Nasal Allergy and Sinus Infection: The Link--and Therapeutic Implications

The prevalence and incidence of sinus infection, or sinusitis, is increasing and has been estimated to affect 31 million persons in the United States each year. It is one of the most common reasons why patients seek a physician's care. If left untreated, sinusitis can cause significant physical symptoms and can negatively affect quality of life by substantially impairing the daily functioning of sufferers. For children, this can mean learning difficulties at school and for adults, a loss of efficiency at work.

Understanding the science behind sinusitis can help clinicians effectively treat affected patients in their daily practice.

Sinusitis may be acute or chronic. Acute sinusitis is characterized by the abrupt onset of viral respiratory infection and subsequent insidious onset of cold-like symptoms that may last for weeks. Conversely, chronic sinusitis usually does not present with an acute onset, and it may last for months or more--even after aggressive treatment. Acute sinusitis is often treated with antibiotics for the recommended time of 2 to 3 weeks. Chronic sinusitis does not respond to antibiotic therapy; instead, the treatment of choice is usually topical or systemic corticosteroids.

The nature of the relationship between allergic rhinitis and sinusitis (acute or chronic) remains a dilemma for clinicians. Allergic rhinitis may affect 10% to 12% of the general population. Because of the anatomic proximity of the nasal passages and the sinus cavities, an association between allergic rhinitis and sinusitis has often been suggested. However, an evidence-based, cause-and-effect relationship between the two has not been clearly defined. Furthermore, the term "sinusitis" is very often not defined properly.

Here I review the evidence relating to the association between allergic rhinitis and acute sinusitis, and to that between allergic rhinitis and chronic sinusitis. I also examine the cause, pathophysiology, and implications of treatment for all of these conditions.

Epidemiology: Clinical Association

Allergic rhinitis is often listed as a predisposing factor for acute sinusitis, and their association is often cited in the literature. However, there have not been any solid epidemiologic studies of this association. Because the number of people who suffer from allergic rhinitis is far greater than those who have sinusitis, many studies determine the prevalence of allergic rhinitis in patients with an established sinus infection. True acute sinusitis is largely diagnosed on x-ray films.

Children with allergies frequently have sinusitis.¹ Various studies have reported a high correlation (from 25% to 75%) between these disorders in children.² One study of adults reported the incidence of allergy to be 25% in those with acute maxillary sinusitis, which was significantly greater than the 16% incidence in the control group.³ The prevalence of sinusitis is significantly higher in children with allergic rhinitis than in children without it.⁴

One study compared the prevalence of sinusitis in children with perennial allergic rhinitis and in those with seasonal allergic rhinitis. The prevalence of sinusitis was significantly higher in patients with perennial allergic rhinitis than in those with seasonal allergic rhinitis (P < .001).⁵ More important, when the subset of patients with perennial allergic rhinitis was compared, patients with mold allergy showed a higher risk of sinusitis than those with non-mold allergy (relative risk, 2.49 vs 1.50, respectively).⁵ This observation was supported by another study in adults with recurrent acute sinusitis, 5% of whom had a positive allergy test result. In that patient group, 92% demonstrated sensitivity to one or more perennial allergens--usually molds and house dust mites.⁶

Holzmann and colleagues⁷ investigated whether allergic rhinitis is a potential risk factor for orbital complications characteristic of acute sinusitis. They found allergic rhinitis in 64% of children with preseptal cellulitis and in 76% of children with sub- periosteal abscess. Similarly, when adults with acute sinusitis were examined, 43% had previously been suffering from allergic rhinitis.⁸

The definition of chronic sinus-itis varies somewhat, depending on the individual clinician's view on the length of clinical symptoms. However, most reports state that symptoms lasting more than 30 days should be considered chronic sinusitis. The symptoms of chronic sinusitis are often a bit more subtle than those attributed to acute infection. Nasal discharge (variable in character), postnasal drip, nasal obstruction, and cough (day and night) are common. Because of the chronic nature of the illness, behavioral changes--such as irritability and acting out--are often evident in children. Adults complain of chronic fatigue and general malaise at work. Again, even though adequately controlled studies are lacking, multiple observations support the association between chronic sinusitis and nasal allergy.

