Frequency of severe reactions following penicillin drug provocation tests: A Bayesian meta-analysis.

BACKGROUND: Patients with a penicillin allergy label tend to have worse clinical outcomes and increased healthcare use. Drug provocation tests (DPT) are the gold-standard in the diagnostic workup of penicillin allergy, but safety concerns may hinder their performance. We aimed to assess the frequency of severe reactions following a DPT in patients with reported allergy to penicillins or other β-lactams.
METHODS: We performed a systematic review, searching MEDLINE, Scopus, and Web of Science. We included primary studies assessing participants with a penicillin allergy label who underwent a DPT. We performed a Bayesian meta-analysis to estimate the pooled frequency of severe reactions to penicillin DPTs. Sources of heterogeneity were explored by subgroup and metaregression analyses.
RESULTS: We included 112 primary studies which included a total of 26,595 participants. The pooled frequency of severe reactions was estimated at 0.06% (95% credible interval [95% CrI] = 0.01%-0.13%; I2  = 57.9%). Most severe reactions (80/93; 86.0%) consisted of anaphylaxis. Compared to studies where the index reaction was immediate, we observed a lower frequency of severe reactions for studies assessing non-immediate index reactions (OR = 0.05; 95% CrI = 0-0.31). Patients reporting anaphylaxis as their index reaction were found to be at increased risk of developing severe reactions (OR = 13.5; 95% CrI = 7.7-21.5; I2  = 0.3%). Performance of direct DPTs in low-risk patients or testing with the suspected culprit drug were not associated with clinically relevant increased risk of severe reactions.
CONCLUSIONS: In patients with a penicillin allergy label, severe reactions resulting from DPTs are rare. Therefore, except for patients with potentially life-threatening index reactions or patients with positive skin tests-who were mostly not assessed in this analysis -, the safety of DPTs supports their performance in the diagnostic assessment of penicillin allergy.

BACKGROUND

β‐Lactam antibiotics constitute the preferred treatment for many infections, but they are not typically prescribed to patients who report a past history of allergic reactions to this drug class. In fact, penicillins correspond to the drug class most patients report to be allergic—between 5% and 10% of individuals from the general population report having a penicillin allergy, and this frequency can reach up to 16% in hospitalized patients. , , , , , However, only a small fraction of these individuals (estimated in 2%–10% in the United States and 18%‐30% in Europe) have a true allergy to β‐lactams. , ,

Patients mislabeled as having a penicillin allergy more frequently receive antibiotics with a broader spectrum, often with lower efficacy and increased side‐effects, leading to poorer clinical outcomes, longer hospitalizations, higher risk of drug‐resistant and healthcare‐associated infections, and increased healthcare costs. , , , , As a result, evaluating and delabeling patients with penicillin allergy has both clinical and economic advantages.

The diagnostic workup of a suspected penicillin allergy comprises a sequence of steps, typically including a complete clinical history, followed by skin tests and potentially in vitro tests (e.g., specific IgE quantification). Ultimately, if negative results are obtained with those tests, a drug provocation test (DPT; i.e., “drug challenge”), consisting in the controlled administration of a drug under strict clinical supervision, is considered to establish or rule out the diagnosis of penicillin allergy. , , , , In patients whose clinical history is poorly compatible with a true penicillin allergy, some experts advocate the performance of direct DPT (i.e., DPT without preceding in vivo or in vitro testing). On the contrary, in patients with history of potentially life‐threatening index reactions (e.g., Stevens–Johnson syndrome [SJS]/toxic epidermal necrolysis [TEN], severe anaphylaxis, or some severe specific organ manifestations), DPT are contraindicated.

While DPTs are the gold‐standard in the diagnosis of penicillin allergy, the possibility of precipitating severe hypersensitivity reactions may prompt safety concerns. However, the frequency of such severe reactions has not been systematically evaluated. Therefore, in this systematic review and meta‐analysis, we aimed to quantify the frequency of severe hypersensitivity reactions following a DPT in patients reporting a penicillin (or β‐lactam) allergy, as well as to explore the impact of different patients' and methodological characteristics on the frequency of such severe reactions.

