What drug allergy

WHAT YOU SOULD HAVE READ BUT ………………… 2018
Drug allergy
Attilio Boner
University of Verona, Italy
attilio.boner@univr.it

Review
Consequences of
missdiagnosis

Prevalence and
Natural History

• Most immune-mediated adverse
drug reactions (IM-ADRs)
involve the skin, and many have
additional systemic features.
• Severe cutaneous adverse drug reactions (SCARs) are an uncommon,
potentially life-threatening.
• T-cell–mediated immunopathology is central to these severe delayed
reactions.
Severe Delayed Cutaneous and Systemic Reactions
to Drugs: A Global Perspective on the Science
and Art of Current Practice
Peter JG, JACI Pract 2017;5:547-563

• Strong HLA-gene associations
have been elucidated for specific
drug-SCAR IM-ADRs such as
Stevens-Johnson syndrome/
toxic epidermal necrolysis.
• SCAR management is complicated by substantial short- and long-term
morbidity/mortality and the potential need to treat ongoing comorbid
disease with related medications.
Peter JG, JACI Pract 2017; 5:547-563

1) SJS - Stevens-Johnson syndrome
2) TEN - Toxic epidermal necrolysis
3) DRESS - Drug reaction, eosinophilia and systemic syndrome
4) FDE - Fixed drug eruption;
5) LDR - Lichenoid drug reaction;
6) AGEP - Acute generalized exanthematous pustulosis
7) SS - Serum sickness
8) SSLR - Serum sickness-like reaction
9) NSAIDs - Nonsteroidal anti-inflammatory drugs

Important features of different clinical phenotypes

Challenge
Drug provocation
test

Optimal step doses for drug provocation tests
to prove beta-lactam hypersensitivity
AM Chiriac, Allergy 2017;72:552–561
• We suggest the following
steps for DPT to BLs:
5–15–30–50% of daily
therapeutic dose with
intervals between doses
of 30 min.
(with additional lower
steps for index reactions
of anaphylaxis).
 To detect eliciting dose
thresholds (reactive doses)
during β-lactam (BL) Drug
provocation tests (DPT).
 182 positive DPT

Optimal step doses for drug provocation tests
to prove beta-lactam hypersensitivity
AM Chiriac, Allergy 2017;72:552–561
• We confirm the safety
of 1-day protocol for
immediate and mild
nonimmediate reactors,
for both children and
adults, with a surveillance
period of 2 h after the
last administered dose,
and a prolonged
surveillance after
discharge of 48 h.
 To detect eliciting dose
thresholds (reactive doses)
during β-lactam (BL) Drug
provocation tests (DPT).
 182 positive DPT

The Importance of Prolonged Provocation in Drug
Allergy - Results From a Danish Allergy Clinic
Fransson S, JACI Pract 2017; 5:1394-1401
 A total of 1,913 provocations
done in 1,659 patients,
median age 46 years.
 Antibiotics, analgesics,
local anesthetics and
other drugs.
• Only 11.0% of the provocations
were positive.
• Only 1 of 5 patients tested
positive on the first dose,
indicating that prolonged
exposure should always be
considered.

Total drug provocation tests (n = 1913)
 A total of 1,913 provocations
done in 1,659 patients,
median age 46 years.
 Antibiotics, analgesics,
local anesthetics and
other drugs.

The investigation algorithm for suspected drug allergic reactions

Drugs in positive provocation tests (n = 211)

Timing of positive tests

Basophil activation test
(BAT)
Other tests

Antibiotic
Sensitivity
Β-lattamici

Oral challenge without skin tests in children with
non-severe beta-lactam hypersensitivity:
Time to change the paradigm? L Moral, PAI 2017;28:724-727
• A systematic review on suspected allergy to penicillins and cephalosporins
found only 2 studies reporting a positive predictive value of skin tests
in children of 36% and 33%, respectively, leading to a high rate of
inaccurate diagnosis.
• Moreover, considering that skin tests are negative in more than
90%-95% of cases, an oral provocation test (OPT) is finally needed
to confirm tolerance in most of these children.

Oral challenge without skin tests in children with
non-severe beta-lactam hypersensitivity:
Time to change the paradigm? L Moral, PAI 2017;28:724-727
• Therefore, OPT to the index antibiotic without skin tests are increasingly
being considered an accepted procedure for children with a suspected
mild non-immediate reaction related to a beta-lactam antibiotic.
• OPT with the index antibiotic, without skin tests, are safe and convenient
for children with a history of a mild reaction with a beta-lactam antibiotic
before it can be recommended in pediatric allergy guidelines.

