Penicillins and cephalosporins are two groups of widely prescribed antibiotics. They belong to the class of beta-lactam (BL) antibiotics because both possess the same BL nucleus. Allergic reactions are common side-effects of BL antibiotics. Studies in the 1960s and 1970s frequently estimated 10% cross-reactivity between penicillins and cephalosporins.1 2 However, at least two recent reviews showed much lower cross-reactivity.3 4 Notably, cross-reactivity is higher between penicillins and first- and second-generation cephalosporins compared with third- and fourth-generation cephalosporins.5 The latter two groups are considered safe alternatives for patients with penicillin hypersensitivity.6 The 10% cross-reactivity rate has recently been questioned as a medical myth.4 7 Yet until 2005, an influential drug reference such as the British National Formulary (BNF) abided by the “10% rule”.8 Faced with such recommendation, an ordinary physician naturally avoids all BL antibiotics in patients with a history suggestive of penicillin hypersensitivity.9 The implications are far-reaching as physicians often resort to expensive, broad-spectrum antibiotics, which may induce antibiotic resistance by selecting out resistant organisms.10 In order to minimise unnecessary exposure to expensive broad-spectrum antibiotics with higher toxicities and to preserve patients’ right to receive commonly prescribed antibiotics, a better understanding of BL cross-reactivity is needed. In the following discussion, the author will review the use of cephalosporins in patients with immediate hypersensitivity to penicillins. Mechanism and epidemiology of cross-reactivity will be discussed, followed by a suggestion for a pragmatic approach.

By definition, ‘cross-reaction’ between two substances is “the interaction of an antigen with an antibody formed against a different antigen with which the first antigen shares identical or closely related antigenic determinants”.11 Hence, antigenic similarity forms the basis of cross-reactivity. Public hospitals often suggest avoiding all cephalosporins indiscriminately for patients with penicillin hypersensitivity, as exemplified by a recent antibiotic guideline.12 What remains unsettled is how far the BL nucleus also acts as a common antigenic determinant. In other words, does structural similarity in the drug nucleus translate into clinically relevant allergic reaction?

The BL nucleus is probably the only structure common to penicillins and cephalosporins. What differentiates between them is that penicillins possess a 5-membered thiazolidine ring attached to the BL nucleus while cephalosporins have a 6-membered dihydrothiazine ring. Secondly, while penicillins have a single 6-positioned side-chain, cephalosporins have a 3-positioned as well as a 7-positioned side-chain.3

When a BL antibiotic is absorbed into the body, the BL nucleus undergoes spontaneous opening. Covalent bonding between the drug and endogenous protein results in a hapten-protein conjugate. In case of penicillins, stable protein conjugates formed include penicilloyl (major) determinants and other minor determinants.13 For cephalosporin, however, haptenic determinants are less clear.14 Once inside the body, cephalosporins undergo rapid fragmentation of the BL nucleus and dihydrothiazine rings. The resulting unstable metabolites do not allow haptenisation of proteins.15 In subjects with BL hypersensitivity, the hapten-protein conjugate has the capability to activate T-cells and the ensuing B-cell response. Specific immunoglobulin (Ig) E antibodies produced by B-cells become attached to the surface of effector cells such as mast cells and basophils. Subsequent exposure to the same drug induces formation of hapten-protein conjugates. Immediate hypersensitivity is the result of cross-linking of adjacent surface IgE molecules by the hapten-protein conjugates that culminates in rapid degranulation of preformed inflammatory mediators such as histamine and tryptase.16

Early cephalosporins before 1980s were contaminated with trace amounts of penicillin during the manufacturing process by the cephalosporium mould. That partly accounted for the higher cross-reactivity rate between penicillins and first-generation cephalosporins.14 Cross-reactivity within penicillins is based on common antigenic determinants. Antibody binding against basic structures such as BL ring or penicilloyl frequently results in higher cross-reactivity rate. More complex motifs, such as side-chains found only in certain sub-groups, are associated with lower cross-reactivity. An in-vitro experiment has identified two types of T-cells responsible for penicillin hypersensitivity. The restricted type is immunologically reactive against a combined penicilloyl and side-chain structure but exhibits little cross-reactivity with penicillins with different side-chains such as amoxicillin or ampicillin. The broad type does react against different penicillins, but not against cephalosporins.17

Epitopes (antibody-binding sites) on penicillin molecules may involve the BL nucleus, the thiazolidine ring, the side-chain or even the new antigenic determinant. Side-chain antigenic determinants account for 42% to 92% of the penicillin hypersensitivity.18 19 Epitopes on cephalosporin molecules are even more heterogeneous than penicillin, and involve the whole molecule.20 R1 side-chain and BL fragment protein conjugates appear to be the major determinants of cephalosporin hypersensitivity.21 R2 side-chain makes little contribution to cephalosporin hypersensitivity, as it disappears when the BL ring is opened.22

Human studies have provided insight into the role of similarity in the R1 side-chains in causing BL cross-reactivity.15 For instance, the 2-amino-2-phenylacetic acid side-chain in ampicillin is also present in first- or second-generation cephalosporins like cephalexin and cefaclor, respectively, but is absent in third- or fourth-generation cephalosporins. Similarly, the same 2-amino-2-(4-hydroxyphenyl) acetic acid side-chain is present in amoxicillin and cefadroxil but not in new generations of cephalosporins.16 In another study on selective amoxicillin hypersensitivity, Miranda et al23 have shown that oral challenge with cephadroxil, a first-generation cephalosporin that shared the same side-chain mentioned above, resulted in a cross-reactivity of 38%. On the other hand, use of cefamandole, a second-generation cephalosporin with a different side-chain from amoxicillin and cephadroxil, did not result in any cross-reactivity.23 Notwithstanding, other authors do not accord with the side-chain hypothesis.24 Fine structure within the side-chain such as methylene group has also been suggested as an antigenic determinant common to penicillins and cephalosporins.25

When dealing with potential cross-reactivity between penicillins and cephalosporins, one should take into account the background hypersensitivity rates in unselected population, which range between 0.7% and 10% for penicillins.26 However, among patients with a history of penicillin allergy, only 10% to 20% exhibit positive allergic reaction to skin test or challenge test.27 28 A non-urticarial, maculopapular skin rash is the most common allergic reaction with a frequency of 1% to 2%. The frequency of anaphylaxis per penicillin course is 0.01% to 0.05%.29 Similarly, background hypersensitivity rates for cephalosporins range between 1% and 10%, while anaphylaxis occurs in less than 0.02%.30 In other words, patients with penicillin hypersensitivity may develop non–cross-reacting allergic response to cephalosporins by coincidence. They are also at increased risk of non-BL hypersensitivity, with a reported rate of 16% to 23%.31 32 A caveat is that, as local prevalence data are lacking, epidemiological data can only be applied to the Hong Kong situation by extrapolation.

Skin test is an in-vivo method used to diagnose IgE-mediated allergic response. Substantial cross-reactivity in terms of skin testing exists between penicillins and first-generation cephalosporins. In the 1970s, Assem and Vickers33 studied 24 patients with penicillin hypersensitivity of which 11 (46%) showed positive intradermal test to cephaloridine; however, this reaction was not observed in any of the patients without penicillin hypersensitivity.33 Dash2 studied 100 patients with clinical reaction to penicillin and demonstrated positive cephalosporin skin test in 11 (11%) patients. However, seven (9.3%) of 75 control subjects without penicillin hypersensitivity also tested positive.2 In another study in the 1980s, Sullivan et al34 recruited 74 patients with penicillin hypersensitivity confirmed by positive skin prick test (SPT). Of these, 38 (50%) also exhibited a positive SPT to cephalothin, another first-generation cephalosporin.34 Audicana et al35 studied 34 patients allergic to penicillin and found that five (14%) had positive skin test to cephalexin, a first-generation cephalosporin, but none to ceftazidime, a third-generation cephalosporin. Romano et al36 studied 128 adult subjects with a history of immediate penicillin hypersensitivity; positive cephalosporin skin test was observed in 11% of them. Of the 128 subjects, 101 (94 skin test negative and 7 skin test positive for cephalosporins) who accepted the challenge could tolerate oral cefuroxime axetil and intramuscular ceftriaxone.36 Although controlled trial is not possible, the implication is that cephalosporins can be safely given to patients with a history of penicillin hypersensitivity but who have negative cephalosporin skin test.

Substantial in-vitro cross-reactivity also exists between penicillins and first-generation cephalosporins. In an early study in 1960s, Abraham et al37 were able to demonstrate haemagglutination antibody against cephalothin (titre of 1:8 or greater) in 22 (69%) of 32 patients who had been given penicillin but denied a history of cephalothin therapy. A subsequent adsorption study using penicilloic acid-solid phase by Zhao et al25 further identified cross-reacting specific IgE antibodies against both benzylpenicillin and cephalothin. Recently, Liu et al38 employed radioallergosorbent test to identify specific IgE antibodies against penicillins and cephalosporins in 420 subjects with penicillin hypersensitivity; cross-reacting specific IgE antibodies occurred in 22.6% of the subjects. Specific cephalosporin IgE antibodies were present in 27.1% of those with specific penicillin IgE antibodies, compared with 14.6% in those without specific penicillin IgE antibodies.38 However, in the absence of cross-linking, demonstration of antibodies cannot be equated with clinical reactivity.2

As skin test and in-vitro test are often inadequate for confirmation of cephalosporin hypersensitivity, one has to rely on a provocation test or the result of drug exposure. In an early review of 701 patients with a history of penicillin hypersensitivity, Petz39 reported an 8.1% reactivity rate to first- or second-generation cephalosporins, compared with 1.9% among those without penicillin hypersensitivity. In another cohort study in the 1980s by Solley et al,40 178 patients with a history of penicillin allergy were given cephalosporins. Positive reaction resulted in two patients, equivalent to a clinical cross-reactivity rate of 1.1%.40 Goodman et al41 reviewed the medical records of 413 patients with a self-reported history of penicillin allergy who underwent anaesthetic procedures that included antibiotic therapy. Only one patient (0.24%) probably developed cross-reactivity to cephalexin, a first-generation cephalosporin.41 Despite the retrospective nature and the lack of confirmatory tests, the low clinical cross-reactivity is reassuring.

Fonacier et al42 reviewed 83 patients with penicillin hypersensitivity who were subsequently given cephalosporins. Seven (8.4%) of them developed an adverse drug reaction. A definite history of penicillin hypersensitivity was found in six (85.7%) of the seven patients. Eleven (13.3%) patients with penicillin hypersensitivity also reported hypersensitivity reaction to other drugs such as non-BL antibiotics and codeine. Regarding the types of cephalosporin, clinical cross-reactivity rates between penicillin and first-, second-, third-, and fourth-generation cephalosporins are 4.6%, 50%, 10.5% and 0%, respectively. Small sample size and potential recall bias undermine the reliability of the study. The role of side-chain is highlighted by a 4-fold increase in the cross-reactivity rate between penicillins and cephalosporins with similar amino-benzyl ring side-chain.

In a large prospective study by Atanasković-Marković et al43 that included 644 children with a history of hypersensitivity reaction to penicillins, rate of cross-reactivity to cephalosporins was 31.5%. If the generations of cephalosporins were taken into account, the cross-reactivity rate with aminopenicillins differed by 100-fold, ranging from 0.3% to 0.7% in third-generation cephalosporins to around 32.4% to 38.5% in first- or second-generation cephalosporins, respectively. This, again, illustrates the relevance of side-chain in cross-reactivity. An interesting corollary is that, in patients with negative skin test to penicillins or cephalosporins, 0% to 1.8% of patients showed positive drug challenge to the test drug. Hence the false-negative rate of skin test is quite low. On the other hand, as patients with positive skin test were not further challenged with drugs to confirm clinical hypersensitivity, the true-positive rate cannot be ascertained.

