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Clinical and Experimental Allergy, 37, 166–173 Continued need of appropriate betalactam-derived skin test reagents for themanagement of allergy to betalactams M. Blanca , A. Romano , M. J. Torres , P. Demolyz and A. DeWeck‰Ã Allergy Service, Carlos Haya Hospital, M ´ alaga, Spain, Department of Internal Medicine and Geriatrics, UCSC-Allergy Unit, Complesso Integrato Columbus, Rome and IRCCS Oasi Maria S.S., Troina, Italy, zAllergy Department, Hopital Arnaud de Vileneuve, Montpellier, France and ‰Allergy Research Laboratory, Gerimmun Immediate allergic reactions to betalactams (BLs) are due to IgE antibodies that recognize the Experimental ring-derived penicilloyl determinant or side-chain structures of common BLs. The presence of Allergy specific IgE antibodies can be demonstrated by skin testing, the determination of specific IgE antibodies in sera or their binding to basophils with subsequent activation upon contact withpenicillins in vitro. Skin tests are still the most sensitive technique followed by in vitro tests,which may sometimes yield useful complementary information. The diversity of the responseto BLs has meant that in some instances, in addition to benzylpenicillin-derived determinants,testing for amoxycillin, cephalosporins or other BLs may also be required to establish thediagnosis. The recent withdrawal from the market of BL-derived materials for skin testing willhave a serious effect on public health, resulting in a return to the pre-1960 era before thesereagents became available. Because of their greater sensitivity, these skin tests cannot yet be replaced by in vitro tests. Furthermore, skin tests are the most readily available form of allergy testing for physicians. This paper reviews the results of skin tests in BL allergy and provides s/n 29009 Malaga, Spain.
E-mail: miguel.blanca.sspa@ Keywords allergy, betalactam, diagnosis, skin test Submitted 20 July 2006; revised 13 October 2006; accepted 14 November 2006 diagnosis of penicillin allergy at the time; this was soonfollowed by the so-called minor determinant mixture Allergic reactions were reported shortly after the intro- (MDM) [9]. Unfortunately, BPO–PLL was removed from duction of penicillins as therapeutic agents [1]. By the the US market in 2004 by Hollister-Stier while Allergo- 1950s, increasing reports of anaphylactic reactions and pharma ceased production of PPL and of MDM in Europe other side-effects testified to a serious public health in 2005. This means that these essential reagents are no problem [1]. Fifty years later, penicillins and the other longer available to the majority of allergologists. This members of the betalactam (BL) family are still the drugs review highlights the usefulness of skin tests with recom- most commonly involved in allergic drug reactions. This mendations about their adaptation to the current clinical trend is expected to continue in the future [2, 3]. Immu- requirements relating to allergy to penicillins and the nological tests have been used since early times to evaluate subjects with allergic reactions. Skin tests werethe first to be applied and both immediate and delayed responses were soon observed [4, 5].
Skin testing with BL is currently a source of public Immediate reactions to BL are still the most important health concern because of the sudden lack of availability cause of allergic drug reactions [2, 3]. Ten percent of world-wide of appropriate reagents for in vivo testing.
ambulatory and hospitalized patients report allergies to Benzylpenicilloyl–polylysine (BPO–PLL), also known as medications containing BL antibiotics [2]. The incidence penicilloyl–polylysine (PPL), was first developed in 1960/ of anaphylactic reactions varies from 0.004% to 0.015% 1961 [6–8] and afforded a major improvement to the [5]. The use of alternative agents may adversely affect the Appropriate betalactam-derived skin test reagents 167 MAJOR DETERMINANT
Benzylpenicillin
Benzylpenicilloyl
MINOR DETERMINANTS
Benzylpenicilloic
Benzylpenicillenic
Benzylpenalmadic
Penicoyl
Penicanyl
Diketopiperazine
Fig. 1. Chemical structures of the penicillin molecule and proposed major and minor determinants.
ability to overcome anti-microbial resistance and the choice of other antibiotics, such as vancomycin or quino-lones, is more costly and more likely to have adverse The BL ring binds covalently to the free amino groups of proteins, forming stable conjugates [19], such as the so- BLs are also often prescribed in the absence of definite called BPO determinant [20]. It was soon shown that the clinical indications, leading to unnecessary high-expo- bulk component of the immunological response was sure rates [12, 13]. Allergic reactions may be merely directed towards this structure [4, 21], hence the denomi- coincidental to BL administration, with no causal rela- nation of the major determinant, although other reactiv- tionship. Subjects are often labelled as allergic to BL with ities of the penicillin molecule had also been described [6, no additional investigations, even though they are not in 22]. Later, it was noticed that some individuals with fact allergic [14]. On the other hand, anaphylaxis to BL is anaphylactic reactions did not respond to this penicilloyl underreported [15]. Amoxycillin (AX) is considered structure but reacted to Benzylpenicillin (BP) directly nowadays the most frequent cause of anaphylaxis to BL applied to the skin. This observation led to the discovery [3, 16, 17]. For many physicians, penicillin skin testing of other so-called MDM [9, 23]. Fewer than 10% of anti- has become a component of antibiotic prescriptions [18].