Oral Challenge without Skin Testing Safely Excludes
Clinically Significant Delayed-Onset Penicillin
Hypersensitivity Confino-Cohen R, JACI Pract 2017; 5:669-675
Background:
• Penicillins are the drug family most commonly associated with
hypersensitivity reactions. Current guidelines recommend negative skin
tests (ST) before re-administering penicillins to patients with previous
non-immediate reactions (NIR).
Objective:
• The objective of this study was to examine whether ST are necessary
before re-administering penicillin to patients with NIR.

 Patients with non-
immediate reactions (NIR)
to penicillins starting longer
than 1 hour after last dose
administration or starting
any time after the first
treatment day or patients
with vague recollection of
their reaction underwent
penicillin ST.
 Disregarding ST results,
patients were challenged
with the relevant
penicillins.
• One-tenth of the
therapeutic dose followed
by the full dose was
administered at 1-hour
interval and patients
continued taking the full
dose for 5 days.

• Immediate reaction was
observed in 9 patients (1.5%): 1-
positive ST, 7-negative ST,
and 1-equivocal ST.
• Late reaction to the first-day
challenge occurred in
24 patients (4%).
• 30 patients (6.1%) developed
mild reactions to the home
challenge regardless of their
ST results.
penicillin ST.
with the relevant
penicillins.

• Immediate reaction was
observed in 9 patients (1.5%): 1-
positive ST, 7-negative ST,
and 1-equivocal ST.
• Late reaction to the first-day
challenge occurred in
24 patients (4%).
• 30 patients (6.1%) developed
mild reactions to the home
challenge regardless of their
ST results.
penicillin ST.
with the relevant
penicillins.
A 5-day oral challenge
without preceding ST
is safe and sufficient
to exclude penicillin
allergy after NIR
developing during
penicillin treatment.

Positive Skin Test or Specific IgE to Penicillin Does Not
Reliably Predict Penicillin Allergy
Tannert LK, JACI Pract 2017; 5:676-683
Introduction:
• According to guidelines, patients are diagnosed with penicillin allergy
if skin test (ST) result or specific IgE (s-IgE) to penicillin is positive.
However, the true sensitivity and specificity of these tests are presently
not known.
Objective:
• To investigate the clinical relevance of a positive ST result and positive
s-IgE and to study the reproducibility of ST and s-IgE.

 25 patients with positive
penicillin ST results,
antipenicillin s-IgE results,
or both were challenged with
their culprit penicillin.
 Patients with a penicillin-
associated anaphylaxis within
3 months, systemic reactions
to or with delayed positive
intracutaneous test (ICT)
results were not further
challenged.
• Only 9 (36%) of 25 were
challenge positive.
• There was an increased
probability of being penicillin
allergic if both ST result
and s-IgE were positive at T0.
• Positive ST result or positive
s-IgE alone did not predict
penicillin allergy.

 25 patients with positive
penicillin ST results,
antipenicillin s-IgE results,
or both were challenged with
their culprit penicillin.
 Patients with a penicillin-
associated anaphylaxis within
3 months, systemic reactions
to or with delayed positive
intracutaneous test (ICT)
results were not further
challenged.
• Only 9 (36%) of 25 were
challenge positive.
• There was an increased
probability of being penicillin
allergic if both ST result
and s-IgE were positive at T0.
• Positive ST result or positive
s-IgE alone did not predict
penicillin allergy.
The best predictor for
a clinically significant
(IgE-mediated) penicillin
allergy is a combination of
a positive case history
with simultaneous positive
ST result and s-IgE or a
positive challenge result.

Skin testing
STs were performed with freshly prepared dilutions of β-lactams:
• benzylpenicillin 20 mg/mL,
• AMP-ampicillin 20 mg/mL,
• AX-amoxicillin 20 mg/mL,
• DX-dicloxacillin 1 mg/mL,
• MC-mecillinam 4 mg/mL,
• minor determinant mixture (sodium benzylpenicillin 0.5 mg,
benzylpenicilloic acid 0.5 mg, and sodium benzylpenicilloate 0.5 mg),
and penicilloyl poly-L-polylysine.