A 5-year retrospective study by Apter et al32 reviewed 534 810 patients in the United Kingdom who received a penicillin followed by cephalosporin of which 64% were tested with first-generation cephalosporins. The authors compared 3920 patients with allergy-like events (ALE) within 30 days of receiving penicillin with 530 890 patients without ALE. Among 3920 patients with ALE after receiving penicillin, 1% cross-reacted with cephalosporins. The unadjusted risk ratios for ALE after the subsequent cephalosporin and sulphonamide challenges were 10.0 (95% confidence interval [CI], 7.4-13.6) and 7.2 (95% CI, 3.8-13.5), respectively, suggesting that patients allergic to penicillin may have an increased tendency for drug hypersensitivity via a mechanism other than cross-reactivity.

In another retrospective study, Daulat et al44 reviewed medical records of 606 patients with a history of penicillin allergy who were subsequently given a cephalosporin. Confirmatory penicillin skin testing was not reported. Clinical allergy occurred in only one patient given cefazolin, a first-generation cephalosporin. This is tantamount to a cross-reactivity rate of 0.165%. As drug allergy was suspected from diagnostic coding only, true penicillin allergy, and hence cephalosporin cross-reactivity, might have been higher.

In a landmark meta-analysis in 2007, Pichichero and Casey15 reviewed nine studies that compared allergic reaction rate to cephalosporins in patients with or without penicillin allergy. Among 47 284 patients with a history of penicillin allergy alone, the odds ratio (OR) for cephalosporin cross-reactivity in general was 2.63 (95% CI, 2.11-3.28; P<0.00001). However, the increased cross-reactivity rate was mainly due to first-generation cephalosporins, as the corresponding ORs for first-, second-, and third-generation cephalosporins were 4.79 (95% CI, 3.71-6.17; P<0.00001), 1.13 (95% CI, 0.61-2.12; P=0.70), and 0.45 (95% CI, 0.18-1.13; P=0.09), respectively. There was actually a trend towards decreased risk of cross-reactivity to third-generation cephalosporins, although the result did not reach statistical significance.

In a cohort study by Solley et al,40 none of the 27 patients with a history of penicillin allergy and a positive penicillin skin test developed clinical reactivity to cephalosporins. On the contrary, two of the 151 patients with allergic history but negative penicillin skin test reacted to cephalosporins, putting to doubt the value of penicillin skin test in predicting cross-reactivity to cephalosporins.40 In another small cohort study by Blanca et al,45 19 patients with confirmed penicillin hypersensitivity were given parenteral cephamandole, a second-generation cephalosporin, followed by oral cephaloridine, a first-generation cephalosporin, if the former was tolerated. Two (10.5%) of the 19 patients cross-reacted with cephamandole while all the remaining 17 patients tolerated cephaloridine.

Sastre et al24 subjected 16 patients with selective amoxicillin hypersensitivity confirmed by skin test or drug challenge with cephadroxil, a first-generation cephalosporin. Two (12%) were found to be cross-reactors.24 Novalbos et al46 recruited 41 patients with a history of penicillin hypersensitivity confirmed by either skin test or drug challenge. Patients were then challenged with three cephalosporins (cephazoline, cefuroxime and ceftriaxone) with side-chains which were different from that of penicillin. None of them cross-reacted with the cephalosporins.46 Hameed and Robinson47 recruited 158 patients with positive penicillin test. Seven (4.4%) of them developed immediate hypersensitivity when given cephalosporins. None of the cephalosporins was from the third generation.47 There is a lack of published reports on anaphylactic reaction to cephalosporins in children with a history of anaphylaxis to penicillins, and only a few such reports in adults have been published.47

Macy and Burchette48 studied 83 patients with a history of adverse reaction to penicillin confirmed by skin test. Post–skin test exposure to cephalosporins in 42 resulted in adverse reaction in one, amounting to 2.4% cross-reactivity rate. The corresponding figure for non-BL was eight (10.8%) out of 74, suggesting that in patients allergic to penicillin, cross-reactivity for non-BLs may be even higher than that for BLs.48 This study and the one by Apter et al32 have significant implications for practitioners who routinely employ non-BL antibiotics for patients with penicillin hypersensitivity.

In a preoperative assessment clinic, Park et al49 recruited 1072 patients with a history of BL allergy for penicillin skin testing. Among the 999 patients who underwent the skin test, 43 had a positive skin test for penicillin and three of those 43 eventually received cefazolin. None developed cross-reactivity.49 Ahmed et al50 reviewed 173 children with a history of penicillin hypersensitivity, with or without a skin test, who underwent cephalosporin challenge. None among those with positive skin test showed reactivity. However, one (0.7%) of the 152 patients with negative skin test had an immediate allergic reaction after cephalexin, underscoring the lack of predictive power of the penicillin skin test.50

In a meta-analysis by Pichichero and Casey,15 1831 patients with a history of penicillin allergy also received penicillin skin test. Compared with patients with negative skin test, the OR for cross-reactivity to any cephalosporin for patients with positive results was 1.48 (95% CI, 0.64-3.41; P=0.36). Corresponding ORs for first-, second-, and third-generation cephalosporins were 4.13 (95% CI, 0.70-24.51; P=0.11), 1.33 (95% CI, 0.32-5.52; P=0.69), and 0.75 (95% CI, 0.15-3.66; P=0.72), respectively.15 There was a trend towards increased risk for first-generation cephalosporins, although the result did not reach statistical significance.

Studies on cephalosporin drug challenge in patients with a history of penicillin hypersensitivity have several inherent limitations. Firstly, retrospective studies are subjected to recall bias. Secondly, the so-called ‘positive reaction’ may include ‘nocebo effects’, ie untoward effects after administration of an inert substance, which may occur in around 27% of subjects.51 Thirdly, as most studies excluded patients with positive penicillin skin test, investigators had no way to tell whether these patients could actually tolerate cephalosporins. Lastly, most studies of cephalosporin challenge were performed in an open, uncontrolled manner. Patients with penicillin allergy who may have underlying multiple drug allergy syndrome will be missed in the absence of a control arm, such as non-BL group.52

Review of published studies, as described above, shows that cross-reactivity between penicillins and cephalosporins, if restricted to clinical reaction or positive drug challenge, varies between 0% and 31.5% (Fig 1). Among the 14 studies that included a total of 6464 patients with penicillin hypersensitivity, 279 showed clinical reactivity or positive challenge to cephalosporins, resulting in an average cross-reactivity rate of 4.32%. Corresponding figures for patients with a history of penicillin allergy alone and those confirmed by investigations are 4.34% and 3.76%, respectively. Studies reporting rates higher than 10% are mainly those involving first- or second-generation cephalosporins, especially when in-vitro or skin tests were employed. It must be emphasised that although cross-reactivity is substantial with first-generation cephalosporins (up to 32%), it is less than 1% for third- and fourth-generation cephalosporins.

A probable reason for the low cross-reactivity stems from the fact that, despite having the same BL nucleus, penicillins and cephalosporins are immunologically different. If the BL nucleus is the common antigenic determinant, one should expect a very high cross-reactivity. However, this is not the case because the BL ring opens in the process of metabolism to form major or minor determinants. Secondly, newer generations of cephalosporin do not share similar side-chains with penicillins, hence cross-reactivity will, generally, not occur. Thirdly, among patients with alleged penicillin hypersensitivity, less than 10% show genuine hypersensitivity. The majority of cases may suffer from transient adverse reaction followed by subsequent tolerance to cephalosporins.7

Despite current recognition of the low cross-reactivity rate, international guidelines are not unanimous in their recommendations regarding the use of cephalosporins in patients with penicillin hypersensitivity. A recent practice parameter from a Joint Task Force in the United States stated that “most patients with a history of penicillin allergy tolerate cephalosporins”.10 If patients with positive penicillin skin test are given cephalosporins, around 2% may cross-react, including some with anaphylactic reactions. If a clinician chooses not to skin test a patient with a history of penicillin allergy but directly prescribe a cephalosporin, the chance of developing a reaction is probably less than 1%. In treating otitis media in children with penicillin allergy, the American Academy of Pediatrics simply suggested prescribing, rather than avoiding, either second- or third-generation cephalosporins.53 Basing on dissimilarity in chemical structures, the Academy considered cross-reactivity between penicillin and second- or third-generation cephalosporins to be ‘highly unlikely’.

A relatively conservative approach is adopted by the Infectious Diseases Society of America (IDSA). In the 2012 clinical practice guideline for bacterial rhinosinusitis, the IDSA recommended third-generation cephalosporins only for patients with non–type I penicillin allergy. Non-BL antibiotics were recommended for those with type I penicillin allergy.54 Even more conservative is the British Medical Association; in the 2014 edition, the BNF advised against using cephalosporins in patients with penicillin hypersensitivity. Nevertheless, if no other alternatives are available, third- and fourth-generation cephalosporins can be used, albeit with caution.55

Skepticism still lingers within the medical community in Hong Kong. For instance, a recent public hospital antibiotic guideline does not differentiate between different generations of cephalosporins, but treats all cephalosporins as having the potential to cross-react with penicillins.56 The IMPACT guideline in Hong Kong has aptly pointed out a deep-rooted preoccupation with cross-reactivity among the medical profession. The guideline suggests that “second, third and fourth generation cephalosporins have negligible cross-reactivity with penicillin”. However, it also raises a common concern that contra-indications indicated in product inserts have resulted in “medico-legal implications when using cephalosporins in patients with penicillin allergy”.57 This concern is understandable but unfounded, for two reasons. Firstly, a legal case appealed to the New Jersey Supreme Court in 1998 has come to the final decision that product inserts alone do not establish a standard of care.3 Secondly, a review of the inserts shows that, rather than contra-indicating the use of cephalosporins, pharmaceutical companies only issue words of caution in patients with penicillin allergy.58 59

For patients with suspected penicillin hypersensitivity, one should begin with careful history and physical examination to establish the likelihood of adverse drug reaction. Clinicians will not do justice by simply avoiding all cephalosporins in patients with so-called penicillin hypersensitivity. Injudicious use of non-BL antibiotics without precaution is falsely reassuring and will expose patients with allergic tendency to further drug hypersensitivity.

Allergological investigations should preferably be done 4 to 6 weeks after resolution of adverse drug reaction.60 One should start from skin testing to confirm penicillin hypersensitivity. Ideally, skin test reagents should include penicilloyl polylysine (PPL) and minor determinant mixture (MDM). Unfortunately, the two major manufacturers, Allergopharma (Hamburg, Germany) and Hollister-Stier (Spokane, WA, US) ceased production of PPL and MDM in 2004. Although Diater (Madrid, Spain) has launched the production of PPL and MDM since 2003, the reagents have not gained widespread popularity in Hong Kong.61 Besides, diagnosis of selective reaction to a single BL requires a long algorithm, which begins testing with PPL and MDM, followed by the culprit drug.5 This may be tedious and time-consuming in daily clinical practice. For pragmatic purposes, it is often the culprit drug and/or a potentially safe alternative that will be tested and prescribed. Non-irritating concentration of the culprit drug should be employed for skin testing.62

Patients with negative penicillin skin test may undergo supervised drug provocation test (DPT) of the culprit drug.3 The aim of DPT is to exclude or confirm the diagnosis of drug hypersensitivity and to find a safe alternative for future use. Drug provocation test generally has a high negative predictive value of 94% to 98%. A caveat is that anaphylactic reactions can still occur among a few cross-reacting patients. Hence, DPT must be performed by experienced personnel in a setting with resuscitation facilities.60 Patients with remote or severe hypersensitivity may be re-tested 2 to 4 weeks later to exclude a small but possible risk of re-sensitisation after initial negative testing. Contra-indications to DPT include a history of severe cutaneous drug reactions (eg Stevens-Johnson syndrome or toxic epidermal necrolysis), severe anaphylaxis or certain medical conditions (eg uncontrolled asthma or pregnancy).63 In the absence of severe or recent immediate penicillin hypersensitivity, patients may choose to receive penicillin directly without skin testing.10 To further ensure drug safety, the first dose may be divided into incremental steps similar to DPT.