METHODS

This systematic review with meta‐analysis follows Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines and the recommendations of the Cochrane Handbook for Systematic Reviews. ,

Eligibility criteria

We included original studies reporting the frequency of severe reactions subsequent to DPTs in patients reporting a penicillin or β‐lactam allergy. Severe reactions were defined as episodes of anaphylaxis, shock, SJS/TEN, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, acute interstitial nephritis, hemolytic anemia, serum sickness, drug fever, or other reactions described by the authors as severe and/or—if no additional information was provided—whose reaction treatment required more than antihistamines or corticosteroids (e.g., epinephrine) to subside. Other positive reactions to DPT were not considered severe, and therefore not taken into account.

We excluded studies deliberately performing DPTs with drugs from another antibiotic class, assessing allergy to cephalosporins exclusively or patients with specific diseases or occupations (e.g., only patients with cancer), or adopting a case‐control approach (as data from those studies do not permit calculation of the risk of severe reactions).

Information sources and search methods

We searched three electronic bibliographic databases (MEDLINE, Web of Science, and Scopus), through June 2019. Search queries are detailed in Table A1. References of included studies and of other relevant studies were further reviewed. No restriction on publication languages or dates were applied.

Study selection and data collection process

After duplicates removal, each study was independently assessed by two reviewers (researchers B.S.P. and A.C.F.), first by title and abstract screening, and then by full text reading. Data were independently extracted by two reviewers using a predefined online form purposely built for this study (a pilot version was built to assess the first 15 studies, and subsequently modified accordingly). For each study, we retrieved information on (i) the year of publication; (ii) country; (iii) participants' age group; (iv) setting (i.e., outpatients, inpatients or other); (v) timing of the index reaction (immediate reactions were defined as those occurring during the first hour after exposure to the culprit drug, and the remainder were classified as nonimmediate reactions , ); (vi) culprit drug class (i.e., whether studies included participants reporting an allergy to any β‐lactam or specifically to penicillins); (vii) whether penicillin re‐exposure occurred as part of a diagnostic workup or for therapeutic reasons; (viii) whether single dose, graded or prolonged (>24 h) DPTs were performed; (ix) the route of drug administration; (x) whether DPTs were preceded by skin/in vitro tests or directly performed; (xi) the drugs tested; and (xii) the period during which patients were followed for adverse reactions. In addition, for each primary study, we retrieved information on the number of participants undergoing a DPT, as well as on the number and type of subsequent severe reactions. Whenever provided, we separately retrieved these data for patients who reported immediate index reactions and for patients reporting anaphylaxis as their index reaction (we were not able to perform separate analyses for index reactions as the information necessary was not consistently provided on primary studies). Specific data regarding DPTs to penicillins were always preferred over data regarding DPTs to overall β‐lactam antibiotics. Disagreements between reviewers in study selection or data extraction were solved by consensus.

Full texts were carefully examined so as not to include the same results/patients more than once. Authors were contacted whenever full texts were not available (or in the two cases they were only available in a language authors were not fluent, with two received responses) or to provide relevant missing information.

Quality assessment

The quality of primary studies was independently assessed by two researchers using an adaptation of a tool developed for prevalence studies. Of the 11 items described, we used six items that were adequate for the aim of this study, namely: (i) if the study's target population was representative of the national population in relation to relevant variables; (ii) if the sample frame was representative of the target population; (iii) if some form of random or consecutive selection was used to select the sample; (iv) if the likelihood of nonresponse bias was minimal (defined as less than 25% follow‐up losses and/or participants with negative skin/in vitro tests not undergoing DPT); (v) if an acceptable/sufficiently complete definition of “severe reaction” was used in the study (or if allergic reactions were described in detail); and (vi) if the same methods of assessment and data collection were used for all subjects.