Drug challenge
• Oral or intravenous challenge (depending on the route of administration at
the initial reaction) with the culprit penicillin was performed 1 week after
T0 under anaphylaxis surveillance by administering 10-fold increasing
doses with 30-minute time intervals starting at 1/100 of a therapeutic
dose until occurrence of an objective reaction or until reaching the
therapeutic dose.
• If negative, the prolonged challenge (dosing at home with the standard
dose regimen for the drug for 7 days) was performed to mimic clinical
practice.
• Patients with s-IgE were challenged more carefully with a dose regimen
starting at 1/1000 of a therapeutic dose followed by doses with
alternating 3-fold and 10-fold increments (3/1000, 1/100, 3/100, 1/10,
3/10, and 1/1).

• What is already known about this topic?
According to guidelines, patients with a positive skin test result or
measurable specific IgE to penicillin should not be challenged.
• What does this article add to our knowledge?
Neither a positive skin test result nor a positive specific IgE predict
clinical allergy to penicillin with certainty and both can fluctuate over time.
• How does this study impact current management guidelines?
Patients with a distant history of anaphylaxis or a more recent non-severe
penicillin-associated reaction should be challenged to establish acute
tolerance.

A Proactive Approach to Penicillin Allergy Testing
in Hospitalized Patients
Chen JR, JACI Pract 2017; 5:686-693
Background:
• Penicillin allergy testing is underutilized in inpatients despite its potential
to immediately impact antibiotic treatment.
• Although most tested patients are able to tolerate penicillin, limited
availability and awareness of this tool leads to the use of costly
and harmful substitutes.
Objective:
• We established an inpatient service at a large academic hospital to
identify and test patients with a history of penicillin allergy with the goals
of removing inaccurate diagnoses, reducing the use of ß-lactam
alternatives, and educating patients and clinicians about the procedure.

 Eligible inpatients were
flagged daily through the
electronic medical record
and prioritized via a
specialized algorithm.
 A trained clinical pharmacist
performed penicillin skin
tests and challenges
preemptively or by provider
request.
• 252 direct evaluations over
18 months.
• Overall, 228 subjects (90.5%)
had their penicillin allergy
removed.
• Of these, 223 were cleared
via testing and 5 by discovery
of prior penicillin tolerance.

• Among patients testing
negative, 85 (38%)
subsequently received
ß-lactams, preventing
504 inpatient days
and 648 outpatient days
on alternative agents.
 Eligible inpatients were
flagged daily through the
electronic medical record
and prioritized via a
specialized algorithm.
 A trained clinical pharmacist
performed penicillin skin
tests and challenges
preemptively or by provider
request.

Allergy Testing in Children With Low-Risk
Penicillin Allergy Symptoms
Vyles D, Pediatrics 2017;140:e20170471
BACKGROUND:
Penicillin allergy is commonly reported in the pediatric
emergency department (ED).
True penicillin allergy is rare, yet the diagnosis results from the
denial of first-line antibiotics.
We hypothesize that all children presenting to the pediatric ED
with symptoms deemed to be low-risk for IgE-mediated
hypersensitivity will return negative results for true penicillin
allergy.

 The majority of the symptoms of penicillin allergy reported by families
are low-risk for true allergy. Vyles D, Acad Pediatr. 2017;17(3):251–255
 These symptoms are often adverse reactions such as maculopapular rash,
vomiting, diarrhea, or other benign symptoms.
 Hives are frequently reported as a symptom of penicillin allergy; however,
in young children, hives can be the result of a bacterial or viral infection
and misinterpreted as an allergy when a penicillin agent is being
administered for treatment.

 The term “low-risk” referred to reactions that were not likely to represent
a severe IgE-mediated or T-cell–driven process.
 Low-risk symptoms of allergy include:
• rash,
• itching,
• diarrhea,
• vomiting,
• runny nose,
• nausea,
• cough, or
• a reported family history of allergy.

 The term “high-risk” was used to refer to reported reactions, either IgE-
mediated or T-cell–driven such as:
• respiratory or cardiovascular involvement (ie, wheezing, difficulty
breathing, airway swelling, syncope, drop in blood pressure, etc).
• cutaneous involvement with a severe reaction was also deemed to be
high-risk (ie, orofacial or limb angioedema).

 Any report of anaphylaxis was also classified as high-risk.
 For potentially T-cell–mediated symptoms, any report consistent with:
• a bullous cutaneous reaction was classified as high-risk; this is in
consideration of Stevens-Johnson syndrome and toxic epidermal
necrolysis.
 Additionally, diffuse erythema that could represent drug reaction with
eosinophilia and systemic symptoms was also classified as high-risk.