Patients who have a history of severe penicillin hypersensitivity, a positive penicillin skin test or DPT may resort to cephalosporins. However, a positive penicillin skin test does not predict cross-reactivity with cephalosporin.30 50 Clinicians may perform skin tests using a cephalosporin with a different side-chain to guide clinical use.10 Unfortunately, the diagnostic accuracy of cephalosporin skin test is difficult to establish.5 Studies generally have shown low sensitivity and positive predictive value.64 65 Nevertheless, skin test for BL hypersensitivity is still considered ‘good’ by the International Consensus in 2014.60 Patients with negative cephalosporin skin test should pass a DPT before finally receiving a cephalosporin. Patients who fail the DPT may be given a non-BL antibiotic or undergo desensitisation, if the cephalosporin is essential.60 A suggested algorithm for investigation and management of suspected immediate penicillin hypersensitivity is summarised in Figure 2.

The available evidence to date does not support the notion of a 10% cross-reactivity rate between penicillins and cephalosporins. Above all, 10% is an oversimplified and indiscriminate generalisation of cross-reactivity. Scientific evidence supports the side-chain hypothesis and a low cross-reactivity rate. Clinicians should adopt a personalised approach towards BL cross-reactivity. Finally, future research on the local prevalence of BL hypersensitivity and cross-reactivity is needed.

No conflicts of interests were declared by the author.

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40. Solley GO, Gleich GJ, Van Dellen RG. Penicillin allergy: clinical experience with a battery of skin-test reagents. J Allergy Clin Immunol 1982;69:238-44. CrossRef

41. Goodman EJ, Morgan MJ, Johnson PA, Nichols BA, Denk N, Gold BB. Cephalosporins can be given to penicillin-allergic patients who do not exhibit an anaphylactic response. J Clin Anesth 2001;13:561-4. CrossRef

42. Fonacier L, Hirschberg R, Gerson S. Adverse drug reactions to a cephalosporins in hospitalized patients with a history of penicillin allergy. Allergy Asthma Proc 2005;26:135-41.

43. Atanasković-Marković M, Velicković TC, Gavrović-Jankulović M, Vucković O, Nestorović B. Immediate allergic reactions to cephalosporins and penicillins and their cross-reactivity in children. Pediatr Allergy Immunol 2005;16:341-7. CrossRef

44. Daulat S, Solensky R, Earl HS, Casey W, Gruchalla RS. Safety of cephalosporin administration to patients with histories of penicillin allergy. J Allergy Clin Immunol 2004;113:1220-2. CrossRef

45. Blanca M, Fernandez J, Miranda A, et al. Cross-reactivity between penicillins and cephalosporins: clinical and immunologic studies. J Allergy Clin Immunol 1989;83:381-5. CrossRef

46. Novalbos A, Sastre J, Cuesta J, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy 2001;31:438-43. CrossRef

47. Hameed TK, Robinson JL. Review of the use of cephalosporins in children with anaphylactic reactions from penicillins. Can J Infect Dis 2002;13:253-8.

48. Macy E, Burchette RJ. Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up. Allergy 2002;57:1151-8. CrossRef

49. Park M, Markus P, Matesic D, Li JT. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol 2006;97:681-7. CrossRef

50. Ahmed KA, Fox SJ, Frigas E, Park MA. Clinical outcome in the use of cephalosporins in pediatric patients with a history of penicillin allergy. Int Arch Allergy Immunol 2012;158:405-10. CrossRef

51. Liccardi G, Senna G, Russo M, et al. Evaluation of the nocebo effect during oral challenge in patients with adverse drug reactions. J Investig Allergol Clin Immunol 2004;14:104-7.

52. American Academy of Allergy Asthma & Immunology. Work group report: cephalosporin administration to patients with a history of penicillin allergy May, 2009 [cited 2014 April 6]. Available from: https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and%20Parameters/Cephalosporin-administration-2009. pdf. Accessed Apr 2014.

53. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics 2013;131:e964-99. CrossRef

54. Chow AW, Benninger MS, Brook I, et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis 2012;54:e72-e112. CrossRef

55. British Medical Association and the Royal Pharmaceutical Society of Great Britain. British National Formulary BNF 66 September 2013. London: BMJ Books; 2014.

56. Ching B. Hospital Authority guideline on known drug allergy checking. Hong Kong: Hospital Authority; 2013.

57. Reducing bacterial resistance with IMPACT—Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy. 4th ed. Hong Kong: Centre for Health Protection; 2012.

58. Ceftriaxone for Injection, USP [package insert] Lake Forest, IL: Hospira; [updated Dec 2010; cited 2014 June 22]. Available from: http://www.hospira.com/Images/EN-2726_32-91495_1.pdf. Accessed Jun 2014.

59. Cefotaxime for Injection, USP [package insert] Bridgewater, NJ: Sanofi; [updated Feb 2014; cited 2014 June 22]. Available from: http://products.sanofi.us/claforan/claforan.pdf. Accessed Jun 2014.

60. Demoly P, Adkinson NF, Brockow K, et al. International Consensus on drug allergy. Allergy 2014;69:420-37. CrossRef

61. Romano A, Viola M, Bousquet PJ, et al. A comparison of the performance of two penicillin reagent kits in the diagnosis of beta-lactam hypersensitivity. Allergy 2007;62:53-8. CrossRef

62. Brockow K, Garvey LH, Aberer W, et al. Skin test concentrations for systemically administered drugs—an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013;68:702-12. CrossRef

63. Aberer W, Bircher A, Romano A, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 2003;58:854-63. CrossRef

64. Romano A, Gaeta F, Valluzzi RL, Alonzi C, Viola M, Bousquet PJ. Diagnosing hypersensitivity reactions to cephalosporins in children. Pediatrics 2008;122:521-7. CrossRef

65. Yoon SY, Park SY, Kim S, et al. Validation of the cephalosporin intradermal skin test for predicting immediate hypersensitivity: a prospective study with drug challenge. Allergy 2013;68:938-44. CrossRef

Helicobacter pylori (HP) is a frequent gastro-intestinal infectious agent having worldwide distribution. It is a Gram-negative, microaerophilic, spiral bacterium that shows particular tropism for the gastric mucosa, and induces a strong inflammatory response with release of various bacterial and host-dependent cytotoxic substances. In 1984, Marshall and Warren1 first described HP. At first, they named the bacterium as Campylobacter pyloridis. Later, it was renamed as Helicobacter pylori.1 2 3 4 Helicobacter pylori has been linked to different forms of gastritis, peptic ulcer disease, low-grade gastric lymphoma arising from mucosa-associated lymphoid tissue, and gastric adenocarcinoma.5 The host, and environmental and bacterial factors are important in the clinical manifestations of infections with this bacillus.6 Apart from its well-demonstrated role in gastroduodenal diseases, some authors have suggested a potential role of HP infection in several extra-intestinal pathologies including haematological, cardiovascular, neurological, metabolic, autoimmune, and skin diseases.2 7 8 The immunological response caused by this bacterium is oriented locally as well as systemically. This immunological response may cause local damage as well as influence the clinical course of other diseases, including those outside the stomach, thus, opening the field of extragastric manifestations of HP infection.9

Gastric colonisation by HP is accompanied by production of large quantities of various pro-inflammatory substances such as cytokines, eicosanoids, and acute-phase proteins. This inflammatory response may lead to the development of antigen-antibody complexes or cross-reactive antibodies (by molecular mimicry) resulting in damage to other organs. In addition, increased permeability of the gastric and intestinal mucosa in infected patients may result in increased exposure to alimentary antigens. The key pathophysiological events in HP infection include initiation and continuance of an inflammatory response.4 6 10 Helicobacter pylori strains have been divided into types I and II. Type I strains express cytotoxin-associated antigen (CagA) and vacuolating cytotoxin antigen (VacA), whereas type II strains do not express any antigens.7 Helicobacter pylori infection is associated with mucosal inflammation due to infiltration by neutrophils and monocytes in the gastric mucosa. Urease, catalase, protease, lipase, and phospholipase are produced by HP, and these enzymes may be involved in the pathogenesis of gastric inflammation.11 Translocation of CagA into the gastric epithelial cells leads to increased levels of pro-inflammatory cytokines such as tumour necrosis factor–α, interleukin (IL)-6, IL-10, and IL-8. The VacA protein interacts with macrophages, B- and T-lymphocytes and causes reduced IL-2 production with resultant suppression of IL-2–mediated T-lymphocyte proliferation. The interaction between HP and B-lymphocytes results in uncontrolled growth and proliferation of predominantly CD5+ B-cells that produce polyreactive and autoreactive immunoglobulin (Ig) M and IgG3 antibodies. The antibodies produced do not result in clearance of the pathogen and may result in further production of autoreactive antibodies, such as anti-H/KATPase antibodies. These autoantibodies have been implicated in the development of gastric atrophy.12 Franceschi et al13 found an epidemiological link between CagA- and VacA-positive HP strains and idiopathic dysrhythmias in a study with 54 dysrhythmic patients.

Helicobacter pylori infection has been considered a potential inducer of several immune-mediated skin disorders. A considerable number of reports have attempted to link HP infection with the development of skin disorders, with numerous studies showing either negative or positive results. Most animal models of diseases do not provide data to support the role of HP in skin disease development. Most of the mechanisms discussed in the literature remain as hypotheses that require more extensive investigation. We need to emphasise that these studies investigating the role of HP, speculate, rather than demonstrate, a pathogenic role for this pathogen. These disorders can be manifestations of systemic vasculitides (Behçet’s disease [BD]) or may be related to skin disorders with presumed autoimmune origin (urticaria, psoriasis, alopecia areata [AA], lichen planus, etc).4

The results of studies investigating HP seropositivity in skin diseases and the effect of eradication therapy (amoxycillin and clarithromycin in triple therapy) are conflicting. Helicobacter pylori infection triggers a marked local inflammatory response and a chronic systemic immune response. It is possible that inflammatory mediators released during the immune response to HP infection may play a role in the pathogenesis of skin diseases. Helicobacter pylori eradication may result in total or partial remission of clinical symptoms in at least some cases of skin diseases with itching. There are also some studies in which certain patients achieved complete remission after successful eradication with appropriate treatment. Helicobacter pylori eradication has no effect on psoriasis, and there is no exact evidence of an association between HP infection and psoriasis. In addition to this, eradication therapy is not always effective for treating chronic urticaria.7 14 Thus, long-term, randomised, placebo-controlled systematic studies on the potential effects of HP eradication in patients with skin diseases are needed.

In this review, skin diseases that are thought to be associated with HP and the results of eradication therapies will be discussed.