Quantitative synthesis of results

In order to quantitatively synthesize the frequency of severe reactions subsequent to DPTs, we performed Bayesian meta‐analyses following a random effects model based on a binomial likelihood (as described by Welton et al. ). We opted for this approach due to the large quantity of studies in which no severe reactions were observed. In fact, one of the advantages of a Bayesian meta‐analysis based on a binomial likelihood concerns its use of exact methods, dealing more adequately with proportions equal to zero (by contrast, a frequentist approach would imply the need for a continuity correction at least to the proportions equal to zero).

Bayesian methods provide estimations of posterior probability distributions of the parameters of interest, based on prior probability distributions and on the observed data. In this study, based on the frequencies of severe reactions reported in primary studies, we obtained, through meta‐analytic methods of weighting, a probability distribution of the frequency of severe reactions. In addition, we obtained probability distributions for the odds ratio (OR) assessing the association between reporting anaphylaxis as index reaction and occurrence of severe reactions following a DPT. Of these posterior probabilities, we collected information on the mean values and respective 95% credible intervals (95% CrI; range of values within which, with 95% probability, the true frequency of severe reactions lies).

We assessed heterogeneity—defined as the existence of differences beyond those that would be expected just by random sampling—by computing estimates of the I 2 statistic. An I 2 > 50% was indicative of substantial heterogeneity. Heterogeneity sources were explored by means of metaregression and subgroup analyses (i.e., a specific type of sensitivity analysis, consisting of separate meta‐analyses restricted to specific categories of retrieved variables). Exponentials of the metaregression coefficients were interpreted as OR.

Both for the effect size measure and for the τ parameter we used uninformative prior distributions (dnorm(0, 0.00001) and dgamma(0.00001, 0.00001), respectively). For each analysis, we ran at least 40,000 iterations with a burn‐in of 15,000 sample iterations. Meta‐analysis was performed using rjags package of software R (version 3.5.0).

RESULTS

Study selection

With our search, we obtained 4603 records, of which 1803 were duplicates (Figure 1). After excluding 2451 records in the screening phase, 351 articles were fully read, of which a total of 112 studies were included in the systematic review. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Of these studies, 108 were included in all general analyses, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , while the remaining four were only included in subgroup analyses as their participants partially overlapped with those of other included primary studies. , , , Sixteen studies found to be eligible were not included in this systematic review since they evaluated patients partially or fully assessed in another study, and which were not restricted to any particular characteristic that would render them available to be included in subgroup analyses.

FIGURE 1

Flow diagram of study selection

Study characteristics

A summary of the included studies is presented in Table A2. Included studies were published between 1965 and 2019, and were mostly performed in North America (n = 46, 41.1%) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Europe (n = 44, 39.3%). , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Thirty‐eight studies (34.9%) analyzed exclusively children , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and 28 (25.7%) only analyzed adult patients. , , , , , , , , , , , , , , , , , , , , , , , , , , , Most studies only included outpatients (n = 69, 66.3%). , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , From the 96 studies reporting information on the timing of the index reaction, 15 studies (15.6%) only evaluated patients reporting immediate allergic reactions, , , , , , , , , , , , , , and 12 studies (10.7%) exclusively evaluated patients reporting non‐immediate index reactions. , , , , , , , , , , ,

Prolonged challenges were performed in 41 (39.4%) of the included studies, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , while graded challenges were performed in 37 (35.6%) studies, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and 17 (16.3%) studies opted for single dose DPTs. , , , , , , , , , , , , , , , , Half of the studies (n = 59, 52.7%) performed a DPT with the suspected culprit drug. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , In 12 studies (10.9%), direct DPTs (DPTs without previous skin/in vitro tests) were performed, , , , , , , , , , , , while in 87 studies (79.1%) challenges were always preceded by previous tests. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Eleven studies (10.0%) included patients undergoing both direct DPTs and DPTs preceded by other tests. , , , , , , , , , ,

Frequency of severe reactions

In the included studies, a total of 26,595 participants underwent a DPT, of whom 93 experienced severe reactions (0.4%). Most reactions were classified as anaphylaxis (n = 80; 86.0%), followed by serum sickness (n = 7; 7.5%), and maculopapular exanthema with systemic symptoms (n = 6; 6.5%). No fatal reactions were observed (Table 1).