 Children aged 4 to 18 yrs old
presenting to the pediatric
ED with parent-reported
penicillin allergy.
 Allergy questionnaire to
parents of 597 children.
% children with
low-risk symptoms
51%
60 –
50 –
40 –
30 –
20 –
10 –
00
(302/597)

penicillin allergy.
% children with
low-risk symptoms
51%
60 –
50 –
40 –
30 –
20 –
10 –
00
(302/597)
Rash and itching
(63%) were the
most commonly
reported allergy
symptoms.

penicillin allergy.
% children with
low-risk symptoms
51%
60 –
50 –
40 –
30 –
20 –
10 –
00
(302/597)
Overall, (100%) were
found to have negative
results for penicillin
allergy and had their
labeled penicillin allergy
removed from their
medical record.

Allergy Symptoms as Reported by Parents
Low-Risk Symptoms Na
(%)
Nonhive rash 73 (73.0)
Itching 63 (63.0)
Hive rash 17 (17.0)
Diarrhea 7 (7.0)
Other 4 (4.0)
Vomiting 2 (2.0)
Nausea 2 (2.0)
Runny nose 1 (1.0)
Cough 1 (1.0)
Headache 1 (1.0)
Dizziness 1 (1.0)
Cannot remember 7 (7.0)
aNot mutually exclusive

CONCLUSIONS:
•All children categorized as low-risk by our
penicillin allergy questionnaire were found to
have negative results for true penicillin
allergy.
•The utilization of this questionnaire in the
pediatric ED may facilitate increased use of
first-line penicillin antibiotics.

Clinical outcomes following inpatient penicillin allergy
testing: A systematic review and meta-analysis
KA Sacco, Allergy 2017;72:1288–1296
 Inpatients having a
documented penicillin
allergy that underwent
penicillin allergy testing.
 24 studies.
96.1%
% patients with a
(-) penicillin skin testing
100 –
090 –
080 –
070 –
060 –
050 –
040 –
030 –
020 –
010 –
000

 24 studies.
96.1%
% patients with a
100 –
090 –
080 –
070 –
060 –
050 –
040 –
030 –
020 –
010 –
000
Inpatient penicillin
allergy testing is
safe and effective
in ruling out
penicillin allergy.

 24 studies.
96.1%
% patients with a
100 –
090 –
080 –
070 –
060 –
050 –
040 –
030 –
020 –
010 –
000
Inpatient penicillin
allergy testing was
associated with
decreased
healthcare cost
in four studies.

Study flow diagram. PST=penicillin skin test, Abx=antibiotics, BLA=B-lactam antibiotic

Tackling inpatient penicillin allergies:
Assessing tools for antimicrobial stewardship.
Blumenthal KG, J Allergy Clin Immunol. 2017 Jul;140(1):154-161.e6.
Background:
Reported penicillin allergy rarely reflects
penicillin intolerance.
Failure to address inpatient penicillin
allergies results in more broad-spectrum
antibiotic use, treatment failures, and
adverse drug events.

internal medicine inpatients
reporting penicillin allergy
in 3 periods:
(1) standard of care (SOC),
(2) penicillin skin testing (ST), and
(3)computerized guideline application
with decision support (APP).
2.0 –
1.0 –
0.0
1.3
OR of penicillin or cephalosporin
use overall
penicillin
skin
testing
1.8
computerized
guideline

internal medicine inpatients
reporting penicillin allergy
in 3 periods:
(1) standard of care (SOC),
(2) penicillin skin testing (ST), and
(3)computerized guideline application
with decision support (APP).
2.0 –
1.0 –
0.0
1.3
OR of penicillin or cephalosporin
use overall
penicillin
skin
testing
1.8
computerized
guideline
Both computerized
guideline application with
decision support and
Skin Testing-when
completed-increased the
use of penicillin and
cephalosporin antibiotics
among inpatients
reporting penicillin
allergy.

This figure displays the
evaluation and treatment
course for patients with
penicillin allergy
hospitalized for a presumed
infection in each of the 3
periods.
The relative frequencies
with which paths
are taken are indicated by
the weight of arrows (ie,
heavier weight indicates
that more patients would
take that path). Positive
and negative downstream
outcomes are shown at the
far right.

This figure displays
the evaluation and
treatment course
for patients with
penicillin allergy
hospitalized for a
presumed infection
in each of the 3
periods.
The relative
frequencies with
which paths
are taken are
indicated by the
weight of arrows
(ie, heavier weight
indicates that more
patients would
take that path).
Positive and
negative
downstream
outcomes are shown
at the far right.

