Produção Nacional
Revisado por pares
Grading local side effects of sublingual immunotherapy for respiratory allergy: Speaking the same language
2013; Elsevier BV; Volume: 132; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2013.03.039
ISSN1097-6825
AutoresGiovanni Passalacqua, Carlos E. Baena‐Cagnani, Jean Bousquet, Giorgio Walter Canonica, Thomas B. Casale, Linda Cox, Stephen R. Durham, Désirée Larenas‐Linnemann, Dennis K. Ledford, Ruby Pawankar, Paul Potter, Nelson Augusto Rosário Filho, Dana Wallace, Richard F. Lockey,
Tópico(s)Food Allergy and Anaphylaxis Research
ResumoSublingual immunotherapy (SLIT) is increasingly used worldwide. Despite its safety being well ascertained, there is no universally accepted system to grade and classify its adverse events (AEs). According to the literature, it seems reasonable to classify and grade systemic side effects by using the previously published World Allergy Organization recommendations. On the other hand, local side effects are the most frequent with SLIT, sometimes leading to its discontinuation. Therefore grading of the severity of local side effects was perceived as necessary for the purpose of uniform reporting, classification, and quantification of this aspect. A World Allergy Organization Taskforce, after examining the available literature and the postmarketing surveillance data, proposed a clinically based grading of the severity of local AEs caused by SLIT. The use of the Medical Dictionary for Regulatory Activities nomenclature for AEs was also included in this context. The proposed grading system for SLIT-induced local reactions is expected to improve and harmonize surveillance and reporting of the safety of SLIT. Sublingual immunotherapy (SLIT) is increasingly used worldwide. Despite its safety being well ascertained, there is no universally accepted system to grade and classify its adverse events (AEs). According to the literature, it seems reasonable to classify and grade systemic side effects by using the previously published World Allergy Organization recommendations. On the other hand, local side effects are the most frequent with SLIT, sometimes leading to its discontinuation. Therefore grading of the severity of local side effects was perceived as necessary for the purpose of uniform reporting, classification, and quantification of this aspect. A World Allergy Organization Taskforce, after examining the available literature and the postmarketing surveillance data, proposed a clinically based grading of the severity of local AEs caused by SLIT. The use of the Medical Dictionary for Regulatory Activities nomenclature for AEs was also included in this context. The proposed grading system for SLIT-induced local reactions is expected to improve and harmonize surveillance and reporting of the safety of SLIT. Sublingual immunotherapy (SLIT) was first described in a double-blind randomized trial in 1986,1Scadding G. Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to dust mite.Clin Allergy. 1986; 16: 483-491Crossref PubMed Scopus (255) Google Scholar with the primary rationale of making immunotherapy safer and more convenient for the patient based on the observation that severe and even fatal adverse events (AEs) can occur with subcutaneous immunotherapy (SCIT).2Windom H.H. Lockey R.F. An update on the safety of specific immunotherapy.Curr Opin Allergy Clin Immunol. 2008; 8: 571-576Crossref PubMed Scopus (45) Google Scholar SLIT has gradually been accepted in clinical practice as a viable alternative to SCIT,3Allergy. 1998; 53: 1-42Google Scholar, 4J Allergy Clin Immunol. 2001; 108: S146-S150PubMed Google Scholar especially in Europe, Latin America, and other parts of the world. It is not US Food and Drug Administration approved for use in the United States.5American Medical AssociationCurrent procedural terminology (CPT) 2005 standard edition. American Medical Association, Chicago2005Google Scholar There are more than 60 randomized double-blind, placebo-controlled trials, several systematic reviews of such trials,6Wilson D.R. Torres L. Durham S.R. Sublingual immunotherapy for allergic rhinitis.Allergy. 