular smooth muscle relaxation, blood pooling in the venous sinusoids and chronic nasal obstruction. It is a particular problem later in pregnancy and tends to resolve very quickly after delivery. It is important to remember that allergic rhinitis and infectious rhinitis are also very common in pregnancy and not every woman who comes into your clinic who is pregnant and having nasal congestion can be diagnosed with rhinitis of pregnancy. Other forms of rhinitis should be investigated as well.
Atrophic rhinitis is characterized by symptoms of nasal congestion despite widely patent nasal cavities. It has a primary and secondary form. Primary atrophic rhinitis causes nasal drainage, crusting, fetid odor, and atrophy of the nasal mucosa and glands. It is a worldwide problem and occurs in the later decades of life. It is thought to be caused by chronic infection with Klebsiella ozaenae. Secondary atrophic rhinitis can be caused by overly aggressive turbinate surgery, other chronic infections, granulomatous disease, trauma and radiation.
So, how do we diagnosis non-allergic rhinitis? A thorough history and physical exam is obviously the starting point. Chronology is important, especially age at onset. Non-allergic rhinitis is more often a disease of the later decades of life. Young kids tend to have allergic rhinitis, rather than non-allergic conditions. So, if it started when the patient was a child, they probably have some sort of allergic phenomenon going on. Seasonal variation might point more in the direction of an allergic source. Information about daily exacerbations associated with various exposures can also be important to elicit from your patients. It is also very informative to ask the patient what the most bothersome symptoms are. Is it rhinorrhea? Is it nasal obstruction? This may help guide your treatment later on. Character of the mucous is also important. If it is thin, clear, running mucous, it points more in the direction of non-infectious source. Severity of the symptoms should be assessed. Associated symptoms like itchy eyes and sneezing are more indicative of an allergic phenomenon. Detailed discussion of possible inciting factors including occupational exposures and indoors versus outdoor exacerbations may lead you to identify the inciting cause and help the patient with avoidance measures in the future. Knowing what medicines they are on can help as well. This can help you in diagnosing drug-induced rhinitis, as well as knowing what treatments the patient has tried in the past to treat their problem. With regard to family history, most patients with allergic rhinitis will have a family member with atopy. Past medical history and past surgical history is important in atrophic rhinitis, i.e. knowing if they have had nasal surgery or some sort of trauma to the nose.
By discussing quality of life issues with the patient you can establish a therapeutic relationship, increasing the chance that they will be compliant with whatever treatment modality you institute. That can be important in patients who have had these symptoms for years and years and have tried multiple different therapies from their primary care provider or other doctor and have not have relief. Establishing that trust is important in getting the patient to comply with your recommended treatment regimen.
On physical examination, a full head and neck physical examination is important. Look in the ear for effusions and in the oropharynx for posterior pharyngeal cobblestoning. The classic signs of allergic disease, like allergic shiners and nasal crease from constantly wiping the nose are thought to be more associated with allergic disease, but can be found in non-allergic rhinitis as well. On nasal exam, make sure you have excellent lighting. Note the mucosal appearance, character of the mucous, size of turbinates, any septal deviations or perforations. Also note the function of the nasal valve, patency of the choanae and size of adenoids. Rule out any polyps and look at the middle meati for purulent discharge.
History and physical are often sufficient to establish a diagnosis of one of the non-allergic rhinitides. However, in some patients it is wise to proceed with skin testing. If you think you have identified an inciting factor, you can do a skin test for that. These are easy, cheap, fast, and accurate and may placate patients who feel like they really do have an allergy. Direct nasal challenges with antigens are based on the idea that some of these patients who do have negative skin tests, may have a local allergy. Whether or not this is an effective means of diagnosis remains controversial because many feel it is not reproducible or reliable in most patients.
As with many things in life, avoiding some things that cause problems can be the most effective treatment. So, the patient can simply stay away from things that they know will bother them. This can be difficult for patients with occupational exposures, whose livelihood depends upon their ability to work in certain environments and be around certain environmental irritants. In the case of rhinitis of pregnancy, it has been shown that some gentle exercise, elevating the head of the bed while sleeping, and using Breathe Right strips can provide some relief.
Steroids are very common treatment in non-allergic rhinitis, especially helpful in NARES and idiopathic rhinitis when the primary symptom is nasal congestion. There is a wide variety of nasal steroids. None have been proven to be more effective than the others, but what does differ is the delivery vehicles and other additives in the preparation, which in some patients can cause irritation and other side effects. Therefore, being flexible with what you prescribe to certain patients is worthwhile in increasing their likelihood of their use of these products on a regular basis.