Antibiotic
Sensitivity
macrolides

Steroid
Antihistaminic
Sedativi della tosse
sensitivity

Non-steroid
anti-inflammatory drugs
(NSAIDs)

Natural evolution in patients with nonsteroidal
anti-inflammatory drug-induced urticaria/angioedema
I. Doña, Allergy 2017;72:1346–1355
 38 patients with NSAIDs-
induced urticaria/angioedema by
positive drug provocation test
(DPT) with acetylsalicylic acid
during 2005-2012 (V1)
 Prospectively re-evaluated by
DPT with ASA/other NSAIDs
at two time points between 2013
and 2015 (V2 and V3).
63.15%
% patients
developing tolerance
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00

Natural evolution in patients with nonsteroidal
anti-inflammatory drug-induced urticaria/angioedema
I. Doña, Allergy 2017;72:1346–1355
 38 patients with NSAIDs-
induced urticaria/angioedema by
positive drug provocation test
(DPT) with acetylsalicylic acid
during 2005-2012 (V1)
 Prospectively re-evaluated by
DPT with ASA/other NSAIDs
at two time points between 2013
and 2015 (V2 and V3).
63.15%
% patients
developing tolerance
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
Patients may develop
tolerance to
NSAIDs over time

Anestetici,
in sala operatoria,
Radio contrast media
Disinfettanti (clorexidina)

% patients with
a (+) SPT
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00 –
Evaluation of periprocedural hypersensitivity reactions
Iammatteo M, Ann Allergy Asthma Immunol. 2017;119:349-355
 Periprocedural hypersensitivity
reactions (HSRs) defined as
occurring
• soon before,
• during, or
• soon after a medical procedure
or operation with or without
general anesthesia.
 A 7-year retrospective medical
record review of 34 patients.
64.7%

Skin Test Reagents
Abbreviations: ID, intradermal test; NMBA, neuromuscular blocking agent;
SPT, skin prick test

Agents with (+) skin test results to
administered periprocedural agents
All agents identified by skin
or latex IgE testing
NMBAs, neuromuscular blocking agent A total of 87 skin test or latex IgE assay results
were positive, including 16 equivocal test results,
in 31 of 34 patients (91.2%)
Anesthetic

Results of skin tests to administered
periprocedural agents
• Fentanyl was the most
commonly known administered
periprocedural agent in at
least 21 cases but was
identified as a causative
agent in only 1 patient.
• Ondansetron was the
causative agent in 50% of
the 6 cases it was given.
• Cefazolin was also considered
the culprit in 50% of the
16 cases it was known to be
administered.
• NMBAs, neuromuscular
blocking agents.
PeriproceduralAgent

 In conclusion, induction agents were the most common culprits in our
patient population.
 Given the variability in skin test concentrations used in different centers across
the United States with data published on small sample sizes, there is a need to
establish national guidelines and a referral network to standardize the evaluation
of periprocedural HSRs and increase the generalizability of results with pooling
of nationwide data.
 National guidelines for the stepwise approach to the management and evaluation
of perioperative anaphylaxis have been established in Great Britain and Ireland,
with consensus documents jointly published by the Association of Anaesthetists
of Great Britain and Ireland and the British Society for Allergy and Clinical
Immunology.

Progestogen Hypersensitivity:
Heterogeneous Manifestations with a Common Trigger
Buchheit KM, JACI Pract 2017; 5:566-574
• Hypersensitivity to progestogen, previously known as
autoimmune progesterone dermatitis, is an increasingly
recognized clinical entity that presents specific
diagnostic and treatment challenges.
• Clinical presentations are heterogeneous,
but can consist of hypersensitivity symptoms
associated with the progesterone surge
during the luteal phase of the menstrual
cycle or after exposure
to exogenous progestins.

• Hypersensitivity to progestogen, previously known as
autoimmune progesterone dermatitis, is an increasingly
recognized clinical entity that presents specific
diagnostic and treatment challenges.
• Clinical presentations are heterogeneous,
but can consist of hypersensitivity symptoms
associated with the progesterone surge
during the luteal phase of the menstrual
cycle or after exposure
to exogenous progestins.
• With the increasing use of exogenous
progesterone for contraception and
fertility, more cases of hypersensitivity to
exogenous progestins have been described.