2005; 60: 3-8Crossref Scopus (606) Google Scholar, 7Calamita Z. Saconato H. Pelà A.B. Atallah A.N. Efficacy of sublingual immunotherapy in asthma. Systematic review of randomized clinical trials.Allergy. 2006; 61: 1162-1172Crossref PubMed Scopus (281) Google Scholar, 8Penagos M. Passalacqua G. Compalati E. Baena-Cagnani C.E. Orozco S. Pedroza A. et al.Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age.Chest. 2008; 133: 599-609Crossref PubMed Scopus (236) Google Scholar, 9Penagos M. Compalati E. Tarantini F. Baena-Cagnani R. Huerta J. Passalacqua G. et al.Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials.Ann Allergy Asthma Immunol. 2006; 97: 141-148Abstract Full Text PDF PubMed Scopus (283) Google Scholar, 10Compalati E. Passalacqua G. Bonini M. Canonica G.W. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis.Allergy. 2009; 64: 1570-1579Crossref PubMed Scopus (179) Google Scholar, 11Di Bona D. Plaia A. Scafidi V. Leto-Barone M.S. Di Lorenzo G. Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a systematic review and meta-analysis.J Allergy Clin Immunol. 2010; 126: 558-566Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 12Radulovic S. Calderon M.A. Duncan W. Durham S. Sublingual immunotherapy for allergic rhinitis.Cochrane Database Syst Rev. 2010; : CD002893PubMed Google Scholar, 13Calderon M.A. Penagos M. Sheikh A. Canonica G.W. Durham S. Sublingual immunotherapy for treating allergic conjunctivitis.Cochrane Database Syst Rev. 2011; : CD007685PubMed Google Scholar and a World Allergy Organization (WAO) position paper14Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, et al, editors. WAO position paper on sublingual immunotherapy. Allergy 2009;64(suppl 91):1-15.Google Scholar about SLIT. The safety profile of SLIT is superior to that of SCIT15Cox L. Larenas-Linneman D. Nolte H. Weldon D. Finegold I. Nelson H.S. Sublingual immunotherapy: a comprehensive review.J Allergy Clin Immunol. 2006; 117: 1021-1035Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar; no fatalities have been reported, and severe systemic reactions are rare. The rate of AEs after SLIT is variable in the reported studies, but local AEs are predominant. More importantly, the report and description of such reactions are less than ideal, making it difficult to compare adverse reactions among studies, to identify risk factors, and to recommend appropriate action to take when a reaction occurs. Therefore a uniform grading system of AEs associated with SLIT, especially of local reactions, is necessary. This is appropriate because the WAO and other regional organizations recently approved a grading system for systemic adverse reactions to SCIT.16Cox L. Larenas-Linnemann D. Lockey R.F. Passalacqua G. Speaking the same language: the World Allergy Organization subcutaneous immunotherapy systemic reaction grading system.J Allergy Clin Immunol. 2010; 125: 569-574Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar The main advantages of using a widely agreed upon grading system in SLIT are (1) uniformity in reporting and comparing the safety of extracts, doses, and regimens; (2) improved epidemiologic knowledge on the safety of SLIT; (3) increased value of the postmarketing surveillance studies; (4) the possibility of identifying risk factors for AEs; and (5) provision of guidelines to doctors and patients on how to respond to a particular AE (ie, to continue, adjust, or stop treatment). This document was based on randomized double-blind, placebo-controlled trials published in English and mentioned in the WAO position paper,14Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, et al, editors. WAO position paper on sublingual immunotherapy. Allergy 2009;64(suppl 91):1-15.Google Scholar studies with the same characteristics, postmarketing surveys, and case reports published up to December 2011. To date, the safety profile of SLIT has been overall favorable. Systemic side effects (rhinitis, asthma, urticaria, angioedema, and