Approximately, 15% to 25% of the population will experience at least one episode of urticaria in their lifetime, and an estimated one fourth of these people will have chronic urticaria.14 15 Chronic urticaria is a skin disorder characterised by recurrent, transitory, itchy wheals, which occur daily or almost daily, and persist for longer than 6 weeks in the absence of a physical cause. The clinical symptoms are caused by the release of histamine and other vasoactive mediators induced by the binding of an allergen to the specific receptor on mast cells.16 The factors that have been identified as possibly being important in the pathogenesis of chronic urticaria include infections, food additives, medications, malignancy, physical factors, and vasculitis.14 17 The aetiology of chronic urticaria is unknown in 50% to 60% of cases, and this group is defined as chronic idiopathic urticaria (CIU). Patients having demonstrable histamine-releasing autoantibodies are classified as CIU and they have very strong association with autoimmune diseases such as thyroiditis, vitiligo, insulin-dependent diabetes mellitus, rheumatoid arthritis, and pernicious anaemia.18 An association between HP and CIU has been proposed. One of the suggested pathogenic mechanisms is an increase in gastric vascular permeability during infection resulting in increased exposure of the host to alimentary allergens. The other one is immunological stimulation by chronic infection leading to, through mediator release, a non-specific increase in sensitivity of the cutaneous vasculature to vasopermeability-enhancing agents. Another hypothesis is that infection with HP may induce production of pathogenetic antibodies, possibly, by molecular mimicry.3 6 7 Helicobacter pylori infection might be a source of circulating immune complexes and these immune complexes may trigger urticaria.5 19 20

The results of studies investigating HP prevalence in patients with chronic urticaria and the effect of eradication are conflicting. Fukuda et al21 performed a study to assess the prevalence of HP infection and effect of bacterial eradication on skin lesions in patients with CIU (n=50). They found that 52% of the patients (n=26) with CIU were HP-seropositive, while 48% of the control subjects were HP-seropositive (statistically non-significant). Of the 26 patients with CIU infected with HP, 19 received eradication therapy, and eradication was successful in 17 of them. Of these 17 patients, six (35%) had complete remission and 11 (65%) had partial remission. On the other hand, of the nine patients without HP eradication, only two (22%) showed partial remission and seven (78%) had no improvement.21 According to this study, eradication of HP would be a valid choice for the treatment of CIU if patients were infected with HP.

Wedi et al22 studied prevalence of HP-associated gastritis in chronic urticaria. A potential infectious trigger could be identified in 43 (43%) of 100 patients with chronic urticaria. Of patients with focal lesions, 26 (60%) had HP-associated gastritis. Elevated HP IgA and/or IgG antibodies were found in 47 (47%) patients. Of the 47 seropositive subjects, 25 underwent endoscopy with biopsies. Gastritis of antrum (100%) and/or corpus (46%) was confirmed histologically in all these patients. In 91% of subjects, urticaria disappeared or improved after eradication treatment, whereas only 50% of untreated HP-seropositive subjects improved spontaneously. The reported association between HP and urticaria is consistent with an aetiological role of HP but does not prove it. However, the disappearance or improvement of urticaria in almost all subjects (91%) after HP eradication provides strong evidence for a causal relationship between HP gastritis and urticaria.22

Schnyder et al23 identified 46 patients with CIU. Infected patients were treated in a double-blind placebo-controlled crossover study with amoxycillin and lansoprazol. They assessed HP status by enzyme-linked immunosorbent assay (ELISA) IgG and ¹³C urea breath test (¹³C-UBT). Of the 50 patients, 14 (28%) had a positive serology for HP and 12 (24%) had active HP infection, as demonstrated by ¹³C-UBT. Of the 46 (92%) patients with CIU followed up for 6 months, 19 (41%) had CIU resolved within 6 months without any or only symptomatic treatment (mainly non-sedating antihistamines). Eleven of 12 patients with active HP infection participated in the double-blind crossover study. Eradication could be achieved in three (27%) subjects and in four (36%) individuals a resolution of the chronic urticaria was observed. Urticaria resolved in only one patient after successful eradication treatment, whereas the urticaria disappeared without eradication of HP in three patients. Thus, in this study, neither the frequency of HP infection nor the response to treatment indicated a causal relationship between chronic urticaria and HP infection.23

Moreira et al24 evaluated 21 patients with CIU using ¹³C-UBT. Triple therapy (amoxycillin, clarithromycin, and omeprazole) were given to infected patients for 7 days. The results of therapy were assessed by ¹³C-UBT 1 month after therapy. Urticaria and gastro-intestinal symptoms were assessed on enrolment and for 6 months after eradication. Prevalence of HP infection was 71% (15/21); HP eradication rate was 86% (12/14). Three patients had clinical improvement with total resolution of urticaria, starting immediately after eradication therapy.

In another study,25 78 patients with chronic urticaria were checked for the positivity of autologous serum skin test (ASST) and ¹³C-UBT; 21 patients had both positive ASST and positive ¹³C-UBT (group A), and 24 patients had negative ASST and positive ¹³C-UBT (group B). All patients with positive ¹³C-UBT received eradication treatment. The effect of HP eradication on chronic urticaria was evaluated by urticaria activity score (UAS), measured at study entry, and at 8 and 16 weeks. At week 8, baseline UAS reduced from 4.7 ± 1.1 to 2.4 ± 1.4 (P=0.027) in group A and from 4.3 ± 1.5 to 2.3 ± 1.2 (P=0.008) in group B, but there was no statistical significance between the two groups. In control group and in six patients with HP eradication failure, no changes in UAS were noted. The authors concluded that an improvement in UAS was related to HP eradication, irrespective of ASST positivity.25

In a cohort of 42 patients with CIU, Di Campli et al16 found that 55% were infected by HP; 88% of infected patients, in whom the bacterium was eradicated after therapy, showed a total or partial remission of urticaria symptoms. Conversely, symptoms remained unchanged in all uninfected patients. According to this study, HP eradication was associated with remission of urticaria symptoms, suggesting a possible role of HP in the pathogenesis of this skin disorder.

Daudén et al26 evaluated 25 patients with chronic urticaria using ¹³C-UBT to find a 68% prevalence of HP infection; this value did not differ from that in the general population. After eradication therapy, only one patient showed complete remission of urticaria and two patients showed partial remission. These results support a lack of relationship between HP infection and the course of CIU.

There are many studies in the literature showing the interactions between HP and chronic urticaria. However, the results of studies investigating HP prevalence in patients with urticaria and the effect of eradication are conflicting. For this reason, more randomised and case-control studies are necessary to prove an association between HP and CIU.

Rosacea is a common chronic facial dermatosis in adults which primarily affects those aged 30 to 60 years, with women being more often affected than men, especially in the early disease stages.27 28 It is characterised by transient or persistent central facial erythema, visible blood vessels, and often, papules and pustules.4 29 The skin manifestations progress in stages. The disease lasts for years, with episodes of improvement or exacerbation. Alcohol, sun exposure, and consumption of coffee and other products containing caffeine, as well as hot or spicy food, may precipitate exacerbation. Four subtypes of the disease have been recognised: erythematotelangiectatic, papulopustular, phymatous, and ocular rosacea.28 Although rosacea is a common disease, its cause remains a mystery. Endocrinological, pharmacological, immunological, infectious, climatic, thermal, and alimentary factors are implicated as triggers in its aetiology.27 30 There is no laboratory benchmark test and aetiopathogenesis and physiology of the condition are not exactly understood. The role of microorganisms in the development of rosacea has been addressed in a variety of studies, but clear evidence for their pathogenic role has not been demonstrated. The relationship between rosacea and HP infection has previously been investigated by a number of researchers. Rosacea has often been related to hypochlorhydria, gastritis, and abnormalities in jejunal mucosa. The seasonal behaviour of peptic ulcer and of rosacea is similar. Moreover, metronidazole benefits both rosacea and peptic ulcer; in the latter case, the effects are due to its activity on HP. It is proposed that the bacterium, through the production of specific cytotoxins and the release of vascular mediators like histamines, might be the triggering factor for the development of rosacea. These clues suggest that HP may be actively involved in the pathogenesis of rosacea.31 32

Diaz et al33 examined a series of 49 patients to assess the potential association between the severity of rosacea and direct and serological evidences of HP infection. Patients with rosacea were classified by severity into non-inflammatory/erythematotelangiectatic or inflammatory/papulopustular rosacea, and were tested for current HP infection and evidence of previous exposure by using ¹³C-UBT and ELISA test for IgG antibodies to the 120 kDa (CagA) antigen of HP. Positive ¹³C-UBT and ELISA tests were more likely to be observed in patients with inflammatory rosacea, although not statistically significant (odds ratio [OR]=3.0; P=0.15 and OR=2.9, P=0.16, respectively). However, when the two assays were interpreted in series, patients with inflammatory/papulopustular rosacea were 4.5 times more likely to exhibit positive test results on both ¹³C-UBT and ELISA versus at least one negative result (OR=4.5; P=0.06). This study provides sufficient evidence suggestive of a positive association between the severity of rosacea and the presence of HP to warrant further research.33

Utaş et al31 evaluated 25 rosacea patients and 87 age- and sex-matched healthy controls to investigate the effect of HP eradication therapy in patients with rosacea. They detected IgG and IgA antibodies against HP in both groups. An upper gastro-intestinal endoscopy and a rapid urease test were performed on the 13 patients with rosacea. Amoxycillin 500 mg 3 times daily, metronidazole 500 mg 3 times daily, and bismuth subcitrate 300 mg 4 times daily were administered to patients positive for HP. There was no statistical difference in seropositivity between the two groups. In HP-positive rosacea patients, there was a significant decrease in the severity of rosacea after eradication. These findings suggest that HP may be involved in rosacea, and that eradication treatment may be beneficial.31

Bamford et al34 evaluated 320 patients with rosacea using the rapid whole blood test and the UBT in a randomised, double-blind, placebo-controlled clinical trial. A total of 145 patients were seropositive for HP; 50 patients had a positive UBT for HP and 44 patients were enrolled in the study (the rest did not complete the study or had side-effects). The treatment group received a 14-day therapy including clarithromycin 500 mg orally 3 times a day, and omeprazole 40 mg orally once a day. There was no statistical difference when the results of active treatment were compared with those of placebo. It was concluded that treating HP infection had no short-term beneficial effect on the symptoms of rosacea to support the suggested causal association between HP infection and rosacea.34

In a prospective study, Boixeda de Miquel et al35 studied 44 patients diagnosed with rosacea; HP infection was determined, and infected patients were treated with eradication therapy. A subgroup of 29 infected patients in whom eradication had been achieved was followed up for a mean (± standard deviation [SD]) duration of 16.8 ± 17.8 months. Complete improvement was observed in 10 (34.5%) patients, relevant improvement in nine (31.0%), poor improvement in five (17.2%), and absence of improvement in five (17.2%) cases. Regarding subtype of rosacea, there was a relevant improvement in 83.3% of cases with papulopustular type as opposed to 36.5% of cases with erythematous predominance (P=0.02). This study suggests a correlation between HP and rosacea, and that it is worthwhile to investigate for HP infections as an appreciable percentage of patients diagnosed with rosacea and HP infection benefited from eradication therapy, predominantly in the papulopustular subtype.35

Argenziano et al36 evaluated serum IgG, IgA anti-HP and anti-CagA antibodies by means of ELISA and immunoenzymatic method (RADIM) in a group of 48 patients with rosacea. They found IgG antibodies in 81% of the rosacea patients with dyspepsia and 16% of the rosacea patients without dyspeptic symptoms. The IgA anti-HP antibodies were present in 62% of patients with dyspepsia and in 6% of patients with no upper gastro-intestinal symptoms. Anti-CagA antibodies were seen to be present in 75% of patients with both rosacea and gastric symptomatology, and were prevalent in patients affected by rosacea with papular symptoms versus rosacea with erythematous symptoms. This study, thus, suggested a correlation between rosacea and HP infection.36