Benninger⁹ studied outpatients and reported that 54% of those with chronic sinusitis also had allergic rhinitis. A 50% incidence of positive allergy skin test in adult patients who had undergone sinus surgery has been shown,¹⁰ and atopy has been demonstrated in 94% of adult patients who had undergone spenomastoidectomy.¹¹ van Dishoeck and Franssen¹² reported allergy as an underlying factor in 40% to 67% of patients with chronic sinusitis. Several studies have shown similar results in children; in allergic children with symptoms of allergic rhinitis and/or asthma, there is a higher frequency of sinusitis,¹ and 37% of children with sinusitis have skin test results positive for allergy.¹³

Based on clinical observations made by both primary care physicians and specialists, we can conclude that a positive association exists between nasal allergy and acute or chronic sinusitis in both adults and children.

Pathogenesis of Acute Sinusitis in Patients With Allergic Rhinitis

Although many clinical observations support the contention that patients with allergic rhinitis are vulnerable to acute sinusitis, a unified hypothesis that would aid in the understanding of the pathophysiology of sinusitis is still lacking. However, if we trace the underlying pathogenic mechanism, it may be possible to arrive at a reasonable conclusion.

Clinical evidence indicates that acute sinusitis is usually preceded by a viral infection.^14-16 During the initial stages, there is increased mucus because of infection. Patients with rhinitis often sneeze and blow their nose to get rid of nasal discharge. A recent study suggests, however, that as the discharge is expelled, as much as 17% of it is sucked into the sinus cavities by force.¹⁷ This fluid contains allergen(s), viral particles, and bacteria; once inside the sinus cavities, the bacteria adhere to the mucosal lining. The stimulation of epithelial cells by bacterial products (lipopolysaccharide by Gram-negative or lipoteichoic acid by Gram-positive bacteria) causes the production of interleukin (IL)-8, tumor necrosis factor a, and mucin.¹⁸ Chemotactic factors are then released to recruit inflammatory cells, especially polymorphonuclear cells.

As mentioned, acute sinusitis is more likely to develop in patients with perennial allergic rhinitis--especially those who are sensitive to molds. Does mold allergy contribute to the pathogenesis of sinusitis? In their study of the interaction between fungal allergens and epithelial cells, Kauffman and coworkers¹⁹ reported that the possibility exists. They found significant desquamation of epithelial cells and cytokine production (IL-6 and IL-8) and concluded that damage to the epithelial cells by the proteases of fungi may result in further enhancement of the passage of macromolecules of antigens over the mucosal membrane. This results in more mast cell activation and recruitment of eosinophils and neutrophils. Locally produced mucin and lectin contribute to the high viscoelasticity of mucus seen with sinusitis.²⁰

Interestingly, an animal experiment also supports the contention that allergic rhinitis could be an important factor in the development of acute sinusitis. Mice were first sensitized with ovalbumin and then infected with Streptococcus pneumoniae--one of the organisms most commonly isolated in the sinus fluid of patients with sinusitis. Once eosinophilia had developed in these mice because of allergy, more neutrophils and bacteria were recovered from the sinus cavities. This suggests that it was an ongoing allergic reaction in the sinuses, and not at distant sites, that made the animals prone to an established sinus infection.²¹

The overall inflammatory process enhances the production of mucopurulent material in the sinus cavities, which is a hallmark of sinus pathology. The sequence of this pathology is illustrated in Figure 1.