hypotension) make up a minority of the adverse reactions because local reactions (oropharyngeal or gastrointestinal) are most frequently reported. Table I reports local AEs, as described in the literature, plus their coding according to the Medical Dictionary for Regulatory Activities (MedDRA)17Medical Dictionary for Regulatory Activities (MedDRA). Maintenance support services and organization. Available at: http://www.meddramsso.com/. Accessed July 2012.Google Scholar for reporting AEs. In this system AEs are hierarchically classified in 5 levels of detail, starting from the more general (system organ class) to the more specific (lowest level term). Each level better details the AEs and terminology of the previous levels. For example, Table I shows the 2 more detailed classification levels with the associated codes.Table IDescription of local side effects related to SLIT (MedDRA 14.1)Local side effectMedDRA preferred termMedDRA codeMedDRA low-level termMouth/earAltered taste perceptionDysgeusia10013911Taste alterationItching of lipsOral pruritus10052894Itching of mouthSwelling of lipsSwelling of lips10024570Swelling of lipsItching of oral mucosaOral pruritus10052894Itching of mouthSwelling of oral mucosaMucosal edema10030111Mucosal swellingItching of earsEar pruritus10052138Ear pruritusSwelling of tongueSwollen tongue10042727Swelling of tongue, nonspecificGlossodyniaGlossodynia10018388GlossodyniaMouth ulcerMouth ulceration10028034Mouth ulcerTongue ulcerTongue ulceration10043991Tongue ulcerationThroat irritationThroat irritation10043521Throat irritationUvular edemaPharyngeal edema10034829Pharyngeal edemaUpperNauseaNausea10028813Nausea gastrointestinalStomach acheAbdominal pain, upper10000087Stomach acheVomitingVomiting10047700VomitingLowerAbdominal painAbdominal pain10000081Abdominal pain gastrointestinalDiarrheaDiarrhea10012735Diarrhea Open table in a new tab The current knowledge of adverse reactions caused by SLIT is based on randomized controlled trials (RCTs), postmarketing surveys, and case reports. The safety of SLIT in RCTs is reviewed in the 2009 WAO position paper14Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, et al, editors. WAO position paper on sublingual immunotherapy. Allergy 2009;64(suppl 91):1-15.Google Scholar and in other reviews.15Cox L. Larenas-Linneman D. Nolte H. Weldon D. Finegold I. Nelson H.S. Sublingual immunotherapy: a comprehensive review.J Allergy Clin Immunol. 2006; 117: 1021-1035Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar, 18André C. Vatrinet C. Galvain S. Carat F. Sicard H. Safety of sublingual swallow immunotherapy in children and adults.Int Arch Allergy Immunol. 2000; 121: 229-234Crossref PubMed Scopus (178) Google Scholar, 19Gidaro G.B. Frati F. Sensi L. Marcucci F. Incorvaia C. Ciprandi G. The safety of sublingual-swallow immunotherapy: an analysis of published studies.Clin Exp Allergy. 2005; 35: 565-571Crossref PubMed Scopus (155) Google Scholar André et al18André C. Vatrinet C. Galvain S. Carat F. Sicard H. Safety of sublingual swallow immunotherapy in children and adults.Int Arch Allergy Immunol. 2000; 121: 229-234Crossref PubMed Scopus (178) Google Scholar examined 8 trials performed with vaccines from a single manufacturer involving 690 subjects (347 receiving active treatment plus 343 receiving placebo), of whom 218 were children aged 5 to 16 years (103 receiving active treatment plus 115 receiving placebo). Systemic reactions were mild, and the incidence did not differ in the active versus placebo groups. The oral and gastrointestinal side effects were more frequent with SLIT, with a similar rate in adults and children. Another review15Cox L. Larenas-Linneman D. Nolte H. Weldon D. Finegold I. Nelson H.S. Sublingual immunotherapy: a comprehensive review.J Allergy Clin Immunol. 