HDRs, previously called type B or bizarre [
17] are not directly related to the drug action but are individual responses in predisposed patients. These reactions are defined as quantitatively and qualitatively abnormal, unpredictable and often dose-independent. Concerning their pathogenesis, they are distinguished between non-immune and immune (or allergic). HDRs are less frequently described in the literature with respect to the ADRs in the elderly. It is well established that only certain drugs or biological agents have the structural characteristics of immunogenicity, being able to trigger immunopathological responses. Most drugs or their metabolites, however, have no such immunogenic properties. Therefore, in order to elicit an immune response, a phenomenon of haptenization is necessary. A typical example is provided by β-lactam antibiotics that have high reactivity with carrier proteins, able to induce an IgE-mediated reaction in predisposed patients. Moreover, there are drugs potentially able to induce clinical manifestations similar to allergic reactions, though immunological mechanisms are other than IgE-mediated reaction: ASA and NSAIDs, ACE inhibitors, opioids, iodinated contrast media, antibiotics such as ciprofloxacin and vancomycin, and muscle relaxants with ammonium group. It is known that allopurinol is able to elicit an hypersensitivity syndrome characterized by severe skin involvement, worsening of renal function with fever, leukocytosis and eosinophilia that can be fatal [
18]. It recognizes an immunological genesis determined by T lymphocyte clones specific for its metabolite, oxypurinol. Risk factors for the development of this syndrome are represented by an age ≥ 65 years, chronic renal insufficiency, concomitant treatment with thiazide diuretics and intermittent therapy with allopurinol [
19,
20]. HDRs represent 5–10% of all adverse reactions to drugs [
21], but as they are unpredictable and potentially lethal, they represent the most important kind of adverse reactions both in youth and elderly. In our study population the rate of HDRs was 30%, that is much higher than previously reported, presumably due to the fact that in our area many patients affected by ADRs are not referred to specialist’s evaluation. Risk factors related to patients are female gender, previous reactions to medications, genetic factors such as familiarity for drug allergy, association with particular MHC antigens, acetylator phenotype, and a personal history of atopy [
22]. Other risk factors comprise concomitant diseases such as viral infections, chronic liver disease or chronic renal failure [
23]. Moreover, renal failure not clinically apparent may result in an increased risk of ADRs, especially in water-soluble drugs, such as insulin and glibenclamide [
4,
24]. According to Beyth, the risk is correlated with the number of drugs taken and with the number of pathologies, as well as with the nutritional status and with alterations of pharmacodynamics and pharmacokinetics of the molecule involved [
25]. In the present study we observed that gender as well as multiple therapeutic regimens are risk factors in older age for HDRs, with an higher rate than patients aged under 65 years. Smoking habit, alcohol abuse and personal and familiar history of atopy did not differ between younger and older subjects. Atopy and previous reactions to drugs do not seem to represent risk factors in the elderly, while we observed a positive association with multiple drugs intake. This offers confirmation to previous observations about the lack of association of atopy and HDRs [
26], although this could be influenced by the severity of reactions in atopic subjects [
27]. The main clinical manifestation according to our data is skin involvement, as previously described in a study conducted on a cohort of 2644 subjects. In that study, after allergy testing HDRs were diagnosed in 2.1% of cases; 96% of symptoms were cutaneous (urticaria, angioedema, erythema, Steven Johnson syndrome, and psoriasis-like reactions). It was also observed that the peak of HDRs dramatically decreases in the eighth decade of life, with significant prevalence in females (80%). In the same study, comparing the two groups of patients (elderly and aged < 65 years), the family history and personal history of atopy was similar, comorbidities and multiple treatment regimen were instead a peculiarity of the elderly [
26]. Some authors have found that HDRs are less frequent and less severe in children and in elderly, probably due to immaturity and involution of the immune system typical of these periods of life [
28]. This is in contrast with our data that shows that anaphylactic shock is more frequent in > 65 years aged than in younger patients. In addition, in the present study antibiotics, medications for cardiovascular disease, NSAIDs and ASA were the drugs most frequently responsible for HDRs in the elderly. We observed that ASA and NSAIDs are the main factors of drug reactions in > 65 years aged while antibiotics are the main factor in < 65 years aged patients. Some chronic degenerative diseases such as atherosclerosis are favored by inflammatory phenomena that tend to induce chronic vascular endothelial lesions typical of this disease. A common mechanism appears to contribute to atherosclerosis and atopy [
29]. The activation of perivascular mast cells promotes atherosclerosis by the release of inflammatory cytokines that contribute to the activation and chemotaxis of macrophages, which incorporate the excess fats becoming “foam cells” (fatty cells) and generate the atherosclerotic plaque [
30]. Similarly, it is believed that leukotrienes play an important role in promoting atherosclerosis. A genetic variant of the 5-lipoxygenase has been associated both with asthma and atherosclerosis [
31]. In turn, the inflammatory cytokines released by mast-cells and macrophages in the genesis of the atherosclerotic plaque can form the protein component to which the hapten drug can bind, even in absence of albumin, the production of which by the liver is always reduced in the elderly [
32]. A recent study has also highlighted that the increased DNA methylation predisposes the elderly to respiratory allergic diseases, but could also predispose to HDRs [
33]. The misuse of complementary and alternative medicine and polypharmacy during different degenerative diseases afflicting the elderly is another risk factor for the development of drug allergy [
34]. A recent retrospective survey on 161 hospitalized patients (mean age 63 years) who had an HDR to medications during their hospital stay suggested that the administration of proton pump inhibitors (PPI), used in 83% of hospitalized patients, could favor the occurrence of HDRs, especially to NSAIDs. In fact, with the suppression of gastric acid, PPIs increase the persistence of labile proteins able to bind stably to other drugs taken by oral route, thus preventing the complete denaturing of the other drugs [
35]. Similarly, in a case report a patient aged 60 years developed generalized urticaria immediately after a second course of therapy with diclofenac and PPI, the latter having been used previously for gastroesophageal reflux. The authors postulated that allergy to diclofenac could have been favored by suppression of gastric acid and confirmed it on a murine model of sensitization [
36]. Considering the extensive use of PPIs as gastroprotective drugs in older patients treated with low dose ASA as a preventive therapy of myocardial ischemia, one could speculate that PPI might represent a co-factor in HDRs to ASA. In conclusion, the purpose of this study was to find data able to suggest the basis to develop strategies to minimize the incidence of HDRs in the elderly, as the Beers criteria have served to reduce significantly the phenomenon of inappropriate prescriptions in this time of life. According to the results, the comorbidity and proinflammatory status of the immune system, typical of the elderly, such as metabolic disorders, cardiovascular diseases, and osteoporosis may favor the onset of HDRs. In these patients not only beta-lactam antibiotics, able to elicit IgE-mediated responses, but also drugs that are able to elicit non IgE or cell-mediated drug reaction, as ASA, NSAIDs, ACE inhibitors or cyclooxygenase and bradykinin inhibitors have to be administered with caution in older patients. At the same time, in order to re-evaluate the issue of HDRs in the elderly and to establish shared parameters about the administration of drugs at risk of reactions, responsible for anaphylaxis or urticaria-angioedema syndrome, the incidence of HDRs in geriatric age and the risk factors for this type of reactions should be estimated. Based on adequate data, guidelines for the management of HDRs in the elderly should be issued.