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Quantitative assessment of the adherence to sublingual immunotherapy
Letters to the Editor 1219
J ALLERGY CLIN IMMUNOL VOLUME 113, NUMBER 6
TABLE I. Reactions to testing with histamine and saline
Device
No. of tests, histamine
Mean wheal size, histamine (mm)
Smallpox needle Multitest II DermaPik II Quick Test Greer Track Smallpox needle Multitest II DermaPik II Quick Test Greer Track
Arm, 84 Arm, 80 Arm, 100 Arm, 72 Arm, 96 Back, 158 Back, 168 Back, 200 Back, 176 Back, 352
6.15 6.2 6.33 6.09 5.01à 7.06§ 6.34 6.42 5.44 5.12
SD, histamine (mm)
Pseudo– false-negative reactions (%)*
Falsenegative reactions (%)
Wheal size specificity, saline, 0.95 quantile (mm)
Wheal size specificity, saline, 0.99 quantile (mm)
Specificity of 3 mm wheal to saline (%)
Discomfort (0 = none to 10 = severe) mean
1.44 1.4 1.5 1.54 1.68 1.63 1.49 1.78 2.15 1.8
2.4 1.1 2.0 4.2 6.2 0.6 0 0.5 2.3 4.0
0 1.1 0 1.3 5.2 0.6 0.6 1.5 5.1 6.3
0 0 0 0 0 0 0 0 0 0
0 0 4.5 4.5 0 3.5 3.5 0 4 3.5
100 100 0.98 0.99 100 0.99 0.97 100 0.99 0.98
— — — — — 3.8 4.4 4.6 5.0 4.4
Harold S. Nelson, MD Catherine Kolehmainen, RN Jennie Lahr, RT James Murphy, PhD Andrea Buchmeier, AB National Jewish Medical and Research Center 1400 Jackson St Denver, CO 80206 REFERENCES 1. Adinoff AD, Rosloniec DM, McCall L, Nelson HS. A comparison of six epicutaneous devices in the performance of immediate hypersensitivity skin testing. J Allergy Clin Immunol 1989;84:168-74. 2. Nelson HS, Rosloniec DM, McCall LL, Ikle D. Comparison performance of five commercial prick skin test devices. J Allergy Clin Immunol 1993; 92:750-6. 3. Nelson HS, Lahr J, Buchmeier A, McCormick D. Evaluation of devices for skin prick testing. J Allergy Clin Immunol 1998;101:153-6. doi:10.1016/j.jaci.2004.01.566
Quantitative assessment of the adherence to sublingual immunotherapy To the Editor: For historical reasons, immunotherapy has been administered subcutaneously for many decades. After serious adverse events caused by subcutaneous immunotherapy (SCIT) were reported,1 safer administration routes were studied, and sublingual immunotherapy (SLIT) immediately appeared as a promising option. Currently, SLIT is considered a viable alternative to SCIT2 on the basis of its clinical efficacy and good safety profile (see review3). SLIT is self-administered at home; therefore, one of the most important concerns is the adherence (‘‘the degree to which the patient’s behavior coincides with the medical prescription’’).4 To date, no quantitative study is available on this topic. With SLIT in tablets, the adherence could be evaluated by randomly asking patients to count the remaining tablets at a given moment. We used that method to assess the adherence to SLIT in real life.