2006; 117: 1021-1035Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar examined the safety of SLIT in the studies available up to October 2005. There were 1,047 adverse reactions from a total of 386,149 doses, which is 2.7 per 1,000 doses in 41 studies with sufficient information to analyze. The occurrence of severe reactions was 0.096 per 1,000 doses in studies that specified the severity of the reactions. Overall, 14 serious AEs were considered most likely treatment related (0.033/1,000 doses). In another review the occurrence of AEs was evaluated according to the SLIT dose, which was expressed as the ratio of SLIT and the equivalent SCIT.19Gidaro G.B. Frati F. Sensi L. Marcucci F. Incorvaia C. Ciprandi G. The safety of sublingual-swallow immunotherapy: an analysis of published studies.Clin Exp Allergy. 2005; 35: 565-571Crossref PubMed Scopus (155) Google Scholar This review concluded that oral side effects were more frequent with low doses of allergen ( 200 patients) performed with grass extracts (Table II).20Durham S.R. Yang W.H. Pedersen M.R. Johansen N. Rak S. Sublingual immunotherapy with once-daily grass-allergen tablets: a randomised controlled trial in seasonal allergic rhinoconjunctivitis.J Allergy Clin Immunol. 2006; 117: 802-809Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar, 21Dahl R. Kapp A. Colombo G. de Monchy J.G. Rak S. Emminger W. et al.Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis.J Allergy Clin Immunol. 2006; 118: 434-440Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar, 22Didier A. Malling H.J. Worm M. Horak F. Jäger S. Montagut A. et al.Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis.J Allergy Clin Immunol. 2007; 120: 1338-1345Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 23Wahn U. Tabar A. Kuna P. Halken S. Montagut A. de Beaumont O. et al.Efficacy and safety of 5 grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis.J Allergy Clin Immunol. 2009; 123: 160-166Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 24Ott H. Sieber J. Brehler R. Fölster-Holst R. Kapp A. Klimek L. et al.Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study.Allergy. 2009; 64: 179-186Crossref PubMed Scopus (113) Google Scholar, 25Bufe A. Eberle P. Franke-Beckmann E. Funck J. Kimmig M. Klimek L. et al.Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy.J Allergy Clin Immunol. 2009; 123: 167-173Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar, 26Blaiss M. Maloney J. Nolte H. Gawchik S. Yao R. Skoner D.P. Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents.J Allergy Clin Immunol. 2011; 127: 64-71Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 27Nelson H.S. Nolte H. Creticos P. Maloney J. Wu J. Bernstein D.I. Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults.J Allergy Clin Immunol. 2011; 127: 72-80Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar The overall occurrence of systemic side effects is similar between the placebo and active groups in most studies. Oral side effects are quite frequent and invariably occur in more than 50% of patients receiving active SLIT, but their duration generally does not exceed 10 days, and discontinuation because of side effects is almost always less than 5%. Also, serious AEs reported in these trials are rare and usually not related to treatment. Of note, the occurrence and severity of AEs gradually decrease in the subsequent years of treatment, as reported in some follow-up assessment of previous trials.28Didier A. Worm M. Horak F. Sussman G. de Beaumont O. Le Gall M. et al.Sustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis.J Allergy Clin Immunol. 2011; 128: 559-566Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 29Durham S.R. Emminger W. Kapp A. de Monchy J.G. Rak S. Scadding G.K. SQ-standardized sublingual grass immunotherapy: Confirmation of disease modification 2 years after 3 years of treatment in a randomized trial.J Allergy Clin Immunol. 2012; 129: 717-725Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar, 30Halken S. Agertoft L. Seidenberg J. Bauer C.P. Payot F. Martin-Muñoz M.F. et al.Five-grass pollen 300IR SLIT tablets: efficacy and safety in children and adolescents.Pediatr Allergy Immunol. 