Szlachcic37 studied 60 patients (aged 30-70 years) with visible cutaneous rosacea symptoms and 60 age- and gender-matched controls without skin diseases but with dyspeptic symptoms similar to those of rosacea and without endoscopic changes in gastroduodenal mucosa (non-ulcer dyspepsia [NUD]) to examine the prevalence of HP infection verified by ¹³C-UBT, Campylobacter-like organism test (CLO-test), HP culture, and serology (IgG and IgA). All the subjects underwent gastroscopy during which mucosal biopsy samples were taken from the stomach (antrum and corpus) and tested for rapid urease CLO-test (Jartoux-H.p.-test; Procter & Gamble Pharmaceuticals, Weiterstadt, Germany) and bacterial culture on special agar plates with the addition of 5% horse serum and antibiotics that blocked the growth of non-HP bacteria. Furthermore, the biopsy samples of antral and fundal mucosa were taken for histological evaluation using the Sydney classification. To confirm HP infection in the stomach, the ¹³C-UBT was performed. Additionally, the levels of IgG and IgA anti-HP antibodies were measured in plasma and saliva by ELISA, CLO-tests were performed, and bacterial cultures were performed with material from the oral cavity (saliva, dental plaque, and gingival pocket fluid). The tests were conducted before and 4 weeks after anti-HP therapy. All subjects with diagnosed HP infection received 1-week triple therapy with omeprazole (2×30 mg), clarithromycin (2×500 mg), and metronidazole (2×500 mg). In the group of 60 subjects with skin lesions typical of rosacea, 53 (88.3%) were diagnosed as having HP infection in the stomach, compared with only 39 (65%) of the NUD controls, confirmed by at least two HP tests (¹³C-UBT, CLO-test, or culture). The overall difference in HP prevalence between rosacea patients and NUD controls was statistically significant. A large proportion of the rosacea subjects (72%) had chronic active gastritis, involving predominantly the antral portion of the stomach (antritis). About 10% of the subjects had chronic active multifocal inflammation of the stomach (gastritis multifocalis), and the remaining 18% had both antritis and chronic inflammation of the body of the stomach (corpusitis). Only antral chronic active gastritis without involvement of the fundal gland area was histologically documented in the NUD controls. The titres of the anti-HP IgG antibodies in the plasma were significantly lower in the NUD controls than in the rosacea subjects. After application of the systemic and local therapy in the oral cavity, HP was eradicated from the stomach in 97% and from the oral cavity in 73% of treated patients. Of the 53 subjects with cutaneous rosacea symptoms and HP infection, 51 showed disappearance or improvement of skin lesions after eradication of HP, and the best results were seen in cases with mild or moderate skin symptoms. This study proposed that rosacea is a disorder with various gastro-intestinal symptoms closely related to gastritis, especially involving the antral mucosa, and that eradication of HP leads to improvement of symptoms of rosacea and reduction in related gastro-intestinal symptoms.37

Thus, many studies have suggested that HP is involved in the aetiology of rosacea, at least as a triggering factor, and that eradication treatment provides symptomatic relief.

Psoriasis vulgaris is a chronic, debilitating skin disease that affects millions of people worldwide. The underlying pathophysiology of psoriasis involves Th1 and Th17 cells, and most likely, their interaction with cells involved in innate immunity. It is characterised by periods of exacerbation and remission. Clinically, red plaques (due to dilatation of blood vessels) with silver- or white-coloured scales (due to rapid keratinocyte proliferation) that are clearly demarcated from adjacent, normal-appearing, non-lesional skin are usually seen. Individuals with psoriasis have areas of involved skin (lesional skin) as well as areas of normal-appearing uninvolved skin (non-lesional skin). Lesions often occur at sites of epidermal trauma, such as the elbows and knees, but can appear anywhere on the body. Psoriatic arthropathy is seen approximately in 7% to 8% of psoriatic patients. Other co-morbidities observed in individuals with psoriasis can include cardiovascular disease, diabetes mellitus (mainly type II), metabolic syndrome, obesity, impaired quality of life, and depression.38 A number of bacterial and fungal pathogens have been proposed as causal for psoriasis.5 Several recent reports have pointed to a possible relationship between HP infection of gastric mucosa and psoriasis, and have suggested that HP may be one of the organisms capable of triggering psoriasis.39 Qayoom and Ahmad40 detected HP antibodies in 20 (40%) psoriatic patients and five (10%) patients of control group. Healthy individuals without any gastro-intestinal complaints were taken as controls. Patients taking antibiotics or medications for upper gastro-intestinal problems were excluded from the study. Helicobacter pylori serology was done in both groups using ELISA test. As the number of seropositive individuals was significantly different in the two groups, the authors concluded that the data supported a causal role of HP in the pathogenesis of psoriasis.40 Fabrizi et al41 conducted a study with 49 patients (age range, 5-19 years): 20 patients with psoriasis and a control group of 29 patients without skin disorders. Patients who had an equivocal clinical picture or who were taking antibiotics, antacids, or other medications for their gastric complaints were excluded. All patients were tested for HP infection with ¹³C-UBT. Of the 20 patients with psoriasis, two (10%) had a positive test result. Of the 29 patients without skin disorders, five (17%) had a positive test result. This study showed that there was low prevalence of HP infection in children and teenagers with psoriasis, and that this relationship was not different from that in children without skin disorders. These data did not support a relationship between HP infection and psoriasis, at least in childhood.41 Fathy et al42 compared 20 patients with chronic plaque–type psoriasis with 20 healthy, age- and sex-matched controls for HP infection by using HP IgG quantitative enzyme immunoassay (ELISA test). The mean (± SD) prevalence of HP IgG seropositivity in psoriatic patients was significantly higher compared with controls (67.7 ± 32.5 vs 33.9 ± 15.1; P<0.05), and higher values were correlated with severe psoriasis. Based on these results, the link between HP and psoriasis might be supported. Large-scale studies and further investigation for the eradication of HP in psoriatic patients with HP seropositivity are required for a definite confirmation.42 In a study by Onsun et al,43 300 patients with plaque-type psoriasis and 150 non-psoriatic healthy controls were evaluated to determine the prevalence of HP seropositivity in psoriasis, the relationship between Psoriasis Area and Severity Index (PASI) scores and HP infection, and the impact of HP infection on the response to treatment. A stool antigen test for HP was performed in both patients and controls. Severity of disease was assessed using PASI scores in all patients. Fifty patients were selected at random from 184 psoriatic patients infected with HP. These 50 were assigned to one of two groups: the first group (n=25) received HP treatment and acitretin, while the second group (n=25) received acitretin monotherapy. Additionally, 25 patients who received only HP treatment without any systemic treatment were also compared with the two groups. Eight weeks later, the patients’ PASI scores were measured and compared. The prevalence of HP infection was 61.3% in psoriatic patients (n=184) and 59.3% in controls (n=89/150; P>0.05). The mean PASI score was 5.92 ± 5.50 in patients with psoriasis who were HP-positive while it was 0.79 ± 0.54 in patients with psoriasis who were HP-negative (P<0.001). Patients who received acitretin and who were also treated for HP infection showed more rapid improvement than those who received acitretin alone (mean decrease in PASI score, 3.38 ± 1.99; P<0.001 vs 1.22 ± 0.77; P<0.05). Patients who received only HP treatment also showed significant improvement versus controls (decrease in mean PASI score, 2.85 ± 1.25; P<0.001). This study suggests that HP infection plays a role in the severity of psoriasis, and that eradicating such infections enhances the effectiveness of psoriasis treatment.43

Behçet disease, first described by Hulusi Behçet in 1937, is a multisystemic, chronic, relapsing vasculitis of unknown origin that affects nearly all organs and systems. Involvement of the gastro-intestinal system is called Entero-Behçet disease.44 Cakmak et al45 studied 40 patients with BD using fibre-optic oesophagogastroduodenoscopy and UBT. Helicobacter pylori was found in 26 (65%) patients with BD and in 28 (70%) controls (no statistical significance by Chi squared test, P>0.05). In a study by Avci et al,46 anti-HP IgG was positive in 41 (83.7%) patients with BD and in 35 (71.4%) controls. The difference was not statistically significant (P=0.22).46 Ersoy et al47 evaluated 45 BD patients and 40 controls to study the prevalence of HP. They found no significant difference between the two groups in terms of prevalence of HP (73% vs 75%) and eradication rate (75% vs 70%).47

Henoch-Schönlein purpura (HSP), also known as a leukocytoclastic vasculitis of small vessels, primarily involves the skin, gastro-intestinal tract, joints, and kidneys. The pathogenesis of HSP remains unclear, but a wide variety of conditions such as bacterial or viral infections, vaccinations, drugs, and other environmental exposures may be responsible for the onset. Hoshino48 reported a 33-year-old man who presented with HSP accompanied by gastric HP infection. The gastro-intestinal manifestations and purpuric rashes were dramatically resolved after HP eradication therapy.48

Mytinger et al49 reported a 13-year-old boy with HSP associated with HP infection. Treatment of the HP infection was accompanied by prompt resolution of the HSP.

Alopecia areata is a disease of the hair follicles, with strong evidence supporting an autoimmune origin, although the exact pathogenesis of the disease is not clear.50 It affects 1% to 2% of the population,5 and occurs in all ethnic groups, ages, and both sexes.51 The pattern of hair loss can vary and can affect any part of the body. Alopecia areata frequently occurs in association with other autoimmune diseases such as autoimmune thyroiditis, lichen planus, psoriasis, Sjögren syndrome, and idiopathic thrombocytopenic purpura.50 Abdel-Hafez et al51 compared 31 patients with AA and 24 healthy volunteers of similar gender ratio for the presence of HP surface antigen (HpSAg) in stool. Optical density values for HP infection were positive in 18 (58.1%) of all 31 patients evaluated, while these were negative in 13 (41.9%) patients. In the control group, 10 (41.7%) of 24 yielded positive results. Although the mean HpSAg level was higher in the AA group, the difference was not statistically significant. This study did not support the relationship between HP and AA.51 Campuzano-Maya50 reported the case of a 43-year-old man with an 8-month history of AA of the scalp and beard areas. He had a history of dyspepsia and the UBT confirmed HP infection. The patient went into remission from AA after HP eradication therapy. This association, however, must be confirmed with epidemiological studies.50 Rigopoulos et al52 also reported no increased prevalence of HP infection in patients with AA.

Sweet’s syndrome, or acute febrile neutrophilic dermatosis, is characterised by the acute onset of fever, leukocytosis, and erythematous plaques infiltrated with neutrophils. It has been associated with inflammatory and neoplastic diseases, but most cases are idiopathic. An association between HP and Sweet’s syndrome has been proposed. Kürkçüoğlu and Aksoy53 reported a 42-year-old woman with Sweet’s syndrome. Her endoscopic biopsy specimens from gastric mucosa disclosed chronic active gastritis and showed HP organisms. After eradication therapy, the skin lesions subsided. New case reports and clinical trials are necessary to confirm this association.

Although some studies have shown that HP has a role in the pathogenesis of some dermatological diseases, it is not known whether HP is a trigger or the causative agent for the disease. The results of studies investigating HP seropositivity in skin diseases and the effect of eradication are conflicting. For this reason, systematic studies examining the relationship between dermatological entities and infection with HP, and documentation of the effect of HP eradication are needed to further our understanding on this topic.

1. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1:1311-5. CrossRef

2. Franceschi F, Gasbarrini A. Helicobacter pylori and extragastric diseases. Best Pract Res Clin Gastroenterol 2007;21:325-34. CrossRef

3. Realdi G, Dore MP, Fastame L. Extradigestive manifestations of Helicobacter pylori infection: fact and fiction. Dig Dis Sci 1999;44:229-36. CrossRef

4. Kutlubay Z, Karakus O, Engin B, Serdaroğlu S, Tüzün Y. Helicobacter pylori infection and skin diseases. In: Manfredi M, de’Angelis GL, editors. Helicobacter pylori: detection methods, diseases and health implications. New York: Nova Science Publishers; 2013: 323-35.

5. Leontiadis GI, Sharma VK, Howden CW. Nongastrointestinal tract associations of Helicobacter pylori infection. Arch Intern Med 1999;159:925-40. CrossRef

6. Hernando-Harder AC, Booken N, Goerdt S, Singer MV, Harder H. Helicobacter pylori infection and dermatologic diseases. Eur J Dermatol 2009;19:431-44.