• Autoimmune progesterone dermatitis (APD) has varied manifestations
ranging from immediate-type symptoms such as urticaria, asthma, or
anaphylaxis to delayed-type hypersensitivity symptoms presenting as
chronic dermatitis.
• The term APD does not accurately represent the heterogeneous clinical
manifestations of hypersensitivity to progesterone and there is little
evidence to support an autoimmune pathomechanism for this disease.
• Therefore, more recently the term progestogen hypersensitivity
(PH) was proposed as a more accurate term to describe
this syndrome. Foer D, J Allergy Clin Immunol Pract 2016;4:723-729

1) Progesterone Metabolism And Physiologic Roles
• Progesterone has a broad range of metabolic and physiologic effects
related to embryogenesis, the menstrual cycle, lactation, and pregnancy.
• Progesterone is an important metabolic intermediate in the production of
other endogenous steroids such as sex hormones and corticosteroids as
well as a neurosteroid important in brain function.
• Progesterone is important for causing changes to the endometrium during
the luteal phase to prepare the uterus for implantation.
• If pregnancy does not occur, progesterone levels decrease resulting in
menstruation.
• During implantation and gestation, progesterone decreases the maternal
immune response allowing for pregnancy.
• Fall in progesterone levels is believed to trigger lactation and labor.

The menstrual cycle
FSH: Follicle stimulating hormone
GnRH: gonadotropin-releasing hormone
LH: leutinizing hormone

2) Mast Cell Expression Of Estrogen And Progesterone Receptors
• Several investigators have demonstrated the presence of progesterone
receptors on human mast cells (MCs).
• Treatment of human MC lines in vitro with
physiological concentrations and progesterone
resulted in significantly increased release
of ß-tryptase.
progesterone
ß-tryptase

3) Potential pathomechanisms for PH
• Progesterone levels begin to rise 24 to 48 hours before
ovulation and tend to peak at day 20-21 of a 28-day cycle,
which prepares the uterus for implantation of the ovum.
• The majority of patients with hypersensitivity to endogenous
progesterone experience symptoms during the peak progesterone levels
of the luteal phase occurring the week before menstruation and dissipate
a few days into menses; however, reactions can persist throughout the
menstrual cycle.
• PH needs to be differentiated from catamenial anaphylaxis, which begins
during menses and can persist throughout the follicular phase.

• It is unclear how patients become sensitized to progestogens.
One theory is that sensitization occurs with exposure of exogenous
progesterone or synthetic progestins used for contraception or hormonal
supplementation, which results in formation of progestogen-specific
IgE antibodies.
• Many cases of PH are related to supratherapeutic doses of progesterone
used for fertility treatments.
• However, there are multiple reports of patients who have never been
exposed to exogenous progestogen who develop PH.

• An alternative proposed mechanism for sensitization is corticosteroid
cross-sensitization by corticosteroids that have a similar structure to
progesterone (hydrocortisone allergy)
• However, corticosteroid cross-sensitization does not explain PH in
patients without documented corticosteroid allergy, and many patients
with PH tolerate topical and oral corticosteroids as treatment for PH.
Schoenmakers A, Contact Derm 1992;26:159-62.
• Evidence that type I, immediate hypersensitivity plays a role in the
underlying pathogenesis of PH is supported by positive immediate skin
prick or intracutaneous testing to progesterone in many patients with
suspected PH.

• In patients with immediate-type symptom suggestive of PH but with
negative skin prick testing to progesterone, it has been proposed that
progesterone can modulate MC and/or basophil reactivity causing direct
hormone induced MC activation and release of bioactive mediators.
• Shelley et al. initially used the term autoimmune to describe PH because
their patient reacted to endogenous progesterone; however, as discussed
below, there is now ample evidence that this condition can occur with
endogenous and exogenous progestogens and is more likely an immediate-
type hypersensitivity reaction rather than an autoimmune response.
Shelley WB, JAMA 1964;190:35-8

EPIDEMIOLOGY
• PH is a rare disorder.
• It presents in women of childbearing age with symptoms first occurring
anytime from menarche to menopause.
• A large case series of 24 patients found the average age of onset to be
in the third decade of life, with a mean age of 27.3 yrs (range, 12-47 yrs).
• There does seem to be a relationship between exogenous progestogen
exposure and development of the disease.
Nguyen T, Autoimmun Rev 2016;15:191-197.