2010; 21: 970-976Crossref PubMed Scopus (58) Google ScholarTable IISide effects in large randomized placebo-controlled trials with grass extracts performed in subjects with rhinoconjunctivitis (with/without asthma)ReferenceAge range (y)Patients A/PUpdosing phaseFormulationDurationManufacturerSafety: Main resultsDiscontinuedbecause of AEsDurham et al, 200620Durham S.R. Yang W.H. Pedersen M.R. Johansen N. Rak S. Sublingual immunotherapy with once-daily grass-allergen tablets: a randomised controlled trial in seasonal allergic rhinoconjunctivitis.J Allergy Clin Immunol. 2006; 117: 802-809Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar18-66569/286, 3 dosesNoneTablets6 moALK-AbellóFifty-three percent of patients had AEs, mostly in the mouth. Six had SAEs. Duration of mouth AEs was 4-10 d.Two percent of patients receiving SLIT withdrew because of AEs.Dahl et al, 200621Dahl R. Kapp A. Colombo G. de Monchy J.G. Rak S. Emminger W. et al.Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis.J Allergy Clin Immunol. 2006; 118: 434-440Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar23-35316/318NoneTablets6 moALK-AbellóEighty-four percent of patients receiving SLIT and 64% of patients receiving placebo had AEs. There were more than 80 local SAEs in 5% of the active group and 7% of the placebo group. Eighty-five percent of the AEs were local.Four percent of patients receiving SLIT withdrew because of AEs.Didier et al, 200722Didier A. Malling H.J. Worm M. Horak F. Jäger S. Montagut A. et al.Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis.J Allergy Clin Immunol. 2007; 120: 1338-1345Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar25-47472/156, 3 doses5 dTablets6 moStallergenesSixty-four percent of patients receiving SLIT and 48% of patients receiving placebo had AEs that were mostly local. SAEs occurred in 6% of the active group and 2% of the placebo group. Duration of local AEs was 5-11 d.Five percent of patients receiving SLIT discontinued because of AEs.Wahn et al, 200923Wahn U. Tabar A. Kuna P. Halken S. Montagut A. de Beaumont O. et al.Efficacy and safety of 5 grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis.J Allergy Clin Immunol. 2009; 123: 160-166Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar4-17139/1393 dTablets8 moStallergenesEighty-five percent of patients receiving SLIT and 82% of patients receiving placebo had AEs. Five SAEs were not related to treatment.Five percent of patients receiving SLIT discontinued because of AEs.Ott et al, 200924Ott H. Sieber J. Brehler R. Fölster-Holst R. Kapp A. Klimek L. et al.Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study.Allergy. 2009; 64: 179-186Crossref PubMed Scopus (113) Google Scholar20-50142/671 dSolution5 y, 4 seasonsStallergenesSixty-nine percent of patients receiving SLIT and 62% of patients receiving placebo had AEs. SAEs occurred in 7.5% of patients and were not related to SLIT.Three percent of patients receiving SLIT discontinued because of related AEs.Bufe et al, 200925Bufe A. Eberle P. Franke-Beckmann E. Funck J. Kimmig M. Klimek L. et al.Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy.J Allergy Clin Immunol. 2009; 123: 167-173Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar5-16126/127NoneTablets6 moALK-AbellóEighty-seven percent of patients receiving SLIT and 83% of patients receiving placebo had AEs. SAEs occurred in 4 patients and were not related to SLIT.Four percent of patients discontinued because of SLIT-related AEs.Nelson et al, 201127Nelson H.S. Nolte H. Creticos P. Maloney J. Wu J. Bernstein D.I. Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults.J Allergy Clin Immunol. 2011; 127: 72-80Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar18-63213/225NoneTablets6 moSchering-PloughMost patients receiving SLIT (72.8%) and some patients receiving placebo (27.6%) had AEs. Ninety-eight percent were mild to moderate in severity. Duration of local AEs was 1-7 d.Of patients receiving SLIT, 5.2 discontinued because of side effects.Blaiss et al, 201126Blaiss M. Maloney J. Nolte H. Gawchik S. Yao R. Skoner D.P. Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents.J Allergy Clin Immunol. 2011; 127: 64-71Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar6-18175/179NoneTablets6 moSchering-PloughSeventy percent of patients receiving SLIT and 25% of patients receiving placebo had AEs. Four percent of patients receiving SLIT had urticaria. Duration of local AEs was 1-2 d.Seven percent of patients receiving SLIT discontinued because of side effects.A/P, Active/placebo; SAE, severe adverse event. Open table in a new tab A/P, Active/placebo; SAE, severe adverse event. There are numerous SLIT postmarketing surveys31Di Rienzo V. Pagani A. Parmiani S. Passalacqua G. Canonica G.W. Post-marketing surveillance study on the safety of sublingual immunotherapy in children.Allergy. 1999; 54: 1110-1113Crossref PubMed Scopus (157) Google Scholar, 32Lombardi C. Gargioni S. Melchiorre A. Passalacqua G. Safety of sublingual immunotherapy in adults: a post marketing surveillance study.Allergy. 2001; 56: 889-892Crossref PubMed Scopus (72) Google Scholar, 33Pajno G.B. Peroni D.G. Vita D. Pietrobelli A. Parmiani S. Boner A.L. Safety of Sublingual immunotherapy in children with asthma.Paediatr Drugs. 2003; 5: 777-781Crossref PubMed Scopus (60) Google Scholar, 34Fiocchi A. Pajno G. La Grutta S. Pezzuto F. Incorvaia C. Sensi L. et al.Safety of SLI T in children aged 3 to 7 years.Ann Allergy Asthma Immunol. 2005; 95: 254-258Abstract Full Text PDF PubMed Scopus (115) Google Scholar, 35Drachenberg K.J. Urban E. Proll S. Woroniecki S.R. Sublingual specific immunotherapy for adults and children: a post marketing survey.Allergol Immunopathol. 2004; 32: 76-81Crossref PubMed Google Scholar, 36Agostinis F. Tellarini L. Falagiani P. Canonica G.W. Passalacqua G. Safety of SLIT in very young children.Allergy. 2005; 60: 133Crossref PubMed Scopus (100) Google Scholar, 37Di Rienzo V. Minelli M. Musarra A. Sambugaro R. Pecora S. Canonica W.G. et al.Post-marketing survey on the safety of sublingual immunotherapy in children below the age of 5 years.Clin Exp Allergy. 2005; 35: 560-564Crossref PubMed Scopus (141) Google Scholar, 38Rodríguez-Pérez N. Ambriz-Moreno Mde J. Canonica G.W. Penagos M. Frequency of acute systemic reactions in patients with allergic rhinitis and asthma treated with sublingual immunotherapy.Ann Allergy Asthma Immunol. 2008; 101: 304-310Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 39Agostinis F. Foglia C. Landi M. Cottini M. Lombardi C. Canonica G.W. et al.The safety of sublingual immunotherapy with one or multiple pollen allergens in children.Allergy. 2008; 63: 1637-1639Crossref PubMed Scopus (62) Google Scholar, 40Lombardi C. Gargioni S. Cottini M. Canonica G.W. Passalacqua G. The safety of sublingual immunotherapy with one or more allergens in adults.Allergy. 2008; 63: 375-376Crossref PubMed Scopus (32) Google Scholar for both adult and pediatric subjects, some involving children younger than 5 years. These surveys are summarized in Table III, and show that the overall occurrence of AEs is lower in postmarketing surveys than in RCTs; this holds true especially for local AEs. This is probably the result of many events being judged as minimal by patients and not being reported.32Lombardi C. Gargioni S. Melchiorre A. Passalacqua G. Safety of sublingual immunotherapy in adults: a post marketing surveillance study.Allergy. 2001; 56: 889-892Crossref PubMed Scopus (72) Google Scholar, 35Drachenberg K.J. Urban E. Proll S. Woroniecki S.R. Sublingual specific immunotherapy for adults and children: a post marketing survey.Allergol Immunopathol. 2004; 32: 76-81Crossref PubMed Google Scholar, 40Lombardi C. Gargioni S. Cottini M. Canonica G.W. Passalacqua G. The safety of sublingual immunotherapy with one or more allergens in adults.Allergy. 