TABLE 1

Outcomes of drug provocation tests (DPT) across the included primary studies

	N (meta‐analytical frequency; 95% CrI; I 2)
Patients who performed a DPT	26,595
Patients with a positive DPT	1300 (3.8%; 2.9%–4.7%; 19.8%)
Patients with severe hypersensitivity reactions	93 (0.06%; 0.01%–0.13%; 57.9%)
Anaphylaxis a	80 (0.03%; 0%–0.08%; 65.7%)
Serum sickness	7 (0.01%; 0%–0.03%; 22.7%) b
SJS/TEN	0
AGEP/DRESS	0
Acute interstitial nephritis	0
Hemolytic anemia	0
Drug fever	0
Others c	6 (0.001%; 0%–0.01%; 68.4%) b
Patients with fatal hypersensitivity reactions	0

Abbreviations: AGEP, acute generalized exanthematous pustulosis; CrI, credible interval; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens–Johnson Syndrome; TEN, toxic epidermal necrolysis.

Includes anaphylactic reactions described as such in included primary studies, as well as reactions described in those studies and which are compatible with anaphylaxis criteria.

Meta‐analytical frequency of severe nonanaphylactic reactions = 0.02% (95% CrI = 0%–0.04%; I 2 = 44.2%).

Maculopapular exanthemas with systemic symptoms not qualifying as DRESS.

The Bayesian meta‐analysis identified a frequency of severe reactions of 0.06% (95% CrI = 0.01%–0.13%), albeit with severe heterogeneity (I 2 = 57.9%; Table 2). The meta‐analytical frequency of anaphylaxis was of 0.03% (95% CrI = 0%–0.08%; I 2 = 65.7%), while it was of 0.02% (95% CrI = 0%–0.04%; I 2 = 44.2%) for nonanaphylactic severe reactions. The results of univariable metaregression and subgroup analyses are presented in Tables 2 and 3. A clear decrease in the risk of severe reactions was observed for studies assessing patients reporting non‐immediate reactions (OR = 0.05; 95% CrI = 0–0.31), for studies performing single‐dose DPTs (OR = 0.08; 95% CrI = 0–0.47), and for studies performed in North America (OR = 0.25; 95% CrI = 0.04–0.80; Table A3 presents results stratified by region). We did not find a clear increase in the risk of severe reactions—considering the results of both metaregression and subgroup analysis—with DPTs performed with the suspected drug (OR = 1.74; 95% CrI = 0.27–5.89), with the performance of direct DPTs (OR = 1.00; 95% CrI = 0.47–4.16), or with the possibility of reporting reactions for more than one day (OR = 1.54; 95% CrI = 0.06–8.34).

TABLE 2

Results of metaregression and subgroup analyses for the frequency of severe reactions following penicillins drug challenges