7. Shiotani A, Okada K, Yanaoka K, et al. Beneficial effect of Helicobacter pylori eradication in dermatologic diseases. Helicobacter 2001;6:60-5. CrossRef

8. Bohr UR, Annibale B, Franceschi F, Roccarina D, Gasbarrini A. Extragastric manifestations of Helicobacter pylori infection—other Helicobacters. Helicobacter 2007;1:45-53. CrossRef

9. Figura N, Franceschi F, Santucci A, Bernardini G, Gasbarrini G, Gasbarrini A. Extragastric manifestations of Helicobacter pylori infection. Helicobacter 2010;15 Suppl 1:60-8. CrossRef

10. Cremonini F, Gasbarrini A, Armuzzi A, Gasbarrini G. Helicobacter pylori–related diseases. Eur J Clin Invest 2001;31:431-7. CrossRef

11. Tsang KW, Lam SK. Helicobacter pylori and extra-digestive diseases. J Gastroenterol Hepatol 1999;14:844-50. CrossRef

12. Hasni S, Ippolito A, Illei GG. Helicobacter pylori and autoimmune diseases. Oral Dis 2011;17:621-7. CrossRef

13. Franceschi F, Brisinda D, Buccelletti F, et al. Prevalence of virulent Helicobacter pylori strains in patients affected by idiopathic dysrhythmias. Intern Emerg Med 2013;8:333-7. CrossRef

14. Federman DG, Kirsner RS, Moriarty JP, Concato J. The effect of antibiotic therapy for patients infected with Helicobacter pylori who have chronic urticaria. J Am Acad Dermatol 2003;49:861-4. CrossRef

15. Kocatürk E, Kavala M, Kural E, Sarıgul S, Zındancı I. Autologous serum skin test vs autologous plasma skin test in patients with chronic urticaria: evaluation of reproducibility, sensitivity and specificity and relationship with disease activity, quality of life and anti-thyroid antibodies. Eur J Dermatol 2011;21:339-43.

16. Di Campli C, Gasbarrini A, Nucera E, et al. Beneficial effects of Helicobacter pylori eradication on idiopathic chronic urticaria. Dig Dis Sci 1998;43:1226-9. CrossRef

17. Magen E, Mishal J. Possible benefit from treatment of Helicobacter pylori in antihistamine-resistant chronic urticaria. Clin Exp Dermatol 2013;38:7-12. CrossRef

18. Sianturi GN, Soebaryo RW, Zubier F, Syam AF. Helicobacter pylori infection: prevalence in chronic urticaria patients and incidence of autoimmune urticaria (study in Dr. Cipto Mangunkusumo Hospital, Jakarta). Acta Med Indones 2007;39:157-62.

19. Ben Mahmoud L, Ghozzi H, Hakim A, Sahnoun Z, Zeghal K. Helicobacter pylori associated with chronic urticaria. J Infect Dev Ctries 2011;5:596-8. CrossRef

20. Yadav MK, Rishi JP, Nijawan S. Chronic urticaria and Helicobacter pylori. Indian J Med Sci 2008;62:157-62. CrossRef

21. Fukuda S, Shimoyama T, Umegaki N, Mikami T, Nakano H, Munakata A. Effect of Helicobacter pylori eradication in the treatment of Japanese patients with chronic idiopathic urticaria. J Gastroenterol 2004;39:827-30. CrossRef

22. Wedi B, Wagner S, Werfel T, Manns MP, Kapp A. Prevalence of Helicobacter pylori–associated gastritis in chronic urticaria. Int Arch Allergy Immunol 1998;116:288-94. CrossRef

23. Schnyder B, Helbling A, Pichler WJ. Chronic idiopathic urticaria: natural course and association with Helicobacter pylori infection. Int Arch Allergy Immunol 1999;119:60-3. CrossRef

24. Moreira A, Rodrigues J, Delgado L, Fonseca J, Vaz M. Is Helicobacter pylori infection associated with chronic idiopathic urticaria? Allergol Immunopathol (Madr) 2003;31:209-14. CrossRef

25. Magen E, Mishal J, Schlesinger M, Scharf S. Eradication of Helicobacter pylori infection equally improves chronic urticaria with positive and negative autologous serum skin test. Helicobacter 2007;12:567-71. CrossRef

26. Daudén E, Jiménez-Alonso I, García-Díez A. Helicobacter pylori and idiopathic chronic urticaria. Int J Dermatol 2000;39:446-52. CrossRef

27. Abram K, Silm H, Maaroos HI, Oona M. Risk factors associated with rosacea. J Eur Acad Dermatol Venereol 2010;24:565-71. CrossRef

28. Lazaridou E, Giannopoulou C, Fotiadou C, Vakirlis E, Trigoni A, Ioannides D. The potential role of microorganisms in the development of rosacea [in English, German]. J Dtcsh Dermatol Ges 2011;9:21-5. CrossRef

29. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol 2004;51:327-41; quiz 342-4. CrossRef

30. Del Rosso JQ. Advances in understanding and managing rosacea: part 1: connecting the dots between pathophysiological mechanisms and common clinical features of rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol 2012;5:16-25.

31. Utaş S, Ozbakir O, Turasan A, Utaş C. Helicobacter pylori eradication treatment reduces the severity of rosacea. J Am Acad Dermatol 1999;40:433-5. CrossRef

32. Baz K, Cimen MY, Kokturk A, et al. Plasma reactive oxygen species activity and antioxidant potential levels in rosacea patients: correlation with seropositivity to Helicobacter pylori. Int J Dermatol 2004;43:494-7. CrossRef

33. Diaz C, O’Callaghan CJ, Khan A, Ilchyshyn A. Rosacea: a cutaneous marker of Helicobacter pylori infection? Results of a pilot study. Acta Derm Venereol 2003;83:282-6. CrossRef

34. Bamford JT, Tilden RL, Blankush JL, Gangeness DE. Effect of treatment of Helicobacter pylori infection on rosacea. Arch Dermatol 1999;135:659-63. CrossRef

35. Boixeda de Miquel D, Vázquez Romero M, Vázquez Sequeiros E, et al. Effect of Helicobacter pylori eradication therapy in rosacea patients [in English, Spanish]. Rev Esp Enferm Dig 2006;98:501-9. CrossRef

36. Argenziano G, Donnarumma G, Iovene MR, Arnese P, Baldassarre MA, Baroni A. Incidence of anti–Helicobacter pylori and anti-CagA antibodies in rosacea patients. Int J Dermatol 2003;42:601-4. CrossRef

37. Szlachcic A. The link between Helicobacter pylori infection and rosacea. J Eur Acad Dermatol Venereol 2002;16:328-33. CrossRef

38. Johnson-Huang LM, Lowes MA, Krueger JG. Putting together the psoriasis puzzle: an update on developing targeted therapies. Dis Model Mech 2012;5:423-33. CrossRef

39. Martin Hübner A, Tenbaum SP. Complete remission of palmoplantar psoriasis through Helicobacter pylori eradication: a case report. Clin Exp Dermatol 2008;33:339-40. CrossRef

40. Qayoom S, Ahmad QM. Psoriasis and Helicobacter pylori. Indian J Dermatol Venereol Leprol 2003;69:133-4.

41. Fabrizi G, Carbone A, Lippi ME, Anti M, Gasbarrini G. Lack of evidence of relationship between Helicobacter pylori infection and psoriasis in childhood. Arch Dermatol 2001;137:1529.

42. Fathy G, Said M, Abdel-Raheem SM, Sanad H. Helicobacter pylori infection: a possible predisposing factor in chronic plaque-type psoriasis. J Egypt Women Dermatol Soc 2010;7:39-43.

43. Onsun N, Arda Ulusal H, Su O, Beycan I, Biyik Ozkaya D, Senocak M. Impact of Helicobacter pylori infection on severity of psoriasis and response to treatment. Eur J Dermatol 2012;22:117-20.

44. Tüzün Y, Keskin S, Kote E. The role of Helicobacter pylori infection in skin diseases: facts and controversies. Clin Dermatol 2010;28:478-82. CrossRef

45. Cakmak SK, Cakmak A, Gül U, Sulaimanov M, Bingöl P, Hazinedaroğlu MS. Upper gastrointestinal abnormalities and Helicobacter pylori in Behçet’s disease. Int J Dermatol 2009;48:1174-6. CrossRef

46. Avci O, Ellidokuz E, Simşek I, Büyükgebiz B, Güneş AT. Helicobacter pylori and Behçet’s disease. Dermatology 1999;199:140-3. CrossRef

47. Ersoy O, Ersoy R, Yayar O, Demirci H, Tatlican S. H pylori infection in patients with Behcet’s disease. World J Gastroenterol 2007;13:2983-5.

48. Hoshino C. Adult onset Schönlein-Henoch purpura associated with Helicobacter pylori infection. Intern Med 2009;48:847-51. CrossRef

49. Mytinger JR, Patterson JW, Thibault ES, Webb J, Saulsbury FT. Henoch-Schönlein purpura associated with Helicobacter pylori infection in a child. Pediatr Dermatol 2008;25:630-2. CrossRef

50. Campuzano-Maya G. Cure of alopecia areata after eradication of Helicobacter pylori: a new association? World J Gastroenterol 2011;17:3165-70.

51. Abdel-Hafez HZ, Mahran AM, Hofny ER, Attallah DA, Sayed DS, Rashed HA. Is Helicobacter pylori infection associated with alopecia areata? J Cosmet Dermatol 2009;8:52-5. CrossRef

52. Rigopoulos D, Katsambas A, Karalexis A, Papatheodorou G, Rokkas T. No increased prevalence of Helicobacter pylori in patients with alopecia areata. J Am Acad Dermatol 2002;46:141. CrossRef

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The introduction of robot-assisted surgery, and specifically the da Vinci Surgical System, is one of the biggest breakthroughs in surgery since the introduction of anaesthesia, and represents the most significant advancement in minimally invasive surgery of this decade. One of the first surgical uses of the robot was in orthopaedics, neurosurgery, and cardiac surgery. However, it was the use in urology, and particularly in prostate surgery, that led to its widespread popularity.1 Robotic surgery is also widely used in other surgical specialties including general surgery, gynaecology, and head and neck surgery.

Urology has long been adoptive to advances in technology. It is not surprising that soon after robotic technology was first applied to medical science, it was well received by the urology community. Robotic surgery has applications in many aspects of urological surgery. Since 1998, there have been over 4000 peer-reviewed publications in various specialties on the da Vinci Surgery, of which 46% pertain to urology, 17% to cardiothoracic surgery, 13% to general surgery, 8% to gynaecology, 7% to general surgical topics (including outcomes, trends, and cost-effectiveness for different types of robotic surgery), 4% to paediatric surgery, and 2% to otorhinolaryngology.2

Literature review of current applications of robotics in different surgical specialties with an emphasis on urology was performed. Clinical results as compared with traditional open and/or laparoscopic surgery and a glimpse into the future development of robotics will be discussed. A short introduction on emerging areas of robotic surgery will also be briefly reviewed.

The world’s first surgical robot, ‘Arthrobot’, was born in 1983 and was designed to assist orthopaedic procedures. In 1985, PUMA 560 (Unimate, New Jersey, US) was used to precisely place a needle for computed tomography–guided brain biopsy. This was followed in 1988 by ROBODOC (Integrated Surgical Systems, Delaware, US), a system used in total hip arthroplasty to allow precise preoperative planning, and to mill out precise fittings in the femur for hip replacement. The first application in urology occurred in 1988 at Imperial College (London, UK) with the use of the PROBOT in clinical trials to perform transurethral surgery. In 1993, Computer Motion, Inc (Santa Barbara [CA], US)—the original leading medical robots supplier—released AESOP (Automated Endoscopic System for Optimal Positioning), a robotic arm to assist in laparoscopic camera holding and positioning. The CyberKnife (Accuray, Sunnyvale [CA], US) was introduced in 1994 for stereotactic radiosurgery in neurosurgery. The year 1998 was a significant landmark, with the introduction of ZEUS Robotic Surgical System (Computer Motion, Inc) and the da Vinci Surgical System (Intuitive Surgical, Inc, Sunnyvale [CA], US). Both systems comprised a surgical control centre and robotic arms. The first da Vinci robotic surgical procedure was a robot-assisted heart bypass, and it took place in Germany in 1998.3 In 2000, the da Vinci robot was given approval by the US Food and Drug Administration (FDA) for use in laparoscopic procedures. The first reported robot-assisted radical prostatectomy (RARP) took place in Paris, France, in the same year.4 Intuitive Surgical, Inc took over Computer Motion, Inc in 2003 and is now the sole company marketing robotic surgical devices. Other companies such as Olympus and Samsung are developing new robotic surgical systems, with a promise of lower cost and more compact machines.

