Allergol et Immunopathol 1999;27:24-28.
Non-specific hyperreactivity before and after nasal specific immunotherapy
F. Filiaci*, G. Zambetti**, R. Romeo**, A. Ciofalo**, M. Luce** and F. Germano***
*Assistant professor. **ENT specialist. ***ENT resident. Department of Otorhinolaryngology. University "La Sapienza". Rome, Italy.
SUMMARY
Background: specific local immunotherapy (SLIT) improves symptom scores for allergic rhinitis during treatment and after its conclusion, as confirmed by non-specific tests. However, the duration of clinical and instrumental improvement after discontinuing SLIT is unknown.
Objective: to evaluate the changes in the non-specific reaction time of patients with allergy to Dermatophagoides pteronissinus before and during 3 years of SLIT, and 6, 12, 18, and 24 months after discontinuing SLIT.
Material and methods: sixteen patients were diagnosed by clinical history, positive skin test for D. pteronissinus, RAST, nasal provocation test (NPT) specific for D. pteronissinus, NPT with cold water solution. SLIT was administered by nasal spray. Patients were evaluated before, at 6, 12, 24, and 36 months of SLIT, and 6, 12, and 18 months after discontinuing SLIT. At the beginning of SLIT, the allergen concentration used was similar to that used in NPT. Maintenance doses were administered 3 times a week for 1 year and 2 times a week for 2 years. All patients kept a symptom diary.
Results: after the first year of SLIT, total nasal resistance (TNR) decreased sharply. TNR then remained constant at the end of the second year and decreased at the end of the third year of treatment. Discontinuation of SLIT did not produce evident variations in average TNR at 6 or 12 months, but 3/16 patients at 6 months and 9/16 patients at 12 months complained of symptomatic deterioration. The most evident deterioration was noted at the 18-month post-SLIT visit, in which TNR values were similar to those recorded at the onset of treatment. Positive response to stimulation and increased TNR were found after SLIT in 8/16 patients at 6 months, 13/16 at 12 months, 12/13 at 18 months, and 7/7 at 24 months. The symptom score indicated the return of symptoms. Twelve months after discontinuing SLIT, the patients complained about increased secretion and itching. The initial non-specific hyperreactivity, which had been present in all patients, was not evident in 68.7% after 3 years of SLIT, but persisted in a milder form in 31.3%.
Conclusion: SLIT successfully reduced symptoms of D. pteronissinus sensitivity. Non-specific hyperreactivity was absent at the end of SLIT, but returned by 6 months after discontinuing SLIT. Therefore, SLIT did not maintain the clinical results achieved at the beginning of treatment for more than 12 months.
Key words: Non-specific nasal hyperreactivity. Specific immunotherapy. Non-specific nasal provocation test. Histamine. Allergic rhinitis.
RESUMEN
Antecedentes: la inmunoterapia local específica (ITLE) mejora la puntuación sintomática en la rinitis alérgica durante y después de concluirse el tratamiento, como confirman las pruebas no específicas. Sin embargo, no se sabe cuanto tiempo dura esta mejoría clínica e instrumental después de interrumpirse la ITLE.
Objetivo: analizar los cambios en el tiempo de reacción inespecífico de los pacientes con alergia a Dermatophagoides pteronissinus, antes y durante tres años de ITLE, y a los 6, 12, 18 y 24 meses de concluir la ITLE.
Material y métodos: dieciséis pacientes fueron diagnosticados por la historia clínica, prueba cutánea positiva de D. pteronissinus, RAST, prueba de provocación nasal específica (PPN) de D. pteronissinus, PPN con una solución de agua fría. Se administró la ITLE en aerosol nasal. Los pacientes fueron estudiados antes y a los 6, 12, 24 y 36 meses de ITLE, y 6, 12 y 18 meses después de interrumpir la administración de ITLE. Al principio de ITLE, la concentración de alergeno utilizada fue similar a la utilizada en PPN. Se administraron dosis de mantenimiento tres veces a la semana durante un año y dos veces a la semana durante dos años. Todos los pacientes mantuvieron un diario donde anotaban los síntomas.