	Number of studies	Number of patients	Subgroup analyses		Univariable metaregression—OR (95% CrI) [% iterations with OR > 1]
			Percent of severe reactions (95% CrI)	I 2
All	108	26,595	0.06 (0.01–0.13)	57.9 %
Year of publication	108	26,595	a	a	1.00 (0.99–1.01) [13%]
Geographic region
Europe	40	14,049	0.10 (0.01–0.26)	61.8 %	3.29 (0.62–10.33) [81%]
North America	46	10,198	0.08 (0–0.17)	16.9 %	0.25 (0.04–0.80) [1%]
Age group
Children	37	8223	0.14 (0.02–0.32)	44.6 %	b
Adults c	28	3787	0.21 (0.02–0.37)	15.5 %	1.16 (0.16–3.83) [34%]
Setting
Outpatients only	65	18,748	0.07 (0.01–0.17)	59.5 %	b
Inpatients only	17	1732	0.03 (0–0.09)	20.2 %	0.29 (0.01–1.73) [6%]
Type of clinic where patients were tested
Nonallergy clinic	24	4206	0.02 (0–0.04)	55.4 %	b
Allergy clinic	68	18,800	0.06 (0.01–0.15)	59.7 %	12.07 (0.43–94.01) [13%]
Timing of index reaction
Immediate	24	3162	0.29 (0.01–1.00)	64.4 %	b
Nonimmediate	22	4271	0.001 (0–0.001)	97.0 %	0.05 (0–0.31) [0%]
Culprit drug class (index reaction)
Any penicillin	71	11,658	0.02 (0–0.08)	71.0 %	b
Any β‐lactam	37	14,937	0.14 (0.03–0.29)	45.7 %	3.30 (0.50–12.89) [83%]
Context of DPT/drug exposure
Diagnostic DPT	96	24,044	0.06 (0.01–0.13)	60.4 %	b
Therapeutic exposure	10	2086	0.14 (0.09–0.18)	0.5 %	1.22 (0.03–6.63) [31%]
DPT dosing
Single	17	4893	0.01 (0–0.04)	6.6 %	0.08 (0–0.47) [0%]
Graded d	36	7948	0.07 (0–0.25)	67.0 %	4.32 (0.39–18.81) [86%]
Prolonged d	38	9085	0.07 (0–0.20)	59.5 %	2.50 (0.24–10.65) [68%]
Route of drug administration
Only oral	81	17,193	0.08 (0.02–0.17)	46.0 %	b
Oral and parenteral	18	8558	0.04 (0–0.21)	82.5 %	2.18 (0.24–8.90) [67%]
Diagnostic workup
DPT preceded by previous tests	96	23,265	0.07 (0.02–0.15)	53.7 %	b
Direct DPT	21	3804	0.02 (0–0.12)	74.8 %	1.00 (0.07–4.16) [33%]
Drugs tested in the DPT
Suspected drug not tested	44	9298	0.05 (0–0.17)	59.5 %	b
Suspected drug tested	55	14,447	0.06 (0.01–0.15)	62.1 %	1.74 (0.27–5.89) [60%]
Number of drugs tested in the DPT
One drug	90	21,797	0.07 (0.02–0.16)	47.9 %	b
More than one drug	11	3565	0.90 (0–1.20)	83.8 %	7.17 (0.68–32.20) [93%]
Reporting time for severe reactions
<1 Day	11	1430	0.20 (0.04–0.41)	2.5 %	b
≥1 Day	76	21,551	0.04 (0–0.10)	64.0 %	1.54 (0.06–8.34) [38%]
Studies methodological quality
<3 Items classified as “high risk of bias”	90	24,569	0.06 (0.01–0.14)	59.2 %	b
≥3 Items classified as “high risk of bias”	18	2026	0.11 (0.01–0.26)	4.1 %	0.78 (0.03–3.66) [22%]

Abbreviations: CrI, credible interval; DPT, drug provocation test; OR, odds ratio.

No subgroup analysis performed, as this is a continuous variable (we were only able to perform metaregression analysis).

Reference category.

When analyzing together adults and young adults (≥15 years old), we obtained a frequency of severe reactions of 0.06% (0–0.24%; I 2 = 62.6%).

When comparing studies performing graded and prolonged DPTs, we obtained an OR = 1.17 (0.11–5.01), favoring prolonged DPTs.