The da Vinci Surgical System comprises three components: a surgeon’s console, a patient-side robotic cart with four robotic arms manipulated by the surgeon (one to control the camera and three to manipulate instruments), and a high-definition three-dimensional (3D) vision system. Articulating surgical instruments are mounted on the robotic arms which are introduced into the body through cannulas.2 The US FDA approved the system for general laparoscopic surgery (gallbladder diseases and reflux) in July 2000, for urological procedures in 2001, for mitral valve repair surgery in November 2002, and for gynaecological conditions in 2005.

Robotic surgery by the da Vinci Surgical System (Intuitive Surgical, Inc) has been popularised by its widespread usage in radical prostatectomy (RP). The robotic system overcomes the limitations of the standard laparoscopic approach and allows for precise dissection in a confined space and hence the increasing application of robot-assisted laparoscopic prostatectomy in expert centres. These advantages include stable operator-controlled camera, high-definition 3D magnified view of 10 to 12 times, articulating instruments with seven degrees of freedom, motion scaling, and tremor filtration. Moreover, carbon dioxide insufflation during the procedure helps in reduction of venous ooze, thus leading to improved visualisation and reduced blood loss.5 Across different specialties, the majority of robotic surgeries have been associated with a decreased length of stay, and fewer complications including a lower transfusion rate and in-hospital death rate.6 However, robot-assisted laparoscopic surgery is costlier than laparoscopic surgery and open surgery.

An analysis of new technology and health care costs of 20 different robot-assisted surgeries published in the New England Journal of Medicine in 20107 showed that the use of the robot added 13% (US$3200) to the total average cost of a procedure in 2007. However, there were no large-scale randomised trials to definitely show that robot-assisted surgery was superior to other procedures.7

Additional studies are needed to better delineate the comparative and cost-effectiveness of robot-assisted laparoscopic surgery relative to laparoscopic surgery and open surgery. Robotic surgery provides similar postoperative outcomes to laparoscopic surgery but has a reduced learning curve. Although costs are currently high, increased competition from manufacturers and wider dissemination of the technology may drive costs down. Further trials are needed to evaluate long-term outcomes in order to fully evaluate the value of robots in surgical procedures.8

There has been a continuous expansion of robot-assisted surgery for both upper and lower urinary tract diseases in urology. This is especially true in robotic prostatectomy, where the initial reports of robotic prostatectomy by Menon et al9 led to an exponential growth of robotic surgery in clinically localised prostate cancer. More recently, there has been an increasing number of robotic renal surgeries10 and robotic cystectomy in centres of excellence.11

Prostate cancer is the most common solid organ malignancy in men in the US, and the second leading cause of cancer death. It is the second most common cancer in the world, with a world age-standardised rate of 28 per 100 000 males.12 There is a rapidly increasing incidence of prostate cancer in Asian countries due to a more westernised lifestyle.13 In Hong Kong, prostate cancer is the third most common cancer, accounting for 10.7% of all male malignancies; it is the fifth major cause of cancer death, responsible for 4.1% of all cancer deaths in Hong Kong.14

Radical prostatectomy is a standard treatment option for localised carcinoma of the prostate, with a demonstrated survival advantage when compared with watchful waiting in the randomised controlled trial SPCG-4 (Scandinavian Prostate Cancer Group Study No. 4).15 Radical prostatectomy showed a significant relative risk reduction in cancer-specific mortality as compared with watchful waiting—44% decrease at 10 years, 35% at 12 years, and 38% at 15 years.15 16

However, open RP is associated with high morbidity rates. Schuessler et al17 introduced laparoscopic RP in 1997 with the aim of reducing morbidity. The advantages of laparoscopic prostatectomy, as reported in initial expert series, showed a lower mean blood loss and transfusion rate, decreased mean hospital stay, and earlier removal of the Foley catheter compared with results from open prostatectomy series.18

However, the technical demands of laparoscopic RP prevented its widespread use by the average urologist, with a limited case load. The introduction of the da Vinci Surgical System was a breakthrough in minimally invasive prostatectomy. Menon et al1 from the Vattikuti Urology Institute in Detroit [MI], US are responsible for the development and popularisation of RARP. This technique offers all the advantages of minimally invasive laparoscopic prostatectomy with the added advantage of shorter learning curve and improved ergonomics, leading to the widespread use and acceptance of RARP worldwide.

Ahlering et al19 studied the learning curve for robotic prostatectomies, and found that the robotic system might significantly shorten the learning curve for an experienced open yet laparoscopy-naïve surgeon. The learning curve for achieving 4-hour proficiency has been shown to be 12 patients.19

Robot-assisted RP has overtaken open RP as the most common surgical approach for RP ever since the FDA approval in 2001, and is estimated to account for approximately 80% of all RP procedures in the US.20

However, the rise in robotic procedures was initially not backed by any evidence on clinical benefits. No randomised trial showed the benefits of robotic surgery until the publication of the nationwide series by Trinh et al.21 Data from this series demonstrated superior adjusted perioperative outcomes after RARP in virtually all examined outcomes. Of 19 462 RPs, 61.1% were RARPs, 38.0% were open RPs, and 0.9% were laparoscopic RPs. In multivariable analyses, patients undergoing RARP were less likely to receive a blood transfusion (odds ratio [OR]=0.34; 95% confidence interval [CI], 0.28- 0.40), to experience an intra-operative complication (OR=0.47; 95% CI, 0.31-0.71) or a postoperative complication (OR=0.86; 95% CI, 0.77-0.96), and to experience a prolonged length of stay (OR=0.28; 95% CI, 0.26-0.30) [Table 121].

A recent territory-wide review in Hong Kong22 showed that a total of 235 patients underwent RARP between 2005 and 2009, with a 37.3% rate of trifecta (cancer cure, continence, and return of sexual function) at 12 months, demonstrating the feasibility, safety, and efficacy of RARP in low-to-intermediate volume centres. In a series from a high-volume centre, trifecta rates at 6 weeks, 3, 6, 12 and 18 months after RARP were 43%, 65%, 80%, 86% and 91%, respectively.23

However, the majority of urologists in Hong Kong are not from high-volume centres, thereby, not being able to achieve these benchmark and commendable results. Thus, it is now debated whether robotic prostatectomy should be limited to high-volume centres of excellence. A randomised trial of open versus robot-assisted RP was commenced in October 2010 in Australia.24 Overall, 200 men per treatment arm (400 men in total) are being recruited after diagnosis and before treatment through a major public hospital out-patient clinic and randomised to robotic prostatectomy or open prostatectomy. Clinical outcomes, quality-of-life outcomes, and cost-effectiveness are being critically and prospectively analysed to compare outcomes.24 To date, more than 250 patients have been recruited. Results are eagerly awaited.25

In the recent decade, there has been a stage and size migration of renal tumours. Less than 10% of new cases present with the classic triad of gross haematuria, loin pain, and mass. The incidence of small renal mass has increased by 3.7% per year with widely available abdominal imaging such as ultrasonography over the past decade.26 Numerous studies have shown that renal insufficiency is associated with increased cardiovascular events, hospitalisation, and mortality,27 leading to increasing role of renal-preserving strategies in the treatment of localised renal cell carcinoma. Data from more than 2000 patients who underwent surgery at Memorial Sloan Kettering Cancer Center from 1989 to 2005 showed that radical nephrectomy was an independent factor for new-onset chronic kidney disease.28 According to the European Association of Urology guidelines on renal tumour, nephron-sparing surgery is the standard procedure for solitary renal tumours measuring up to 7 cm in diameter.29 Benefits of nephron-sparing surgery over radical nephrectomy include equivalent oncological outcome in tumours measuring less than 4 cm, and probably up to 7 cm in diameter, avoidance of overtreatment of benign lesions which account for up to 20% of small renal masses, further treatment options available if contralateral kidney recurrence occurs, better quality of life, and decreased overall mortality.30 Moreover, both procedures have comparable survival rates.30

Open partial nephrectomy (OPN) currently remains the standard procedure for partial nephrectomy. However, OPN is associated with significant morbidity: the muscle-cutting flank incision may involve removal of a lower rib, leading to flank bulge, pain, paraesthesia, and hernia formation. The introduction of laparoscopic partial nephrectomy was aimed at reducing the morbidity associated with OPN.

Laparoscopic partial nephrectomy offers the advantages of shorter length of stay, decreased operative blood loss, and a shorter operating time versus OPN. However, it is associated with longer warm ischaemic time, more postoperative urological complications, and increased number of subsequent procedures. State-of-the-art surgical expertise and technique are prerequisites for laparoscopic partial nephrectomy.31 Thus, the procedure is not routinely performed in many centres in view of its prolonged learning curve.

Robot-assisted partial nephrectomy shows promise in bridging the gap between open and laparoscopic approaches, providing similar oncological results to radical nephrectomy and improved morbidity with a shorter learning curve than laparoscopic partial nephrectomy. Robot-assisted partial nephrectomy has been shown to be a safe and viable alternative to laparoscopic partial nephrectomy in some published case series,32 33 providing equivalent early oncological outcomes to laparoscopic partial nephrectomy, and the additional advantages of decreased hospital stay, less intra-operative blood loss, and shorter warm ischaemic time averaging less than 20 minutes. Moreover, operative parameters for robot-assisted partial nephrectomy are less affected by tumour complexity and surgical expertise of the surgeon as compared with laparoscopic partial nephrectomy. A case series published by our centre34 showed that robot-assisted laparoscopic partial nephrectomy was technically feasible, with the advantage of statistically significant decreased warm ischaemic time (31 vs 40 minutes; P=0.032; Table 26).

Radical cystectomy and pelvic lymph node dissection are the standard treatment options for muscle-invasive carcinoma of the bladder. However, this procedure is associated with high morbidity of up to 50% and mortality of up to 5%, even in centres of excellence.35 Data from the Surgical Outcomes Monitoring & Improvement Program Report of the Hong Kong Hospital Authority showed that radical cystectomy is a surgical procedure associated with the highest morbidity and mortality among all surgical operations in Hong Kong.36 From 2009 to 2010, the 30-day crude mortality rate was 9.7%, and the 30-day crude morbidity rate was 65.3%.36

Laparoscopic cystectomy was introduced with the aim of decreasing associated morbidity and length of hospital stay. The first laparoscopic radical cystectomy was performed in 1992.37 Case series performed at expert centres showed that when compared with open surgery, laparoscopic cystectomy resulted in a lower morbidity rate with significantly lower intra-operative blood loss and transfusion rates, lower pain scores, and allowing a more rapid resumption of oral intake and a shorter hospital stay.38 However, laparoscopic radical cystectomy is technically challenging, with a steep learning curve.