Clinical findings*
Dermatologic Eczematous dermatitis
Urticaria
Angioedema
Pruritus
Stomatitis
Erythema multiforme
Petechiae/purpura
Fixed drug eruption
Vesiculobullous/vesiculopustular
lesions
Asthma
Anaphylaxis
Non-dermatologic
*Multiple simultaneous clinical manifestations occur in many patients

The polymorphic cutaneous manifestations of progestogen hypersensitivity
Angioedema
urticaria
Pustules and
plaques
Mummular eczematous
dermatitis
Annular targetoid plaques
Maculopapular rash
Eczematous dermatitis

CLINICAL CHARACTERISTICS
• The timing of symptoms is most frequently associated with the
progesterone surge of the luteal phase of the menstrual cycle, typically
3 to 10 days before menses.
• Therefore, the cyclical nature of PH is a diagnostic clue for clinicians.
• However, symptoms triggered by exposure to exogenous progestins,
such as those used for contraception or fertility treatments, do not
necessarily correlate with the menstrual cycle and some women with
PH have irregular menses.
• Some patients experience symptoms of PH at other times of the
menstrual cycle.

CLINICAL CHARACTERISTICS
• Among patients with pregnancy associated symptoms, PH can begin
intrapartum, and may or may not continue after childbirth.
• PH can also start in the postpartum period, suggesting sensitization
to high levels of progesterone present during pregnancy.
• PH can also be triggered by progestins in oral contraceptive pills (OCPs),
progestin-containing vaginal rings, and progestin-containing intrauterine
devices.
• Notably, high-dose progesterone required for in vitro fertilization (IVF)
can induce PH.

DIAGNOSIS
• The diagnosis of PH is primarily based on a clinical history of
hypersensitivity symptoms correlating with the luteal phase of the
menstrual cycle, or symptoms correlating with exposure to exogenous
progestogens.
• A careful clinical history is required to evaluate other potential triggers,
such as nonsteroidal antiinflammatory drugs (NSAIDs) that are commonly
used in the premenstrual period.
• Progesterone skin prick and intracutaneous testing has been employed
as a diagnostic test.

DIAGNOSIS
• Autologous serum skin tests, with sera obtained during the follicular and
luteal phases of the menstrual cycle, have also been proposed as a useful
tool for diagnosis of PH. Garcia-Ortega P, Obstet Gynecol 2011;117(Pt 2):495-8
• The skin prick test with full concentration pharmaceutical grade
progesterone (50 mg/mL) has been recommended followed by
intracutaneous tests with dilutions starting at a 1:1000 w/v
concentration and increasing to a 1:10 w/v concentration in conjunction
with appropriate negative saline and positive histamine controls.
Hill JL, J Allergy Clin Immunol Pract 2013;1:537-8
• As progesterone is not water soluble, it has to be suspended in an ethanol
or oil diluent. This can frequently lead to a false-positive reaction given
the irritating nature of the ethanol.

DIAGNOSIS
• Given the irritant reactions, the ethanol or oil diluent without
progesterone should be used as a control.
• Although positive skin testing can confirm a diagnosis in a patient with a
compatible clinical history, negative skin testing does not rule out PH.
• Progesterone challenge has been used in the diagnosis of PH.
Wojnarowska F, J R Soc Med 1985;78:407-8.
• The most practical and reliable assay for identifying an IgE-mediated
immune response is by ELISA.

Treatment category Drug class Potential problems
Symptomatic relief Oral antihistamines Incomplete efficacy
Topical glucocorticoids Incomplete efficacy
Systemic glucocorticoids Incomplete efficacy, long-term side effects
Ovulation suppression Combined oral contraceptive pills Possible hypersensitivity reaction to low-dose progesterone
GnRH agonists (ie, leuprolide) Estrogen withdrawal symptoms
Selective estrogen-receptor Estrogen withdrawal symptoms
modulators (ie, tamoxifen)
17-a-Alkylated steroids Hirsutism, mood changes, LFT abnormalitie
(ie, stanozolol, danazol)
Oophorectomy Premature menopause, permanent loss of fertility
Desensitization Rapid desensitization to oral, IM, or Resource intensive, risk of hypersensitivity reactions
intravaginal progestogens during desensitization
Slow desensitization to oral progestins Risk of hypersensitivity reactions during desensitization
GnRH, Gonadotropin-releasing hormone; IM, intramuscular; LFT, liver function test

Slow oral protocol
Oral and intramuscular progestin desensitization protocols
Rapid IM protocol. IM, Intramuscular; IVF, in vitro fertilizationTwo-day oral protocol

Algorithmic approach for
evaluation and treatment of
progestogen hypersensitivity

TREATMENT
• Oophorectomy has been employed as a definitive
treatment for patients with severe PH that cannot
otherwise be managed medically.
• Certainly this approach would be a last resort for the most severe
refractory cases and preferably not in women who still wish to conceive.