TABLE 3

Results of subgroup analyses for the frequency of severe reactions following penicillin drug challenges in patients reporting index immediate reactions

	Number of studies	Number of patients	Subgroup analyses
			Percent of severe reactions (95% CrI)	I 2
Children
Index immediate reactions	10	545	0.64 (0–1.94)	25.3 %
Index immediate reactions with testing of the suspected culprit drug	9	526	0.82 (0.01–1.94)	23.5 %
Adults
Index immediate reactions	4	199	1.62 (0.28–4.05)	4.5 %
Index immediate reactions with testing of the suspected culprit drug	2	95	a	a
Outpatients
Index immediate reactions	16	2848	0.26 (0–1.16)	77.9 %
Index immediate reactions with testing of the suspected culprit drug	13	2612	0.80 (0–1.21)	77.1 %
Inpatients
Index immediate reactions	2	64	b	b
Index immediate reactions with testing of the suspected culprit drug	1	2	b	b

Abbreviations: CrI, credible interval; DPT, drug provocation test; OR, odds ratio.

Convergence not reached;

No cases of severe reactions were observed in the studies assessing inpatients reporting index immediate reactions.

A total of 565 participants in 29 primary studies had reported anaphylaxis as their index reaction, of whom 32 experienced severe reactions. This corresponds to a meta‐analytical pooled frequency of 4.64% (95% CrI = 0.79%‐7.43%; I 2 = 11.4%) versus 0.09% (95% CrI = 0.01%–0.18%; I 2 = 42.0%) for the remaining participants. We, therefore, observed a strong association between reporting anaphylaxis as index reaction and occurrence of severe reactions following a DPT (OR = 13.48; 95% CrI = 7.68–21.53, I 2 = 0.3%).

Risk of bias of individual studies

A risk of bias graph is presented in Figure 2, and the complete analysis of the risk of bias of individual studies may be found in Table A4. Most studies had a high or unclear risk of bias in terms of sample representation. Nevertheless, most studies presented a low risk of bias regarding the other parameters evaluated. A similar frequency of severe reactions following DPTs was found in studies with three or more items classified as “high risk of bias” (0.11%, 95% CrI = 0.01%–0.26%; I 2 = 4.1%), , , , , , , , , , , , , , , , , , when compared with the remaining studies (0.06%, 95% CrI = 0.01%–0.14%; I 2 = 59.2%). , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

FIGURE 2

Risk of bias graph for included primary studies

DISCUSSION

This systematic review included 112 primary studies assessing the frequency of severe reactions following DPTs to penicillins. Results of the meta‐analysis suggest that severe reactions are rare, estimated at a frequency of 0.06%, corresponding to approximately an average of one severe reaction for each 1700 patients undergoing a DPT. Additionally, from the 26,595 assessed patients who underwent a DPT, none had a subsequent fatal reaction. However, it is worth noting that in studies in which direct challenges were not performed, more than 98% DPTs were performed in patients who had had negative skin or in vitro tests. In addition, most of the included studies, following international recommendations, did not challenge patients with a reported history of a severe or life‐threatening index reaction ‐ 79 studies explicitly reported severe cutaneous adverse reactions (e.g., SJS/TEN, which are contraindications for DPTs , , ) as exclusion criteria, of whom 30 did not test patients with history of anaphylaxis or anaphylactic shock either. In fact, when considering patients with an index reaction of anaphylaxis, the estimated frequency of severe reaction rises to 6.0%.

Our results should be carefully interpreted on account of the observed heterogeneity. Such heterogeneity indicates that across included studies, there are important differences in the frequency of severe reactions. To identify the variables explaining such differences, we performed metaregression and subgroup analyses, observing a lower frequency of severe reactions in studies evaluating patients reporting nonimmediate reactions. This mirrors the fact that nonimmediate reactions are typically mild, with the exception of SJS/TEN or other very rare potentially life‐threatening reactions (which are contraindications for DPTs). Furthermore, particularly in children, infectious and other nonallergic rashes are often erroneously reported as nonimmediate hypersensitivity reactions. , , On the other hand, we observed a lower frequency of severe reactions following single‐dose DPTs, which may be explained by selection biases (i.e., patients reporting less severe index reactions having greater chances of receiving single dose DPT), by the lower exposure of participants to the tested drugs, and by the fact that studies opting for single dose DPTs often observed the participants for a smaller period of time (possibly not registering later reactions). However, a similar frequency of severe reactions was observed when comparing studies performing graded versus prolonged DPTs. Finally, we did not observe a clear increase in the frequency of severe reactions when analyzing studies that performed DPTs with the suspected drug (as supported by international recommendations ). We did not observe either a higher frequency of severe reactions in those studies performing direct DPTs. However, care should be taken when interpreting those results as those studies mainly included patients deemed by allergists to have a low risk clinical history.