This multicenter observational study involved outpatients receiving SLIT for respiratory allergy. Patients were diagnosed to have allergic rhinitis and/or asthma on the basis of the typical clinical history of symptoms for at least 2 years, positivity of skin prick tests, and spirometry with methacholine challenge, when indicated. Asthma and rhinitis were graded according to GINA and ARIA guidelines, respectively.2 SLIT for a single relevant allergen was prescribed to patients with comorbid rhinitis and asthma, persistent rhinitis and positive methacholine test, or severe rhinitis during the allergen exposure. SLIT was prepared as soluble tablets to be taken in the morning, kept under the tongue until dissolution (1-2 minutes), and then swallowed. The vaccine was a monomeric allergoid obtained by chemical modification.5 Patients allergic to dust mite received a continuous treatment, whereas for pollens, a preseasonal schedule was used. In both cases, SLIT involved a build-up and a maintenance phase. Detailed printed instructions and additional oral explanation on how taking and managing SLIT were given. All patients received a standard drug therapy for symptoms (oral/nasal antihistamines, inhaled salbutamol, inhaled/ nasal steroids) and were seen for follow-up at regular intervals. Patients were contacted by telephone, without planning an exact date. At the telephone interview, they were asked to count the tablets remaining in the blister. A computerized program, based on the starting date of SLIT and the administration schedule, calculated the expected consumed tablets and the expected remaining tablets. The adherence was measured after 1 year for mite SLIT and at the beginning of the pollen season for pollen SLIT. It was calculated in percentage as expected consumed tablets – remaining tablets/expected consumed tablets 3 100. Patients recorded in a diary the occurrence of side effects after each dose. Local (oral itching/swelling, edema of lips/tongue, nausea or vomiting) and systemic (rhinitis, conjunctivitis, asthma, urticaria/angioedema) side effects
Letters to the editor
*Either the wheal with histamine was less than 3 mm or the flare with histamine was less than 10 mm. Both the wheal with histamine was less than 3 mm and the flare with histamine was less than 10 mm. àSignificantly smaller than the reactions with the other devices (P < .05). §Significantly larger than the reactions with the other devices (P < .05).
1220 Letters to the Editor
J ALLERGY CLIN IMMUNOL JUNE 2004
TABLE I. Characteristics of the patients
N Male/female Age, y (range) Rhinitis alone Rhinitis plus asthma Asthma alone Adherence assessed at
Total
Mites
Pollens
86 38/48 35.4 (14-66) 42 43 1
41 16/25 36.3 (15-65) 19 22 0 13 ± 1 month
45 22/23 34.8 (14-66) 23 21 1 18 ± 2 weeks
Letters to the editor
were graded as mild (no medical advice/treatment required, no dose adjustment), moderate (interference with everyday activities or need for drug treatment or SLIT discontinuation), or severe (life-threatening events needing hospitalization and/or emergency care). In November 2003, 86 patients (mean age, 35.4 years; 44% male) were included (Table I): 41 received SLIT to mite and 45 to pollens (24 grasses, 18 Parietaria, 3 ragweed). The mean duration of the pollen SLIT was 18 ± 2 weeks. The count of the tablets (taken/expected) was 5080/5248 in the mite group and 3952/4050 in the pollen group; therefore, the adherence was 96.8% and 97.6%, respectively (cumulative adherence, 97.3%). Omitted doses were documented in 11 patients. Seven patients postponed the administration of 1 to 2 doses because of concurrent nonallergic illness, 3 patients reported occasional forgetting, and 1 patient skipped multiple doses because of working habits. Eleven mild side effects were reported in 6 (7%) patients: 6 oral itching, 2 rhinitis, 2 nausea, and 1 generalized itching. Because of the high adherence rate, no socioeconomic determinant affecting the adherence could be ruled out. Currently, adherence is one of the major concerns about SLIT managed by the patient at home. The problem is the same with other drugs (inhaled corticosteroids, antihistamines), and it is well known that the low adherence is a major cause of failure or poor efficacy of treatments.6 In the case of immunotherapy, it could be expected that SLIT is inferior to SCIT in terms of adherence, although the experimental data show that the adherence to SCIT is far from being satisfactory, mainly because of inconvenience or side effects.7,8 Thus, in the case of immunotherapy, the safety and tolerability of the treatment should play a relevant role. Measuring the adherence is not easy to do: reliable data could be obtained with electronic recorder devices,9 but this approach is expensive and not applicable to all drugs. With SLIT in solution, one possible approach is to measure the volume of the extract in the returned vials, but this does not exclude that patients have discharged part of the vaccine. Simply counting the returned tablets is not sufficient, because it gives no information about the doses taken. On the contrary, calling the patients randomly and asking to count the tablets immediately avoids that bias: it is unlikely that patients can calculate in seconds the correct number of remaining tablets and the expected consumption. Thus, we are confident that our results reflect the real adherence of patients. The rate of adherence was independent of economical aspects, be-