Pathogenesis of Chronic Sinusitis in Patients With Allergic Rhinitis

One of the common beliefs in the evaluation of patients with chronic sinusitis and nasal allergy is that allergic rhinitis leads to edema of the nasal passages and interferes with adequate drainage from the sinus cavities. The problem with this hypothesis is that the treatment of allergic rhinitis does not always eliminate chronic sinusitis. Another common belief is that allergens somehow penetrate the sinus cavities of people with allergies. However, a study using radiolabeled antigen (ragweed) demonstrated how difficult (in this case, impossible) it is for allergens to penetrate the sinus cavities.²²

Recent understanding of the intricate immune network allows us to explore the immunopathology of chronic sinusitis. The immune balance between helper T cells subtype 1 (T_H1) and T_H2 cells may explain the resultant pathology. Both cells use distinct cytokines to modulate immune responses. For example, T_H1 cells produce T_H1 cytokines, primarily interferon-g and IL-2, which induces cell-mediated immunity. T_H2 cells induce eosinophil-mediated inflammatory responses and counterregulate the T_H1 response by T_H2 cytokines (IL-4, IL-5, and IL-13).²³

The immunopathology of chronic sinusitis is very much the result of the T_H2 cytokine response. There is a high level of IL-5²⁴ or IL-3, IL-4, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF)²⁵ in the sinuses of patients with chronic sinusitis.

The cellular response plays an important role in the immunopathology of chronic sinusitis. In children with chronic sinusitis, eosinophils are always abundant in those with nasal allergy.²⁶ Similar observations have been made in adults.²⁷ The eosinophils are not just present in the mucosa, they are also activated,²⁴ leaving very potent, cell-damaging molecules on the mucosa.²⁷ Thus, eosinophils are active players in the inflammation that occurs with chronic sinusitis, and this is more common in patients with active allergic rhinitis. T lymphocytes were also studied in sinus cavities. Although CD4⁺ cells were increased at the apical portion of the sinus mucosa--suggesting the possible release of chemotactic or growth factors from the epithelium to attract inflammatory cells--the significance of this to allergy is unclear.²⁸

The most interesting hypothesis about chronic sinusitis is that it is the result of neurogenic inflammation within the sinuses. To investigate this possibility, a model of allergen challenge to the nose was developed, and the maxillary sinus secretion sampled.²⁹ The investigators found that after a challenge in one nostril with either grass or ragweed pollens, a significant influx of eosinophils was found in the bilateral sinus cavities compared with controls. They concluded that either homing of eosinophils occurred in both sinus cavities or neurogenic inflammation occurred via the triggering of afferent nerves, leading to an inflammatory response not only in the ipsilateral but also in the contralateral sinus via either central or axonal reflexes.²⁹

One final hypothesis about the possible interaction between allergic rhinitis and sinusitis is that allergic rhinitis causes priming of the circulating leukocytes, with up-regulation of adhesion molecules, which makes those leukocytes more likely to migrate to sites of ongoing inflammation such as those caused by viral sinusitis.³⁰ The sequence of this pathogenesis is illustrated in Figure 2.

Effect of Nasal Allergy Treatment on Sinusitis

Nasal allergy, if left untreated, can cause significant morbidity in both children and adults, substantially affecting quality of life. Treatment includes preventive measures, pharmacotherapy, and immunotherapy with allergy vaccine. In comparing the incidence of sinusitis among patients with nasal allergy, patients with perennial allergic rhinitis--particularly those with significant sensitivity to molds and/or house dust mites--were most susceptible to acute sinusitis. Thus, it is reasonable to assume that controlling rhinitis by controlling the home environment will minimize the recurrence of acute sinusitis. Unfortunately, although its importance is well recognized, outcome studies of acute sinusitis are scarce.^31,32

Similarly, many patients with chronic sinusitis also have nasal allergy. As is the case with preventing acute sinusitis, the management of nasal allergy should be included in the treatment strategy for chronic sinusitis. Clearly, there is an immediate need to establish national, evidence-based practice guidelines to assist clinicians in diagnosing and managing allergic rhinitis coexisting with other airway diseases, such as acute or chronic sinusitis.