**7. Safety and tolerability of SLIT in allergic children**

Over the last 20 years, sublingual allergen immunotherapy has gained popularity based on controlled trails that have demonstrated a favorable safety profile [78, 79]. Although a great number of DB-PC-RCT showed clinical efficacy of SCIT since the British Committee on Safety of Medicines in the UK reported 26 SCIT-related anaphylactic deaths between 1957 and 1986, the interest for alternative routes constantly grows. The risk of subcutaneous immunotherapy (SCIT)-related systemic adverse events (SAEs) still represent a major concern that may, sometimes limit the use of this effective treatment, especially in the pediatric population. On the other side the overall safety of SLIT has been widely proven and accepted [80]. Moreover, Nichani study showed that SLIT can be safely administered to patients who previously experienced systemic reactions in response to subcutaneous allergen immunotherapy.

According to double-blind placebo-controlled-randomized clinical trials (DB-PC-RCTs) for allergic asthma, allergic rhinitis or allergic rhinoconjunctivitis [80–84] and real-life studies only several life-threatening and nonlife-threatening severe systemic reaction related to SLIT are reported [50, 85–87]. Overall prevalence of systemic adverse events was lower than 20% in DB-PC-RCT, whereas the prevalence of severe systemic reactions was between 1 and 2% of total recorded events [88–93]. Most commonly postmarketing surveys reported mild to moderate usually self-resolved systemic reactions [94, 95]. A very important issue concerning SLIT particularly in the pediatric population is to define risk factors for developing systemic reactions. Up to now several potential risk factors are defined: inadequate administration conditions (use of non-standardized extracts, administration of products containing a mixture of many allergens, overdosing [92]), and/or patient-related nonspecific risk factors (include cardiovascular diseases and long-term therapy with noncardioselective betablockers) that are very uncommon in children [96]. Those conditions are considered as special precaution, but not contraindication for SLIT introduction. On the other side uncontrolled asthma or severe asthma, oral lesion, or acute infections can represent temporary contraindication for SLIT. Although previous systemic reaction due to SCIT were considered as absolute contraindication for all kinds of immunotherapy, results from recent studies showed that they do not represent risk factors for further usage of other kinds of ASIT including sublingual [96]. Local adverse reactions are most common SLIT-related side effects although it is not very easy to record them as it is not usually including in postmarketing analysis nor in DB-PC-RCT [50, 85–88]. Its prevalence varies from 50 to 80% and they include oropharyngeal and gastrointestinal reactions such as itching, pruritus, and eczema in oral mucosa and/or diarrhoea, vomitus, and abdominal pain [97–99].

The second issue that is also of a great importance is a matter of tolerability that can have a great impact on overall clinical outcomes [100]. Both systemic and local adverse events may have influence on treatment discontinuation as they are most common after the first administration. In order to improve adherence clinicians should be well educated and trained to recognize local and systemic adverse events and to give also patients adequate explanation how to deal with them, although SLIT has much better safety profile compared with subcutaneous allergen-specific immunotherapy. WAO proposal on grading local adverse events can help to achieve better tolerance and adherence [96].