cause all of our patients had the treatment fully reimbursed by the National Healthcare System, whereas the good safety profile was probably an important determinant. In conclusion, despite the fact that SLIT is self-managed at home, the adherence seems to be satisfactory. Carlo Lombardi, MDa Federica Gani, MDb Massimo Landi, MDc Paolo Falagiani, DVMd Marco Bruno, MDd Giorgio Walter Canonica, MDe Giovanni Passalacqua, MDe a Pneumoallergy Unit Department of Internal Medicine S. Orsola Hospital Brescia, Italy b Allergy Unit San Luigi Hospital, Orbassano Turin, Italy c National Pediatric Healthcare Turin, Italy d Lofarma S.p.A. Milan, Italy e Allergy and Respiratory Diseases Department of Internal Medicine University of Genoa Pad Maragliano L go R Benzi 10 16132 Genoa, Italy REFERENCES 1. Committee on the Safety of Medicines. CSM update: desensitizing vaccines. BMJ 1986;293:948. 2. Bousquet J, van Cauwenberge P, editors. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108(suppl 5):S146-50. 3. Canonica GW, Passalacqua G. Non injection routes for immunotherapy. J Allergy Clin Immunol 2003;111:437-48. 4. Haynes RB. Introduction. In: Haynes RB, Taylor DW, Sackett L, editors. Compliance in healthcare. Baltimore: John Hopkins University Press; 1979. p. 15–21. 5. Mistrello G, Brenna O, Roncarolo D, Zanoni D, Gentili M, Falagiani P, et al. Monomeric chemically modified allergens: immunologic and physicochemical characterization. Allergy 1996;51:8-15. 6. Rabe KF, Vermeire PA, Soriano JB, Maier WC. Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur Respir J 2000;16:802-7. 7. Lower T, Hensy J, Mandik L, Janosky J, Friday GA, Jr. Compliance with allergen immunotherapy. Ann Allergy 1993;70:480-2. 8. Cohn JR, Pizzi A. Determinants of patient compliance with allergen immunotherapy. J Allergy Clin Immunol 1993;91:734-7. 9. Choo PW, Rand CS, Inui TS, Lee ML, Cain E, Cordeiro-Breault M, et al. Validation of patient reports, automated pharmacy records, and pill counts with electronic monitoring of adherence to antihypertensive therapy. Med Care 1999;37:846-57. doi:10.1016/j.jaci.2004.03.013
Safety of cephalosporin administration to patients with histories of penicillin allergy To the Editor: Physicians have prescribed penicillins and cephalosporins for more than 50 years. Both families have similar chemical structures and share a b-lactam ring and thus have a potential for allergic cross-reactivity. Ten
J ALLERGY CLIN IMMUNOL VOLUME 113, NUMBER 6
TABLE I. Reactions to testing with histamine and saline
Device
No. of tests, histamine
Mean wheal size, histamine (mm)
Smallpox needle Multitest II DermaPik II Quick Test Greer Track Smallpox needle Multitest II DermaPik II Quick Test Greer Track
Arm, 84 Arm, 80 Arm, 100 Arm, 72 Arm, 96 Back, 158 Back, 168 Back, 200 Back, 176 Back, 352
6.15 6.2 6.33 6.09 5.01à 7.06§ 6.34 6.42 5.44 5.12
SD, histamine (mm)
Pseudo– false-negative reactions (%)*
Falsenegative reactions (%)
Wheal size specificity, saline, 0.95 quantile (mm)
Wheal size specificity, saline, 0.99 quantile (mm)
Specificity of 3 mm wheal to saline (%)
Discomfort (0 = none to 10 = severe) mean
1.44 1.4 1.5 1.54 1.68 1.63 1.49 1.78 2.15 1.8
2.4 1.1 2.0 4.2 6.2 0.6 0 0.5 2.3 4.0
0 1.1 0 1.3 5.2 0.6 0.6 1.5 5.1 6.3
0 0 0 0 0 0 0 0 0 0
0 0 4.5 4.5 0 3.5 3.5 0 4 3.5
100 100 0.98 0.99 100 0.99 0.97 100 0.99 0.98
— — — — — 3.8 4.4 4.6 5.0 4.4
Harold S. Nelson, MD Catherine Kolehmainen, RN Jennie Lahr, RT James Murphy, PhD Andrea Buchmeier, AB National Jewish Medical and Research Center 1400 Jackson St Denver, CO 80206 REFERENCES 1. Adinoff AD, Rosloniec DM, McCall L, Nelson HS. A comparison of six epicutaneous devices in the performance of immediate hypersensitivity skin testing. J Allergy Clin Immunol 1989;84:168-74. 2. Nelson HS, Rosloniec DM, McCall LL, Ikle D. Comparison performance of five commercial prick skin test devices. J Allergy Clin Immunol 1993; 92:750-6. 3. Nelson HS, Lahr J, Buchmeier A, McCormick D. Evaluation of devices for skin prick testing. J Allergy Clin Immunol 1998;101:153-6. doi:10.1016/j.jaci.2004.01.566
Quantitative assessment of the adherence to sublingual immunotherapy To the Editor: For historical reasons, immunotherapy has been administered subcutaneously for many decades. After serious adverse events caused by subcutaneous immunotherapy (SCIT) were reported,1 safer administration routes were studied, and sublingual immunotherapy (SLIT) immediately appeared as a promising option. Currently, SLIT is considered a viable alternative to SCIT2 on the basis of its clinical efficacy and good safety profile (see review3). SLIT is self-administered at home; therefore, one of the most important concerns is the adherence (‘‘the degree to which the patient’s behavior coincides with the medical prescription’’).4 To date, no quantitative study is available on this topic. With SLIT in tablets, the adherence could be evaluated by randomly asking patients to count the remaining tablets at a given moment. We used that method to assess the adherence to SLIT in real life.
