*3.6. Diagnostic Criteria*

As described in detail above, in order to better stratify the level of evidence for the diagnosis, we are herein proposing the first structured diagnostic approach for the diagnosis of HS to the best of our knowledge. We auspicate that this approach may allow clinicians to stratify patients with a clinical history consistent with the suspicion of HS in probable (criteria A + B) or convincing (criteria A + B + C) HS (Figure 1). According to our criteria, only 6 out of 61 patients had a convincing clinical diagnosis of HS, in 25 patients the clinical diagnosis was probable and in the others the HS diagnosis was doubtful (Table 1). Due to the heterogeneity in the methodologies applied for laboratory tests and missing reporting/lack of data, we decided to exclude laboratory parameters from the diagnostic criteria. We suggest in the future that milk-specific IgG tests with

current diagnostic methods (i.e., immunoenzymatic), in the case of suspected HS, could be studied. Nevertheless, further points remain questionable in our proposed diagnostic approach. First, some cases of occurrence of signs and symptoms during exclusive maternal breastfeeding were reported (e.g., in three out of seven cases in Heiner et al. [3], leading to the question of whether or not minimal quantities of CM passing in breast milk are capable of inducing a clinical response through an IgG-mediated mechanism in the infant). As a second observation, one case of resolution of signs and symptoms without dietary restriction has been described (one out of seven patients from Heiner et al.). Again, a real, controlled OFC of milk was reported only in 6 cases [3,7,11] and a recurrence of clinical manifestations was reported in a further 6 cases (although without details on exact timing of the symptoms' onset) based only on clinical history [5–7,13,14,16], for a total of 12 cases. Moreover, in some cases [13,14] pharmacological therapy was associated to the CM elimination diet, making it difficult to differentiate the effect of each single treatment. Spontaneous resolution of signs and symptoms also occurred in some cases of HS [1]. Furthermore, some studies did not report on the follow-up and specifically on the outcome of any CM reintroduction. In conclusion, even if in a few cases a convincing diagnosis can be made using specific criteria, certainty is lacking due to the incomplete clinical and imaging monitoring of the OFC and the lack of control cases.