body responses appear to be due to these minor determi- Thus, it will be a major public health setback if optimal nants [24]. Figure 1 shows the chemical structures of the skin testing to BL is no longer possible.
penicillin molecule and the major and minor determinants.
c 2007 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 37 : 166–173 For many years, PPL was sold in the USA as a research history of penicillin allergy. Of these, 7.1% had positive reagent ‘not for human use’ by Kremers-Urban, as the FDA skin tests to penicillin determinants; 75% were positive to obstinately refused to register it, requesting much addi- PPL, 10% to MDM, and 14% to BPO and MDM [28]. In tional information (toxicity studies, etc.) as relevant for a summary, in all these studies there was a variable degree new drug. Considering the restricted market and the fact of response to major and minor determinants of BP, with that this chemically well-defined reagent was injected the response to PPL alone or in association with a response intra-dermally into humans in nanogram quantities, these to MDM being positive in over 50% of the cases evaluated.
requests seemed somewhat abusive. More so, as at the The predictive value of a positive test indicated that 50% same time allergologists were still allowed to use their of the patients could develop another clinical reaction own dust (dirt) extracts as skin test reagents. Under after re-exposure while the predictive value of a negative pressure from the National Institute of Allergy and In- test indicated that in the event of further administration of fectious Diseases (NIAID) and the American Academy of BP, there would be good tolerance, or at least just a Allergy, which had sponsored a large-scale study [25], the FDA relented. PPL was introduced onto the US market by Since the late 1980s, a number of further studies appear- Kremers-Urban in 1973. In Europe, PPL had been pro- ed determining the value of major and minor determinants duced and distributed for about 10 years as a research of BP plus the response to AX and AMP minor determi- reagent by the Institute of Clinical Immunology of the nants. The role of PPL and/or MDM in diagnosis became University of Bern, Switzerland. It was finally registered, lower than 50%, with an increasing role for AX over the first for the French market by the Laboratoire des Staller- years [29–33]. This most probably reflects the increasing ge`nes in 1974, and subsequently taken over as PPL and use of AX vs. the older penicillins in the United States and MDM by Allergopharma around 1986. Since then, a large Western Europe. Nevertheless, a recent retrospective study number of studies plus innumerable individual reports in France on 824 patients consulting between 1996 and using both determinants have been published.
2004 for BL allergy revealed 136 with positive skin tests[32]. Among those, 14.7% were positive only to PPL and/orMDM and in an additional 27.6–32%, positive skin tests to Consolidated experience in skin testing with penicillins some other BL were confirmed by positive tests to PPL and/ The first large study was carried out by Green et al., who or MDM. Accordingly, the withdrawal of PPL and MDM evaluated 3000 subjects, of whom 1718 had symptoms would have had the consequence of leaving 20/136 patients compatible with penicillin allergy. PPL plus BP were used undiagnosed, including some with anaphylactic reactions.
and 19% of the cases studied were positive to one or more The situation may become even worse in some other regions penicillin reagents. Among the patients who were posi- of the world where exposure to the older BP still seems to be tive, 54% were only positive to PPL, 22% to BP, and 25% prevalent, as judged from skin testing of the population to BPO and BP [25]. At that time, the recommended [33], in which skin tests to PPL, MDM and BP combined concentration was established at 5 Â 10 À 5 M for PPL in yielded as much as 88.1% positive cases.
Europe and 6 Â 10 À 5 in USA and 10 000 U/mL for BP.
In Spain, a new PPL and MDM kit has been recently In 1981, Sullivan reported a study involving 740 commercialized (Diater Laboratories, Madrid, Spain), with patients, 63% of whom had a positive skin test to one or equivalent results that can be used for the same purpose more penicillin determinants. In this study, in addition to and indications as the previous test [34].
BP, Penicilloic acid (PA) was also used. The percentage ofsubjects responding to PPL was 21%, to MDM 42%, and to PPL plus MDM 45.2%. Interestingly, cases only positive toBP or to PA were observed, with 14.6% of cases respond- Cephalosporins are currently the second most important ing only to PA [26]. The use of ampicillin (AMP) for skin group of BL antibiotics and their chemical structures are testing added no additional information as all AMP- more heterogeneous than those of penicillins. Increasing positive cases were also positive to some BP determinants.
evidence supports the role of this group of antibiotics in In a study carried out by Solley et al. with 778 subjects, the induction of IgE-mediated responses [35, 36].
in addition to major and minor determinants of BP, AMP Although conjugation of cephalosporins to albumin and and methicillin were also used. PPL was positive in 8.2% other proteins is less efficient, these compounds are also of the cases, BP in 20.5%, PA in 10.2%, and both BP and able to produce hapten-carrier conjugates [36].