2008; 63: 375-376Crossref PubMed Scopus (32) Google Scholar Where a more rigorous recording methodology is used (as happens in RCTs), the occurrence of AEs in patients approximates 50%. The majority of AEs in postmarketing studies are reported as oral, mild, and self-limiting, and the rate is less than 10 per 1,000 doses.Table IIIReported rates of AEs in postmarketing surveysReferenceNo. of patientsAge range (y)Follow-up (y)Total AEs (% of patients)Total AEs/1000 dosesLocal AEs (% of patients)Di Rienzo et al, 199931Di Rienzo V. Pagani A. Parmiani S. Passalacqua G. Canonica G.W. Post-marketing surveillance study on the safety of sublingual immunotherapy in children.Allergy. 1999; 54: 1110-1113Crossref PubMed Scopus (157) Google Scholar2682-15330.0837Lombardi et al, 200132Lombardi C. Gargioni S. Melchiorre A. Passalacqua G. Safety of sublingual immunotherapy in adults: a post marketing surveillance study.Allergy. 2001; 56: 889-892Crossref PubMed Scopus (72) Google Scholar19818-6535.50.51.5Pajno et al, 200333Pajno G.B. Peroni D.G. Vita D. Pietrobelli A. Parmiani S. Boner A.L. Safety of Sublingual immunotherapy in children with asthma.Paediatr Drugs. 2003; 5: 777-781Crossref PubMed Scopus (60) Google Scholar3545-153-460.15Not statedFiocchi et al, 200534Fiocchi A. Pajno G. La Grutta S. Pezzuto F. Incorvaia C. Sensi L. et al.Safety of SLI T in children aged 3 to 7 years.Ann Allergy Asthma Immunol. 2005; 95: 254-258Abstract Full Text PDF PubMed Scopus (115) Google Scholar653-7115Not stated6Drachenberg et al, 200435Drachenberg K.J. Urban E. Proll S. Woroniecki S.R. Sublingual specific immunotherapy for adults and children: a post marketing survey.Allergol Immunopathol. 2004; 32: 76-81Crossref PubMed Google Scholar1596-60<16.3Not stated5Agostinis et al, 200536Agostinis F. Tellarini L. Falagiani P. Canonica G.W. Passalacqua G. Safety of SLIT in very young children.Allergy. 2005; 60: 133Crossref PubMed Scopus (100) Google Scholar363-5250.07Not statedDi Rienzo et al, 200537Di Rienzo V. Minelli M. Musarra A. Sambugaro R. Pecora S. Canonica W.G. et al.Post-marketing survey on the safety of sublingual immunotherapy in children below the age of 5 years.Clin Exp Allergy. 2005; 35: 560-564Crossref PubMed Scopus (141) Google Scholar1283-525.60.21.5Rodriguez-Pérez et al, 200838Rodríguez-Pérez N. Ambriz-Moreno Mde J. Canonica G.W. Penagos M. Frequency of acute systemic reactions in patients with allergic rhinitis and asthma treated with sublingual immunotherapy.Ann Allergy Asthma Immunol. 2008; 101: 304-310Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar438-20111.6∗Including systemic side effects only.0.346Agostinis et al, 200839Agostinis F. Foglia C. Landi M. Cottini M. Lombardi C. Canonica G.W. et al.The safety of sublingual immunotherapy with one or multiple pollen allergens in children.Allergy. 2008; 63: 1637-1639Crossref PubMed Scopus (62) Google Scholar333-181414.432Lombardi et al, 200840Lombardi C. Gargioni S. Cottini M. Canonica G.W. Passalacqua G. The safety of sublingual immunotherapy with one or more allergens in adults.Allergy. 2008; 63: 375-376Crossref PubMed Scopus (32) Google Scholar15916-591636.541∗ Including systemic side effects only. Open table in a new tab There have been, until December 2011, 6 case reports41Antico A. Pagani M. Crema A. Anaphylaxis by latex sublingual immunotherapy.Allergy. 2006; 61: 1236-1237Crossref PubMed Scopus (111) Google Scholar, 42Eifan A.O. Keles S. Bahceciler N.N. Barlan I.B. Anaphylaxis to multiple pollen allergen sublingual immunotherapy.Allergy. 2007; 62: 567-568Crossref PubMed Scopus (113) Google Scholar, 43De Groot H. Bijl A. Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tablet.Allergy. 2009; 64: 963-964Crossref PubMed Scopus (105) Google Scholar, 44Blazowski L. Anaphylactic shock because of sublingual immunotherapy overdose during third year of maintenance dose.Allergy. 2008; 63: 374Crossref PubMed Scopus (88) Google Scholar, 45Dunsky E. Goldstein M.F. Dvorin M.J. Belecanech G. Anaphylaxis due to sublingual immunotherapy.Allergy. 2006; 61: 1235Crossref PubMed Scopus (132) Google Scholar of SLIT-induced systemic reactions that have been of a severity to be categorized as anaphylaxis.46Simons F.E.R. Ardusso L. Bilò B. El Gamal Y. Ledford D.K. Ring J. et al.Anaphylaxi
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