Resultados: después del primer año de SLIT, la resistencia nasal total (RNT) disminuyó significativamente. La RNT permaneció constante al final del segundo año y disminuyó al final del tercer año. La interrupción de la ITLE no originó variaciones evidentes en la RNT media a los seis y 12 meses, pero 3/16 pacientes a los seis meses y 9/16 pacientes a los 12 meses refirieron un empeoramiento sintomático. El deterioro más evidente se advirtió en el control a los 18 meses después de concluir ITLE, cuando los valores de la RNT alcanzaron valores similares a los registrados al comienzo de tratamiento. Se observó una respuesta positiva a los estímulos y un aumento de la RNT después de la ITLE en 8/16 pacientes a los seis meses, en 13/16 a los 12 meses, en 12/13 a los 18 meses y en 7/7 a los 24 meses. La puntuación por síntomas indicó que estos habían recurrido. Doce meses después de concluir la ITLE, los pacientes referían un aumento de las secreciones y picores. La hiperreactividad inespecífica inicial presente en todos los pacientes a los tres años de ITLE no fue evidente en 68,7%, pero persistía en una forma más leve en 31,3%.
Conclusión: la ITLE redujo con éxito los síntomas de sensibilidad a D. pteronissinus. La hiperreactividad inespecífica desapareció al final de la ITLE, pero volvió a los seis meses de interrumpirse la ITLE. Por tanto, la ITLE no mantuvo los resultados clínicos logrados al principio del tratamiento durante más de 12 meses.
Palabras clave: Hiperreactividad nasal inespecífica. Inmunoterapia específica. Prueba de provocación inespecífica. Histamina. Rinitis alérgica.
INTRODUCTION
Nasal hyperreactivity can be considered to be an abnormal reaction of the nasal mucosa to endogenous and exogenous stimulation. Endogenous factors include emotional, behavioral o vascular reactions to changes in body position, physical stress, sexual excitation, hormonal incretion due to menstruation, pregnancy or menopause (1, 2).
Exogenous factors that can induce nasal mucosal responses include sharp changes in temperature, cold and/or warm, local and/or general cutaneous stimulation, drugs, gases, and allergens in allergic subjects. The most important symptoms of nasal hyperreactivity are nasal congestion, nasal secretion, sneezing, itching, headaches, and hyposmia due to chronic edema of the nasal mucosa (pre-polypoid condition). Nasal hyperreactivity is particularly frequent in patients suffering from vasomotor and allergic rhinitis. However, such symptoms could also be observed in normal subjects with a shorter and less intensive behavioral pattern.
The tests used to evaluate non-specific nasal responses include the histamine test, metacholine test, and cold-water test (3).
In recent years, specific treatments have found a role in clinical practice and research as a proven alternative to subcutaneous specific immunotherapy. Among these treatments, we have been interested in nasal specific local immunotherapy (SLIT) (4-11) since 1980 (2, 4, 12-14). Specific and/or non-specific tests have been found to produce confirmed improvement of symptom scores during and at the end of nasal therapy (15-19). What was lacking in order to complete our research was to determine the duration of clinical and instrumental improvement after therapy concludes. The aim of this study was to evaluate the changes in the non-specific reaction in patients with allergy to Dermatophagoides pteronissinus, before, during 3 years of specific local immunotherapy, and 6, 12, 18 and 24 months after discontinuing SLIT.
MATERIAL AND METHODS
Sixteen patients ranging in age from 15 to 44 years (mean age 28 years) were studied. In all patients the diagnosis was based on:
* Clinical history.
* Positive skin test for D. pteronissinus.
* RAST.
* Specific nasal provocation test (NPT) for D. pteronissinus (20, 21).
* Non-specific NPT with cold-water solution (water at 2°-3° C) (15).
* Anterior rhinometry before and after provocation (22, 23).
The patients were evaluated before, during (6, 12, 24, 36 months) and after (6, 12, 18 months) SLIT. SLIT was administered in a nasal spray using a nasal spray pump and the dose was increased progressively. At the beginning of SLIT, the administration of an allergen concentration similar to the one used for specific nasal provocation test produced an increase (¾ 30%) in total basic resistance (20).
At this time, non-specific nasal hyperreactivity was evaluated with the non-specific nasal provocation test using a cold-water solution.
To avoid discomfort for the patients, SLIT was administered after pre-treatment with disodium cromoglycate.
The product was titered in internal control units and prepared in a water solution buffered with phenolate and glycerinate (10%) in 5 vials at concentrations of 50 U/ml, 100 U/ml, 250 U/ml, 500 U/ml, 1000 U/ml.
Finally, maintenance doses were administered 3 times a week for one year and 2 times a week for two years.