This multicenter observational study involved outpatients receiving SLIT for respiratory allergy. Patients were diagnosed to have allergic rhinitis and/or asthma on the basis of the typical clinical history of symptoms for at least 2 years, positivity of skin prick tests, and spirometry with methacholine challenge, when indicated. Asthma and rhinitis were graded according to GINA and ARIA guidelines, respectively.2 SLIT for a single relevant allergen was prescribed to patients with comorbid rhinitis and asthma, persistent rhinitis and positive methacholine test, or severe rhinitis during the allergen exposure. SLIT was prepared as soluble tablets to be taken in the morning, kept under the tongue until dissolution (1-2 minutes), and then swallowed. The vaccine was a monomeric allergoid obtained by chemical modification.5 Patients allergic to dust mite received a continuous treatment, whereas for pollens, a preseasonal schedule was used. In both cases, SLIT involved a build-up and a maintenance phase. Detailed printed instructions and additional oral explanation on how taking and managing SLIT were given. All patients received a standard drug therapy for symptoms (oral/nasal antihistamines, inhaled salbutamol, inhaled/ nasal steroids) and were seen for follow-up at regular intervals. Patients were contacted by telephone, without planning an exact date. At the telephone interview, they were asked to count the tablets remaining in the blister. A computerized program, based on the starting date of SLIT and the administration schedule, calculated the expected consumed tablets and the expected remaining tablets. The adherence was measured after 1 year for mite SLIT and at the beginning of the pollen season for pollen SLIT. It was calculated in percentage as expected consumed tablets – remaining tablets/expected consumed tablets 3 100. Patients recorded in a diary the occurrence of side effects after each dose. Local (oral itching/swelling, edema of lips/tongue, nausea or vomiting) and systemic (rhinitis, conjunctivitis, asthma, urticaria/angioedema) side effects
Letters to the editor
*Either the wheal with histamine was less than 3 mm or the flare with histamine was less than 10 mm. Both the wheal with histamine was less than 3 mm and the flare with histamine was less than 10 mm. àSignificantly smaller than the reactions with the other devices (P < .05). §Significantly larger than the reactions with the other devices (P < .05).