Oral antihistamines are generally ineffective for non-allergic rhinitis. In addition, first generation oral antihistamines, such as diphenhydramine, commonly cause drowsiness which can further impair productivity. So, it generally would not be recommended. There are two intranasal antihistamine sprays available on the market, Astelin and Patanase. Only Astelin has been shown in several studies to be effective in non-allergic rhinitis, although Patanase has not been studied here in the United States. It is important to note that both of these can have some systemic absorption and cause drowsiness, so patients should be counseled on this before you initiate therapy.
Anticholinergics such as Atrovent are effective in treating idiopathic rhinitis when the primary complaint is rhinorrhea. It can also be used prior to exposure to particular stimulants that elicit symptoms. They have also been proven to be safe and effective when combined with a steroid or some sort of antihistamine.
Topical decongestants, such as Afrin, are meant only for temporary relief of particularly severe rhinitis symptoms. In patients diagnosed with rhinitis medicamentosa, the treatment is cessation of the topical decongestant and initiation of intranasal corticoid steroids. They are going to be uncomfortable for some time, but the steroids may take the edge off a little bit.
Saline is very popular with otolaryngologists. It is thought to improve mucociliary clearance and can help patients with atrophic rhinitis and other forms of rhinitis by removing mucosal irritants from the nose.
Treatment with capsaicin is being researched right now. Repeated topical applications are thought to cause degeneration of the capsaicin sensitive C-Fibers, thus cutting off that axonal reflexes which are thought to be responsible for producing rhinitis symptoms. There are thought to be some randomized controlled trials showing excellent long term symptom relief for up to a year after a single course of applied capsaicin, either over two weeks every other day, or in one day, one hour apart. Unfortunately, there is no standard formulation of capsaicin available in the United States.
Some think that Botox may be an effective treatment for cutting off the parasympathetic innervations to the nasal mucosa and eliminating the symptoms of rhinitis. One study compared groups using inhaled anticholinergics with patients injected with 10 units of Botox, 5 units on each side into the middle and inferior turbinate. They did show that both of these groups did better than the placebo group. Whether or not this is an economically feasible option is yet to be determined.
Vidian neurectomy, which is section of the vidian nerve between its exit from the vidian canal and its entrance into the sphenopalatine ganglion, has been proposed and used since 1961, when it was described by Golding-Wood for patients with refractory vasomotor rhinitis. It was largely abandoned in the past decades. Multiple other surgical approaches were devised but none were particularly satisfactory and all had a high recurrence rate, with most patients having a return of symptoms in about two years. Also, a report of post-operative blindness in a patient after attempted cautery of the nerve has caused some disfavor towards this procedure. More recently endoscopic vidian neurectomy was described. It has been performed since the early 1990s with improved visualization of the nerve as it exits the canal in the pterygopalatine fossa. However, even though it has been around for almost two decades, there are only some small retrospective reviews with short follow-ups. It has not been thoroughly evaluated. It may find its place in treatment for vestibular vasomotor rhinitis in the future, but at this point, it is not something that is commonly used either.
In summary, although they carry common symptomatology, the non-allergic rhinitides comprise a diverse group of disorders. Our understanding of pathophysiology certainly leaves a lot of room for improvement. Ultimately, better understanding of these maladies may lead to better treatments, which will save money, decrease loss of productivity and improve patients’ outcomes in the future.
NK is a 77-year-old male with multiple medical problems including hypertension, hyperlipidemia, chronic renal insufficiency and obesity, who has been followed in the Michael E. DeBakey Veterans Affairs Medical Center otolaryngology clinic for many years.
He recently began to complain of diffuse, watery rhinorrhea that he reported as persisting for several years and failing to completely resolve with the oral antihistamines and nasal steroid sprays originally prescribed to him by his primary care provider. He stated that he had never had a history of allergies, and that he does not have a history of nasal congestion. There was no seasonal variation to his symptoms. He denied itchy eyes or sneezing. He did have occasional sore throat and complained the drainage was going to the back of his throat. He bemoaned constantly having to wipe his nose. He could not pick out any specific aggravating factors. He had an extensive smoking history, but quit smoking about 1.5 years ago.
On physical exam he had no notable intranasal abnormalities with the exception a large amount of clear mucus. His mucosa was healthy and pink, and his turbinates were of normal size. Based on his history and physical exam a diagnosis of idiopathic rhinitis was made, and the patient was prescribed a trial of ipratropium nasal sprays in addition to continuing his nasal steroid sprays and eliminating his oral antihistamine. Several months later, the patient returned to clinic with much improved control of his nasal symptoms and has continued to use this treatment regimen faithfully.
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