PA (MDM) in 38.9% [27]. Interestingly, in this study skin The first reactions to cephalosporins were attributed to testing with the unmodified penicillins contributed to cross-reactivity with penicillins [37], but increasing evi- 11.6% of the cases and their conjugation to PLL added a dence has shown that some patients can respond to further 13.9%, representing a total of 25.5%.
cephalosporins while tolerating penicillin derivatives The largest study reported was published by Gadde et [38–45]. Skin testing with cephalosporins raises a number al., with 5063 subjects, of whom 776 had a previous of problems; most oral cephalosporins are poorly soluble, c 2007 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 37 : 166–173 Appropriate betalactam-derived skin test reagents 169 skin tests are not widely standardized and different con- However, cases who were in vitro positive but in vivo centrations have been used by different groups. Concen- negative have also been reported [50]. In a study carried trations from 10 to 30 mg/mL have been recommended for out in 290 cases, 13.8% were only RAST positive [61].
intra-dermal testing with some cephalosporins [46]. Data Whether or not this demonstrates pathological sensitiza- suggest that different patterns of positive responses may tion remains unknown, as these skin test negative – RAST- occur; while some cases develop cross-reactivity between positive patients have not been BL challenged.
similar side chains [40, 43, 47], others experience a Other in vitro biological tests exploit the capacity of selective skin response to one cephalosporin only, and in basophils from BL-allergic patients to become activated others cross-reactivity between penicillins and cephalos- and to release histamine and/or sulphidoleucotrienes (CAST) in the presence of the hapten. In such tests,peripheral blood cells are first stimulated in vitro with thehapten. Basophil activation is determined by flow cyto- Comparison between skin tests, specific immunoglobulin E metry from the expression of the CD63 molecule on the determinations and other biological tests cell membrane,1 and the CAST assay quantitates the In addition to skin testing, various in vitro methods are leucotrienes released in the supernatant. Recently, data also available for the diagnosis of immediate hyper- have been reported about the usefulness of these two tests sensitivity to BL. These methods can generally be con- [62–64]. In patients with a positive history and a positive sidered complementary, or in some instances alternative.
skin test, the basophil activation test is positive in about There is a sizeable group of patients with a history of 48–51% of cases, while CAST is positive in 43–47%. When penicillin allergy and negative skin tests but positive drug both tests are combined, positivity increases to 68%, as provocation tests and positive biological tests in vitro [50].
shown in a recent multi-centre study performed by the Originally performed by radioimmunoassay, the first European Network for Drug Allergy (ENDA) with 150 technique was designated RAST [51, 52]; nowadays, the patients [65]. In the same patients, IgE determination was fluoroimmunoassay is the most widely used test [53].
positive in 38%. Although the new biological tests can In a strict sense, no detailed comparative studies have give useful complementary information, skin testing re- yet been carried out. Most studies compared results of mains the method of choice and the first to perform, in vivo tests, usually BP conjugated to PLL and BP or BP/ PA, to an in vitro conjugate of BP with human serumalbumin (HSA). The in vitro equivalent of BP, PA, or other free determinants has never been used. Kraft et al. [54–56] After more than 50 years, skin testing with BL determi- found an excellent correlation between skin tests to BPO nants has proved safe in the hands of experienced person- and RAST to BPO, but in cases with skin tests only positive nel and although fatalities have been described, they to minor determinants the results were variable. Similar concerned patients in whom no prick test was done before results were reported by Basomba et al. [57]. This has been the intra-dermal tests [66, 67]. Skin testing with BP attributed to a high degree of in vitro cross-reactivity determinants has shown a low incidence of side-effects, between MDM and the major determinants [55]. However, in the order of 0.12–1% [68]. However, as MDM-positive it must be pointed out that the specificity of anti-penicillin skin responses are mainly associated with anaphylaxis, IgE antibodies can be assessed by comparing free deter- systemic reactions may occur. In a recent retrospective, minants with conjugates in RAST inhibition tests [58].
case–control study involving 147 skin-test-positive pa- The conjugation of BPO to PLL has also been used, and tients, 13 (8.8%) experienced a systemic reaction during although this gave better results than with HSA, an the tests. These 13 reactors were compared with non- important number of cases still remained skin-test posi- reactors (135 patients who had a positive skin test with no tive but in vitro negative [50]. For side-chain-specific systemic reactions). Anaphylaxis (69%) and a chronology antibodies in particular, PLL or an amino spacer have of less than 1 h after the drug intake (91%) were signifi- been considered better carriers than HSA. In general, with cantly more frequent in reactors as compared with non- all these carriers, a good correlation has been found reactors (43% and 35%, respectively) [69].