All the patients kept a symptom diary to evaluate the symptom score for obstruction, secretion, sneezing, and itching. The symptom scores were 0 = absent, 1 = mild, 2 = medium, 3 = moderate, 4 = severe (24).
RESULTS
Average total nasal resistance (TNR) (Fig. 1) before SLIT was 1.79 ± 0.71 mm H2O/P/min. At the end of the first year of SLIT, TNR decreased notably, attaining an average of 1.26 ± 0.43 H2O/P/min that remained constant from the end of the second year of local therapy 1.28 ± 0.51 H2O/P/min and then decreased at the end of the third year of therapy 0.91 ± 0.40 H2O/P/min. Discontinuation of SLIT did not produce evident variations in average TNR values (0.75 ± 0.55 H2O/P/min at 6 months, 0.94 ± 0.48 H2O/P/min at 12 months), although some patients complained of symptomatic deterioration compared with the moment when SLIT was discontinued: 3/16 patients (18.7%) at 6 months and 9/16 patients (56.2%) at 12 months. The most evident deterioration was noted at the 18-month control visit after the discontinuation of therapy, when the average TNR value was similar to the value registered before starting SLIT.
Figure 1.--Rhinometric values of total nasal resistance (TNR) before, during, and 6, 12, 18 and 24 months after discontinuation of specific local immunotherapy (SLIT).
Average TNR continued to deteriorate in the next 6 months, reaching a value of 2.68 ± 0.69 H2O/P/min, at which point all patients reported a subjective deterioration of symptoms. The evolution of TNR was more important in light of the symptom score (Fig. 2) for sneezing, nasal secretion, nasal congestion, and itching obtained from the diary of symptoms kept by the patient. From the third year of SLIT until the symptoms returned, there was an increase in symptoms at 6 months with respect to the amount of sneezing (4/16). Twelve months after discontinuing SLIT, the symptoms that the patients complained most about were sneezing and nasal congestion rather than secretion and itching. The latter symptoms, although considered insignificant at 12 months, were noted by patients at 18 months even if their intensity was less than that of sneezing and nasal congestion.
Figure 2.--Evolution of the symptom score before, during, and 6, 12, 18 and 24 months after discontinuation of specific local immunotherapy (SLIT).
It is well known that non-specific hyperreactivity in allergic patients is directly proportional to allergen exposure. With SLIT, the initially non-specific hyperreactivity (Fig. 3) present in all patients in different ways was not evident in 11/16 patients (68.7%) after 3 years of immunotherapy, but it persisted in 5 patients (31.3%) in a milder form than before treatment.
Figure 3.--Non-specific hyperreactivity evaluated by a non-specific nasal provocation test with isotonic cold solution (water at 2-4° C) before, during, and 6, 12, 18 and 24 months after discontinuation of specific local immunotherapy (SLIT).
At the times of the scheduled follow-up visits (6, 12, 18 and 24 months), patients who had a positive response to stimulation had higher TNR:
* 8/16 patients at 6 months
* 13/16 patients at 12 months
* 12/13 patients at 18 months
The increase in TNR values was milder in all 7/7 patients studied 24 months after therapy was discontinued.
DISCUSSION
The therapy described in this study was appropriate, risk-free and well-tolerated. The conclusions of this study can be summarized as follows:
* SLIT alleviated the symptoms of D. pteronissinus sensitivity.
* Non-specific hyperreactivity disappeared at the end of SLIT, but reappeared 6 months after therapy was discontinued. Four of 16 patients complained of subjective symptoms consisting of increased sneezing.
* The clinical results obtained at the onset of SLIT were not maintained more than 12 months after discontinuing SLIT.
In our opinion, the shortcomings of SLIT can be attributed to the length of treatment, to the form of administration of the allergen solution (which is better, aerosol or powder?), to the induction of a loco-regional response instead of a general response as in traditional IT, or to the presence of a neurogenic phlogotic component of the nasal hyperreactivity that becomes established over years and tends to perpetuate the clinical situation.
Other studies are underway to examine this problem in depth and to clarify the questions raised by this study.
In patients undergoing SLIT, we also perform the non-specific nasal provocation test (NSNPT) with histamine (19). This is a more reliable and accurate test than nasal provocation with isotonic solution at 2-4° C. Use of NSNPT should allow nasal reactivity to be assessed before and after SLIT.
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Correspondence:
Prof. Franco Filiaci
Clinica Otorinolaringoiatrica
Università "La Sapienza"
Viales del Policlinico 155
00161 Roma. Italy