The region was also identified as a variable potentially explaining heterogeneity. In fact, in European studies, we observed higher frequency of severe hypersensitivity reactions and lower heterogeneity when compared to their North American counterparts, and a more evident increased risk of such reactions among adults. These differences may point to regional differences in the type of assessed patients, with a possibly higher predominance of low‐risk patients in North America.

This study has some limitations, in part due to the characteristics of primary studies. In particular, there is the possibility of selection biases, which may have resulted in overestimation or underestimation of the true frequency of severe reactions. In fact, 77% of primary studies explicitly reported to be performed in allergy clinics and/or involving allergy specialists, potentially affecting sample representativity. Also, during the selection process, 69 primary studies were excluded for not reporting the frequency of severe reactions—it is possible or potentially even likely that in those studies, severe reactions were not mentioned because they did not occur. This would render our 0.06% estimate an overestimate of the true frequency of severe reactions following a DPT. In addition, the exclusive assessment of patients referred to specialized clinics and/or lack of testing of patients with unconvincing penicillin allergy histories would also result in overestimating the frequency of severe reactions (for instance, we would expect that patients referred to specialized clinics may represent those with a higher risk of having a true penicillin allergy and that no testing would be performed in patients with intolerance reaction histories). On the other hand, in most studies, only patients with no history of particularly severe index reactions and with negative skin or in vitro tests underwent DPTs. This could, in turn, have resulted in an underestimation of the frequency of severe reactions.

Another important limitation concerns the severe heterogeneity found, mirroring not only the nature of this meta‐analysis (i.e., a quantitative synthesis of frequencies of a rare event), but also the differences in eligibility criteria and DPTs protocols across primary studies. In order to explore possible sources of heterogeneity, we performed metaregression and subgroup analyses, ceasing to detect severe heterogeneity in 11 out of 27 subgroup analyses. Unfortunately, on account of the scarcity of severe reactions, we were not able to perform multivariable metaregression analyses to identify adjusted moderators of heterogeneity. We attempted to circumvent this limitation by performing stratified analyses on the region.

Finally, information on index reactions was inconsistently reported across primary studies—except for anaphylaxis, we were not able to assess the risk of severe reactions associated with each type of index reaction.

The main strength of this study is its meta‐analytical approach for the quantitative synthesis of rare events. The main advantage of Bayesian meta‐analysis based on a binomial likelihood concerns its use of exact methods, allowing for dealing more adequately with zero‐cells (in this case corresponding to the majority of included primary studies, in which no severe reactions to DPTs were observed). By contrast, classical frequentist meta‐analytical methods would possibly result in an overestimation of the true frequency of such reactions. In addition, for the Bayesian meta‐analysis, we used noninformative priors, whose effect was further diluted by including a large number of primary studies, further decreasing the risk of priors dominating the results. Another methodologic strength concerns the performance of metaregression and subgroup analyses, aiming to identify patient or clinical characteristics associated with differences in the outcomes. Finally, we performed a comprehensive search, encompassing three different electronic bibliographic databases and not using exclusion criteria based on the date or language of publication.