OTHER REPRODUCTIVE HORMONE HYPERSENSITIVITY SYNDROMES
A) Estrogen hypersensitivity
• This syndrome characteristically presents as
a premenstrual flare of urticaria or a delayed-type dermatitis.
• It is confirmed by a positive immediate or delayed intracutaneous
estrogen test or an estrogen challenge.
• In patients with symptoms related to exogenous estrogen exposure,
withdrawal of oral estrogen therapy is advised and has been effective.
• A dendritic cell-mediated allergic mechanism has been postulated.

B) Catamenial anaphylaxis
• In catamenial anaphylaxis, symptoms correlate with the onset of the
menstrual cycle, not the period of peak progesterone concentrations.
• Catamenial anaphylaxis occurs when progesterone and
estrogen levels decline significantly at the onset of menses.
• Catamenial symptoms are triggered by endometrial release
of prostaglandins (PGs), which are highest on day 1 of the menstrual cycle.
• Burstein et al report a patient with recurrent anaphylaxis occurring in the
first 24 hours after onset of menses, who had improvement of symptoms
after treatment with indomethacin, which inhibits PGs.
Burstein M, Ann Allergy 1991;66:36-8.

C) Lactation-associated anaphylaxis
• In most cases, the onset of symptoms occurs in the first few days after
delivery and is associated with the act of breastfeeding or manual
expression of breast milk.
• The anaphylactic events have been associated with elevated serum
tryptase.
• Symptoms can occur with subsequent pregnancies.
• It has been proposed that the rapid decrease in progesterone leads to an
exaggerated histamine response.

C) Lactation-associated anaphylaxis
• Hypersensitivity to hormones associated with lactation such as prolactin
and oxytocin has also been explored, but no positive skin testing to these
hormones has been elicited in patients.
• It is also possible that the use of NSAIDs in the postpartum period may
be responsible for the anaphylactic.
• In some patients, the symptoms resolve after several days of
breastfeeding.
• When symptoms do not resolve, treatment with suppression of lactation is
employed.

Approach to hypersensitivity reactions
from intravenous iron preparations
CA Morales Mateluna, Allergy 2017;72:827-830
• Oral iron is the treatment of choice for iron deficiency anemia.
• However, this form of therapy might not be adequate for some patients
for a variety of reasons (intolerance, malabsorption, compliance, etc.).
• Parenteral iron was introduced in the 1930s.
• Due to frequent toxic reactions, intravenous iron compounds encased
in carbohydrate shells were developed, eventually leading to the
introduction of an iron preparation encased in a dextran shell in the
1950s.

Approach to hypersensitivity reactions from
intravenous iron preparations
• Compared with earlier preparations, dextran iron caused fewer adverse
reactions, but a meta-analysis published in 2002 estimated the incidence
of life-threatening HSRs at 0.61%.
• These reactions have been demonstrated to be caused by preexisting
IgG and IgM antibodies to dextran in some patients.
• The introduction of nondextran iron preparations (NDIPs) has led to a
further decrease in HSRs, now considered rare events.
• Despite the very low rate of HSRs to NDIPs, these drugs are considered
dangerous and re-administration after HSRs is strongly discouraged.
• Rare fatalities associated with NDIPs have been anecdotically reported.

31 patients with
mild to severe
reactions
to intravenous iron
preparations.
SPTs and basophil activation tests
(BATs) were negative
in all patients tested

31 patients with
mild to severe
reactions
to intravenous iron
preparations.
 controlled re-administration (CRA)
were performed in 15 patients:
• 12 patients tolerated the
procedure, including 3 with
a previous grade IV HSR.
• 2 patients developed urticaria
• 1 developed urticaria and dyspnea.

31 patients with
mild to severe
reactions
to intravenous iron
preparations.
The
pathophysiology
of HSRs to
IVIPs remains
currently unclear.
SPTs and BATs
provided no
additional
information.

31 patients with
mild to severe
reactions
to intravenous iron
preparations.
However,
in appropriate
situations,
CRA under
surveillance
can be safely
performed in
most patients.

Desensitization
treatment
Reaction prevention

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