Robot-assisted radical cystectomy (RARC) was introduced as an attempt to offset the high technical skill required for laparoscopic cystectomy, and was the first procedure performed in 2003 by Beecken et al.39 A recent retrospective analysis40 on consecutive series of patients undergoing radical cystectomy (100 RARCs and 100 open radical cystectomies) with curative intent over a 4-year period suggests that patients undergoing RARC have perioperative oncological outcomes comparable with open radical cystectomies, and lower overall and major complication (Clavien score ≥3) rates (35% vs 57%; P=0.001 and 10% vs 22%; P=0.019, respectively), less blood loss, and shorter hospital stay versus open radical cystectomies. There were no significant differences between the two groups for pathological outcomes, including stage, number of nodes harvested, or positive margin rates.40

Although the results for RARC are encouraging, long-term functional and oncological control rates are still unknown. Randomised, multi-institutional comparisons of these techniques will be required before widespread adoption of the procedure.

Reconstructive procedures including pyeloplasty, ureteric reimplantation, appendicovesicostomy, and augmentation enterocystoplasty are increasingly performed with the assistance of the robot.41 Data on pyeloplasty showed that the robotic approach is associated with a lower transfusion rate and a shorter length of stay as compared with the open and laparoscopic approaches (Table 36).

Robot-assisted microsurgery is being utilised to a greater degree in andrology including procedures such as vasectomy reversal, subinguinal varicocelectomy, targeted spermatic cord denervation (for chronic orchialgia), and microsurgical testicular sperm extraction.42

The da Vinci Surgical System was approved for use in gynaecological surgery in the US in 2005. Applications of robotics in gynaecology include hysterectomy, myomectomy, oophorectomy, ovarian cystectomy, resection of endometriosis and lymphadenectomy, with an increasing role of robotic surgery in gynaecological oncology.

Endometrial carcinoma is the most common malignancy of the female reproductive organs and the consensus in the literature is that robotic surgery is preferable to open surgery and is equivalent to laparoscopy in many aspects.43 The robotic platform offers distinct advantages in certain populations, such as the morbidly obese, and is becoming a commonly used procedure.43

Similarly, in cervical carcinoma, the published data comparing robotic radical hysterectomy to traditional laparoscopy or laparotomy showed that the robotic approach produces more favourable perioperative outcomes, including a lower blood loss, shorter length of stay, and equivalent or lower rates of intra-operative and postoperative complications.44

Hysterectomy for benign conditions is one of the most commonly performed procedures in women, with a one in nine chance of a woman undergoing the procedure in her lifetime.45 Between 2007 and 2010, the utilisation of robot-assisted hysterectomy for benign gynaecological disorders increased substantially. However, robot-assisted and laparoscopic hysterectomy had similar morbidity profiles, offered little short-term benefit, but resulted in substantially more costs.46 A 2012 Cochrane review of robotic surgery for benign gynaecological diseases showed that robotic surgery was not associated with improved effectiveness or safety, but increased the cost of the procedure substantially.47

The existing limited evidence shows that robotic surgery does not benefit women with gynaecological diseases in terms of effectiveness or safety. Further well-designed randomised controlled trials with complete reported data are required to confirm or refute this conclusion.

Laparoscopic colorectal surgery has become the preferred standard of care in colorectal surgery and has been proven to be as safe and effective as open surgery, and associated with a lower blood loss and shorter length of stay. Robotic technology aims to overcome some of the limitations of conventional laparoscopic surgery. However, the role of robotics in colorectal surgery remains controversial. Delaney et al48 compared robotic versus traditional laparoscopic colorectal surgery, and reported that robotic colectomy was a feasible and safe procedure, but involved greater costs and longer operating times.

In a comparative study between robotic versus laparoscopic right hemicolectomy, deSouza et al49 reported that the robotic approach was safe and feasible, but associated with longer operating times and higher costs as compared with pure laparoscopic approach. However, there were similar rates of overall morbidity, lymph node dissection, blood loss, conversion rate, and length of hospital stay in both groups, showing no benefit of robotic approach for right hemicolectomy over laparoscopic surgery.

The emerging role of robotic surgery in colorectal conditions is in rectal pathologies, especially in patients with a narrow pelvis. Total mesorectum excision (TME) has been established as a standard surgical technique in rectal cancer surgery.50 Laparoscopic TME in a narrow pelvis and locally advanced disease is a technically demanding procedure, and it is associated with a high conversion rate, high positive surgical margin, and poor continence and erectile function.51 52

Robotic nerve-sparing TME was shown in a randomised study to have significantly shorter length of stay (6.9 days vs 8.7 days, P<0.001) with similar mean operating time, conversion rate, and specimen quality as compared with its counterpart laparoscopic procedure.53 In another series by Kim et al,54 robotic TME showed a shorter recovery time for erectile function as compared with laparoscopic TME (6 vs 12 months). The authors postulated that the precise identification of anatomical planes and smaller neural components was facilitated by magnified view and superior movement of wristed robotic instruments.54

Recent studies48 49 50 51 52 53 54 55 have confirmed robotic colorectal surgery to be feasible and oncologically safe with potentially significant benefits in rectal surgery. However, we await long-term results concerning oncological outcome.

The application of robotics in general surgery has been evolving, and the number of procedures has been growing over the past decade, especially in bariatric surgery, fundoplication, and hepatobiliary surgery, although robotic approach is not routinely employed for those procedures.

Bariatric procedures can be complex and challenging in view of large patients, large livers, thick abdominal walls and substantial visceral fat, making exposure, dissection and reconstruction difficult. The first robotic bariatric procedure was an adjustable gastric banding procedure performed by Belgian surgeons in September 1998.56 Since then, the robotic approach has become an option to standard laparoscopy. Robotic procedures in bariatric surgery include robotic adjustable gastric banding, robotic sleeve gastrectomy, robotic gastric bypass, and biliopancreatic diversion with duodenal switch.57 Robotic bariatric procedures appear to have a decreased rate of gastro-intestinal leaks, lower risk of needing follow-up surgery, and a lower conversion rate to open surgery.58

Robotic Heller myotomy for achalasia has been shown to result in fewer oesophageal tears, and improved quality of life after surgery in studies as compared with traditional laparoscopic surgery.59

Local data on the feasibility and safety of robotic surgery for hepatocellular carcinoma showed favourable short-term outcomes, including hospital mortality and morbidity rates of 0% and 7.1%, respectively; the mean hospital stay was 6.2 days. The 2-year overall and disease-free survival rates were 94% and 74%, respectively. However, the long-term oncological results remain uncertain.60

Thyroid surgery is traditionally performed via a collar incision. However, with a large portion of patients being young females, there is a demand for avoiding the transverse cervical incision. This led to the introduction of endoscopic techniques, with the advantages of better cosmetic outcome and reduced paraesthesia of the anterior neck.61 However, these endoscopic techniques are technically demanding and time-consuming.

The introduction of the da Vinci Surgical System has further revolutionised the surgical management of thyroid diseases. Robotic surgery overrides the drawbacks of endoscopic surgery, being associated with better visualisation and improved fine manipulation within the deep and narrow cervical space. Better visualisation is achieved through 10 to 12 times of magnification and 3D images, facilitating enhanced precise anatomical dissection. Robotic thyroidectomy is also associated with a shorter learning curve than endoscopic thyroidectomy and causes less musculoskeletal strain to the surgeon.62

The use of robots in thyroid surgery is rapidly increasing. Results are promising in case series, with more than 6000 procedures being performed in Korea between 2007 and 2011.63 However, randomised controlled trials comparing robotic with conventional open or endoscopic surgery are needed to assess the long-term oncological outcomes and functional outcomes.63

The use of robotics in the field of head and neck surgery was adopted recently, with the first case series published in 2006.64 Robotic surgery allows transformation of open surgical management of head and neck cancer to a transoral minimally invasive approach. Robotic approach in head and neck surgery has provided surgeons with the ability to access anatomical locations that were previously managed only via open techniques. This has resulted in decreased overall morbidity and excellent functional results with equivalent oncological outcomes. Transoral robotic surgery provides access to the oropharynx, hypopharynx, larynx, oral cavity, parapharyngeal space, and skull base via the oral aperture. It is useful in resection of the tumour and in free-flap reconstruction.

The advantages of robotic surgery in patients with head and neck cancer are access to anatomical sites not accessible to conventional endoscopy, absence of a neck incision, absence or decreased duration of tracheotomy, absence or decreased duration of nasogastric or gastric feeding tube, and decreased length of hospital stay.65

Studies have shown that transoral robotic surgery is a feasible option for surgical management of head and neck tumours, which is associated with reduced morbidity.65 66 However, long-term data are required for oncological outcomes.

The first robotic cardiac procedure was performed in the US in 1999,67 and was one of the earliest applications of robotic surgery. Robotic cardiac surgical procedures have been performed to repair and replace the mitral valve, bypass coronary arteries, close atrial septal defects, implant left ventricular pacing leads, and resect intracardiac tumours.

A US study compared robotic sternotomy and thoracotomy approaches to mitral valve surgery outcomes in more than 700 patients with mitral valve disease over a 3-year period. The median cardiopulmonary bypass time was 42 minutes longer for robotic than complete sternotomy, 39 minutes longer than for partial sternotomy, and 11 minutes longer than for right mini-anterolateral thoracotomy (P<0.0001). Moreover, the robotic procedure was associated with a longer median myocardial ischaemic time compared with conventional procedures (P<0.0001). The quality of mitral valve repair was similar among matched groups. Neurological, pulmonary, and renal complications were similar among groups. However, the robotic approach was associated with the lowest occurrences of atrial fibrillation and pleural effusion and the shortest hospital stay (median 4.2 days); the hospital stays with robotic surgery were 1.0, 1.6, and 0.9 days shorter than for complete sternotomy, partial sternotomy, and right mini-anterolateral thoracotomy, respectively (P<0.001 for all comparisons). This series showed that robotic repair of posterior mitral valve leaflet prolapse is as safe and effective as conventional approaches. Technical complexity and longer operating times for robotic repair are compensated for by lesser invasiveness and shorter hospital stay.68

Robotic thoracic procedures include resection of primary lung cancer, oesophageal tumours, thymic diseases, and mediastinal tumours.69 Another US series with 168 patients which compared patients who underwent robotic pulmonary resection with propensity-matched controls undergoing lobectomy by rib- and nerve-sparing thoracotomy showed that the robotic group had reduced morbidity (27% vs 38%; P=0.05), lower mortality (0% vs 3.1%; P=0.11), improved mental quality of life (53 vs 40; P<0.001), and shorter hospital stay (2.0 vs 4.0 days; P=0.02). Moreover, with the additional technical modification of completely portal robotic lobectomy with four arms, both the median operating time (3.7 vs 1.9 hours; P<0.001) and conversion rates to traditional thoracotomy (12/62 vs 1/106; P<0.001) were lowered.69

Despite being one of the first specialties to utilise the robotic technology, it is still unclear whether the technical advantages bring about direct merits for patients. Results have been mixed, with no unequivocal evidence on benefits of the robotic approach. Further evidence is awaited on the use of robotics in the cardiothoracic field.

Laparoendoscopic single-site surgery (LESS) and natural orifice transluminal endoscopic surgery are novel techniques that have the potential to further minimise the invasiveness and morbidity of surgery. However, the technical difficulty of the procedure is increased with the need for specialised instruments. Robotic technology is rapidly evolving, and with the development of new robotic prototypes for single-port surgery, it is expected that robotic-LESS will move forward with the goal of minimising complications and improving outcomes.70

Robotic surgery with the da Vinci Surgical System is increasingly being applied in a wide range of surgical specialties, especially in urology. It aims to improve outcomes as compared with open surgery, and to overcome the limitations of laparoscopic/ thoracoscopic techniques. Despite the increasing popularity of robotic surgery, except in RARP, there is no unequivocal evidence to show the superiority of robotic surgery over traditional laparoscopic surgery in other surgical procedures. Cost-effectiveness is also an issue due to the high installation and maintenance costs. We eagerly await the introduction of different robotic systems by competitors. Further randomised studies are required to ascertain the long-term results and potential benefits of robotic surgery. We eagerly await the results of the ongoing randomised trial of open versus robotic RP from Australia.

No conflicts of interest were declared by authors.

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