In conclusion, and from a clinical point of view, this study suggests that overall, severe reactions are rare, occurring at an average of one reaction for each 1700 patients undergoing a DPT. In addition, the included primary studies did not report any fatal reactions; indeed, in a comprehensive search of the literature beyond the eligibility criteria of this systematic review, we only found one death described after a DPT to a penicillin, although this case was potentially attributable to resensitization to clavulanate. However, our results also point that the risk of a severe reaction is not the same for all patients. In fact, our overall results cannot be generalized to patients with potentially life‐threatening non‐IgE‐mediated index reactions (e.g., SJS/TEN)—in whom DPT is contraindicated—or to patients with positive penicillin skin tests, and we also identified that patients reporting an index anaphylactic reaction had almost 80 times more risk of developing severe reactions to DPT than the remaining participants. In fact, only one in each 100,000 DPT in patients reporting nonimmediate reactions are expected to result in severe reactions. This value rises to one in each 345 DPT in patients reporting immediate reactions, and to one in each 22 DPT in patients reporting a history of anaphylaxis. This highlights the importance of a thorough characterization of the index reaction (e.g., by a structured clinical history) prior to the diagnostic workup. Consistently, we observed that more than three‐quarters of reported severe reactions consisted of anaphylaxis, highlighting the need for prompt recognition and treatment of anaphylactic reactions. A detailed characterization of the index reaction may also identify those low‐risk patients who may undergo a direct DPT, in whom our results did not identify an increased risk of severe reactions. , Testing the suspected culprit drug did not associate with clear increased risk of severe reactions, and therefore should be encouraged.

To the best of our knowledge, this is the first systematic review with meta‐analysis assessing the frequency of severe reactions following DPTs. Future primary studies may allow for a more thorough exploration of this issue, by providing more details on their methodology (particularly regarding eligibility criteria and DPT procedures) or even anonymized individual participant‐level data (Table 4). The results of this study support, from a safety point of view, the performance of DPTs during the diagnostic workup of penicillin allergy, particularly if a detailed allergy history has been obtained, evidence‐based recommendations are followed and there is appropriate supervision by an allergy specialist. This is particularly important, since delabeling patients reporting a penicillin allergy has been recommended as an antibiotic stewardship tool, to contribute to a more adequate prescription of antibiotics, minimizing patients' risks and improving clinical and economic outcomes.

TABLE 4

Limitations of current evidence and key aspects for future studies

Limitations of current evidence	Key requirements needed for future studies
Heterogeneity and insufficient description of eligibility criteria	Clear description of eligibility criteria
Absence of studies with representative national or state‐wide representation	Conduction of multicentric studies with standardized methods
Inconsistent reporting of participants' demographic and clinical data	Clear description of the methodology used for performing DPT
Inconsistent or incomplete description of DPT procedures	Standardization of DPTs protocols
Potential selection bias related to the exclusion of less and/or more severe allergic patients	Consistent and detailed report of severe reactions to DPTs (e.g. clinical manifestations and timing)
Limited data from Latin America, Asia and Africa	Publication of anonymized patient‐level data OR presentation of stratified results by different reaction phenotypes and risk groups

Abbreviation: DPT, drug provocation test.

CONFLICT OF INTEREST

Kimberly G. Blumenthal has a clinical decision support tool for inpatient beta‐lactam allergy evaluation used at Partners HealthCare Systems and licensed to Persistent Systems.

AUTHOR CONTRIBUTIONS

António Cardoso‐Fernandes: data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing‐original draft (equal). Kimberly G. Blumenthal: conceptualization (equal); writing‐original draft (equal); writing‐review and editing (equal). Anca Mirela Chiriac: conceptualization (equal); writing‐original draft (equal); writing‐review and editing; (equal). Isabel Tarrio: data curation (equal); formal analysis (equal); investigation (equal). David Afonso‐João: formal analysis (equal); investigation (equal). Luis Delgado: conceptualization (equal); writing‐review and editing (equal). João Almeida Fonseca: conceptualization (equal); writing‐review and editing (equal). Luís Filipe Azevedo: conceptualization (equal); formal analysis (equal); methodology (equal); writing‐review and editing (equal). Bernardo Sousa‐Pinto: conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing‐original draft (equal).