between the clinical situation and the results of the skintest and the in vitro test [59, 60]. In a study involvingsubjects who were skin-test positive to either BPO and/or MDM, in vitro testing was positive to BP in 68% of cases The two main methods used for the diagnosis of immedi- and to AX in 52%, but when both haptens were used the ate hyper-sensitivity to BL are prick and intra-dermal positivity increased to 74%. On the other hand, in subjects testing [68, 70]. Although patch testing is used by some, with a selective response to AX, the sensitivity of thetest was 41% [53]. Thus, if only the IgE in vitro test is 1Basophil activation tests commercially available as BASOTEST (Orpegen, performed, an important number of cases will be missed.
Heidelberg, Germany) or FLOW CAST (B ¨ulmann, Allschwil, Switzerland).
c 2007 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 37 : 166–173 this is not considered to be a useful method for IgE- the patients, though generally of lesser intensity, may mediated reactions. Some perform patch tests in situations require the skin test to be performed by experienced where the type of clinical reaction reported by the patient personnel and in an adequate emergency-ready setting.
With classic BP determinants (BPO, MDM), the reported Prick testing is performed by pricking the skin with an frequency of side-effects is low and reactions usually appropriate needle or lancet through the allergen solution. If mild, varying from 0.1% to 0.7% [25, 26, 28, 75]. In the response is negative, intra-dermal tests are then carried patients with positive skin tests, figures of 13% have been out. This is done by the injection of 0.02–0.05 mL of the hapten solution, raising a small bleb that is initially deli-neated. These are usually performed on the volar forearm,but may involve other parts of the body such as the back.
The drug to test has to be freshly re-constituted and Penicillin allergy is a slowly subsiding phenomenon [56, taken directly from the vial. Mandatory reagents used are 76, 77]. The natural history of BL hyper-sensitivity tells us PPL and MDM. The maximum concentrations recom- that allergic subjects tend to become negative after drug mended for PLL are 5 Â 10 À 5 M and for MDM 2 Â 10 À 2 M.
avoidance for a variable time, a matter of 6–12 months for In the USA, the concentration of PPL is 6 Â 10 À 5 M.
specific IgE [56] and of a few years for skin sensitivity [26, Because MDM is not available in the USA for everyday 78]. Specific T cell reactivity, on the other hand, usually practice, most authors have used BP at a maximum persists for many years [79, 80]. In theory, although a very low concentration of drug is used in skin tests, a possibi- The appearance of side-chain-specific reactions to AX lity for re-sensitization still exists. This has been reported has necessitated the use of this antibiotic for testing. This after slight contact with penicillins, at concentrations is particularly relevant in some European countries, such even lower than those used in skin testing [81].
as Spain or France, although it has also been reported to Most studies involving re-sensitization include both be relevant in other countries [68]. Concerning AMP, no skin tests plus a drug provocation test. This implies that specific reactions have been reported with this antibiotic, in the event of re-sensitization, it cannot be easily and it can therefore be considered optional [73, 74]. The attributed to the role of skin testing [26]. Nevertheless, in maximum concentrations recommended for aminopeni- most studies, and even including drug provocation, fig- ures are usually low [82, 76]. In a study carried out by Cephalosporin skin testing is also becoming progres- Nugent et al. [83] in a group of 329 cases, 2.5% of the sively more necessary, not only to evaluate primary initially negative cases converted to positive after skin sensitization but also cross-reactivity. Great variability exists with cephalosporins, especially with prick testing.
In most instances, concentrations up to 2 mg/mL areconsidered non-irritant, although studies in negative control groups show that concentrations as high as Despite the advent of various complementary and alter- native in vitro diagnostic methods, skin testing remains a In patients reporting symptoms of severe reactions or in central need for the diagnosis of BL allergy, a public patients with special risk factors, intra-dermal testing and health problem of continued importance. Some recent even prick testing must be done first with several 10-fold studies already show that the withdrawal of PPL and dilutions that are gradually increased until the appearance MDM will have deleterious effects on the diagnosis of BL of a positive response or up to the maximum recom- allergy. Public health authorities and physicians should mobilize for continued access by the community to these Readings are made 15–20 min after application of the hapten. In the prick test, a weal larger than 3 mm indiameter accompanied by erythema with a negativeresponse to the control saline is considered positive. In intra-dermal testing, the weal area is marked initially and15–20 min after testing. An increase in the diameter 1 Idsoe O, Guthe T, Wilcox RR, de Weck AL. Nature and extent of penicillin side reactions, with particular reference to fatalities greater than 3 mm is considered positive. Patients should from anaphylactic shock. Bull WHO 1968; 38:159–88.
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