1220 Letters to the Editor
J ALLERGY CLIN IMMUNOL JUNE 2004
TABLE I. Characteristics of the patients
N Male/female Age, y (range) Rhinitis alone Rhinitis plus asthma Asthma alone Adherence assessed at
Total
Mites
Pollens
86 38/48 35.4 (14-66) 42 43 1
41 16/25 36.3 (15-65) 19 22 0 13 ± 1 month
45 22/23 34.8 (14-66) 23 21 1 18 ± 2 weeks
Letters to the editor
were graded as mild (no medical advice/treatment required, no dose adjustment), moderate (interference with everyday activities or need for drug treatment or SLIT discontinuation), or severe (life-threatening events needing hospitalization and/or emergency care). In November 2003, 86 patients (mean age, 35.4 years; 44% male) were included (Table I): 41 received SLIT to mite and 45 to pollens (24 grasses, 18 Parietaria, 3 ragweed). The mean duration of the pollen SLIT was 18 ± 2 weeks. The count of the tablets (taken/expected) was 5080/5248 in the mite group and 3952/4050 in the pollen group; therefore, the adherence was 96.8% and 97.6%, respectively (cumulative adherence, 97.3%). Omitted doses were documented in 11 patients. Seven patients postponed the administration of 1 to 2 doses because of concurrent nonallergic illness, 3 patients reported occasional forgetting, and 1 patient skipped multiple doses because of working habits. Eleven mild side effects were reported in 6 (7%) patients: 6 oral itching, 2 rhinitis, 2 nausea, and 1 generalized itching. Because of the high adherence rate, no socioeconomic determinant affecting the adherence could be ruled out. Currently, adherence is one of the major concerns about SLIT managed by the patient at home. The problem is the same with other drugs (inhaled corticosteroids, antihistamines), and it is well known that the low adherence is a major cause of failure or poor efficacy of treatments.6 In the case of immunotherapy, it could be expected that SLIT is inferior to SCIT in terms of adherence, although the experimental data show that the adherence to SCIT is far from being satisfactory, mainly because of inconvenience or side effects.7,8 Thus, in the case of immunotherapy, the safety and tolerability of the treatment should play a relevant role. Measuring the adherence is not easy to do: reliable data could be obtained with electronic recorder devices,9 but this approach is expensive and not applicable to all drugs. With SLIT in solution, one possible approach is to measure the volume of the extract in the returned vials, but this does not exclude that patients have discharged part of the vaccine. Simply counting the returned tablets is not sufficient, because it gives no information about the doses taken. On the contrary, calling the patients randomly and asking to count the tablets immediately avoids that bias: it is unlikely that patients can calculate in seconds the correct number of remaining tablets and the expected consumption. Thus, we are confident that our results reflect the real adherence of patients. The rate of adherence was independent of economical aspects, be-
cause all of our patients had the treatment fully reimbursed by the National Healthcare System, whereas the good safety profile was probably an important determinant. In conclusion, despite the fact that SLIT is self-managed at home, the adherence seems to be satisfactory. Carlo Lombardi, MDa Federica Gani, MDb Massimo Landi, MDc Paolo Falagiani, DVMd Marco Bruno, MDd Giorgio Walter Canonica, MDe Giovanni Passalacqua, MDe a Pneumoallergy Unit Department of Internal Medicine S. Orsola Hospital Brescia, Italy b Allergy Unit San Luigi Hospital, Orbassano Turin, Italy c National Pediatric Healthcare Turin, Italy d Lofarma S.p.A. Milan, Italy e Allergy and Respiratory Diseases Department of Internal Medicine University of Genoa Pad Maragliano L go R Benzi 10 16132 Genoa, Italy REFERENCES 1. Committee on the Safety of Medicines. CSM update: desensitizing vaccines. BMJ 1986;293:948. 2. Bousquet J, van Cauwenberge P, editors. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108(suppl 5):S146-50. 3. Canonica GW, Passalacqua G. Non injection routes for immunotherapy. J Allergy Clin Immunol 2003;111:437-48. 4. Haynes RB. Introduction. In: Haynes RB, Taylor DW, Sackett L, editors. Compliance in healthcare. Baltimore: John Hopkins University Press; 1979. p. 15–21. 5. Mistrello G, Brenna O, Roncarolo D, Zanoni D, Gentili M, Falagiani P, et al. Monomeric chemically modified allergens: immunologic and physicochemical characterization. Allergy 1996;51:8-15. 6. Rabe KF, Vermeire PA, Soriano JB, Maier WC. Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur Respir J 2000;16:802-7. 7. Lower T, Hensy J, Mandik L, Janosky J, Friday GA, Jr. Compliance with allergen immunotherapy. Ann Allergy 1993;70:480-2. 8. Cohn JR, Pizzi A. Determinants of patient compliance with allergen immunotherapy. J Allergy Clin Immunol 1993;91:734-7. 9. Choo PW, Rand CS, Inui TS, Lee ML, Cain E, Cordeiro-Breault M, et al. Validation of patient reports, automated pharmacy records, and pill counts with electronic monitoring of adherence to antihypertensive therapy. Med Care 1999;37:846-57. doi:10.1016/j.jaci.2004.03.013
Safety of cephalosporin administration to patients with histories of penicillin allergy To the Editor: Physicians have prescribed penicillins and cephalosporins for more than 50 years. Both families have similar chemical structures and share a b-lactam ring and thus have a potential for allergic cross-reactivity. Ten