Late systemic-allergic reactions to inhabwt

albrgen immunotherapy
Mark A. Greenberg, MD, MAJ, MC,+ Clark R. Kaufman, MD, MAJ, MC,**
Gabriel E. Gonzalez, MD, MAJ, MC,*
Zorian P. Trusewych, DO, MAJ, MC,***
Cheryl D. Rosenblatt, MD, CDR, MC,**** and
Richard J. Summers, MD, COL, MC***
Fort Bragg, N.C., Fort Benning, Ga., Washington, D.C., and Bethesda, Md.

Late systemic-allergic reactions (dejined as occurring between 30 minutes and 6 hours ajter
injection) to inhalant allergen immunotherapy were prospectively studied in four allergy treatment
centers; 35,674 injections were administered to 712 patients. Twenty-nine patients (4% of ail
patients) experienced 33 late reactions. Fifty-six injections (0.16% of all injections) were
associated with the 33 late reactions. The most common clinical manifestation of a late reurtion
was urticaria. However, objective respiratory airway involvement, as manifested by wheezing
andlor stridor, occurred in IO (27%) of the late reactions. Delayed reactions involving wheezing
andlor stridor were only related to injections from maintenance vials, and all these more
severe reactions occurred no later than 60 minutes after injection. We conclude that late
systemic-allergic reactions account for a signijicant percent of the total nlsmber of
systemic-allergic reactions to inhalant allergen immunotherapy. It is our belief that a
60-minute postinjection waiting period for injections administered from maintenance vials of
extract would enhance the safety of inhalant allergen immunotherapy. (.I ALLERGY CLIN IMML!NOL
1988;82:287-90.)

Systemic-allergic reactions to injections of aller-
gen extract are a well-documented complication of
immunotherapy.‘-’ * An important attribute of the
systemic-allergic reaction that has been inadequately
studiedis time of onset after extract injection. In 1922,
Cooke5noted that “constitutional reactions” could oc-
cur hours after an injection of extract. Figley,6in 1930,
reported that urticaria, nasal symptoms, and/or chest
tightness could occur several hours after extract in-
jection. Levine’ reported in 1979 that nearly 50% of
From the *Allergy and Immunization Clinic, WomackArmy Com-
munity Hospital, Fort Bragg, N.C., **Allergy and Immuniza-
tion Clinic, Martin Army Hospital, Fort Benning, Ga., ***Al-
IergyiImmunology Service, Walter Reed Army Medical Center,
Washington,DC, and ****Allergy/Immunology Service, Na-
tional Naval Medical Center, Bethesda, Md.
Received for publication June 15, 1987.
Accepted for publication Feb. 16, 1988.
Correspondence:Mark A. Greenberg, MD, 3460 Sugar Cane Cir-
cle, Fayetteville, NC 28303.
No reprints available.
The opinions or assertionscontained herein are the private views
of the authors and are not to be construed as official or as re-
flecting the views of the Department of the Army or the De-
partment of Defense.
the systemic reactions in his personal experience oc-
curred later than 30 minutes after injection.
We recently reported that late systemic reactions,
occurring from 35 minutes to 6 hours after injection,
accountedfor 38% of all reactions to allergen injec-
tions.g In this study, the most comma clinical
manifestations of the late reaction were generalized
pruritus and u&aria. However, five of the 20 late
reactions involved the upper and/or lower airways,
asmanifestedby wheezing and/or strider. Thesemore
severelate reactionsoccurred at both maintenanceand
increasing doses.
In an attempt to better characterize late systemic-
allergic reactions, we extended our study for an ad-
ditional year. The clinical characteristics of 33 late
reactions are now reported.
METHODS
Complications of allergen imsmtnotherapy, excluding
venoms, were recorded in all patients receiving immuno-
therapy from July 1984 through June 1986 at the following
hospitals: Walter Reed Army Medical Center, W&sh&@m,
D.C.; National Naval Medical Center, B&e&, Md.;
Martin Army Community Hospital, F&t Beming, Ga.; and
Womack Army Community Hospital, Fort Rragg , N C. Ex-
287
 J. ALLERGY CLIN. IMMUNOL.
288 Greenberg et al.
AUGUST 1988

TABLE I. Manifestations of late curred: 48 (59%) immediate reactions and 33 (41%)

systemic reactions late reactions. Twenty-nine pstients (4%), 10 male
No. (%I
and 19 female patients, experienced the 33 late re-
actions. Four patients accounted for eight reactions
Objective reactions (n = 24) (two reactions per patient).
Urticaria 12 cm Of the 33 late reactions, nine were classified as
Angioedema 2 (8) subjective and 24 were classified as objective (Table
Urticaria and wheezing 4 (17) I). Urticaria was the most common objective mani-
Wheezing 4 (17) festation of a late reaction. However, 10 (4.2%)of the
Laryngoedema(stridor) and 1 (4) objective late reactions involved the upper and/or
wheezing
1
lower respiratory airways, as manifestedby wheezing
Laryngoedema(stridor) (4)
and/or stridor (laryngoedema). All these more severe
Subjective reactions (n = 9)
Pruritus (generalized) 2 (22) reactions were treated in an emergency room or phy-
Pruritus and chest tightness 2 (221 sician’s office with epinephrine injections and anti-
Chest tightness 1 (11) histamines.
Chest and throat tightness 4 (44 Fifty-six injections (representing 0.16% of all in-
jections) were associated with the 33 late systemic
reactions (Table II). (It should be noted that patients
could receive one to three injections per clinic visit.)
tract formulae were preparedat the US Army Allergen EX- Thirty-six (64%) injections were administered from
tract Laboratory at Walter Reed Army Medical Center. vials containing the highest concentration of antigen
Methods of extract preparation, treatment schedules, and (“maintenance vials”), and 20 (36%) injections were
details regarding injection administration have been de- drawn from more dilute vials. Sixteen injections were
scribed elsewhere.’ Patients reported as experiencing late
associatedwith the 10 objective reactions involving
systemic reactions in our initial article have been included
in the present study.’ the respiratory airways, and all these injections were
Systemic-allergic reactions were defined as the occur- drawn from maintenancevials.
rence of subjectivecomplaints or objective findings within Of the 33 late systemic reactions, 22 (27%) oc-
6 hours after injection. Subjective reactions were defined curred between 30 and 60 minutes after injection,
as the occurrence of generalized pruritus, shortness of seven(9%) occurred between 1 and 2 hours after in-
breath, and throat or chesttightness.Objectivereactions jection, and four (5%) occurred after 2 hours and up
were defined as the occurrence of urticaria (local or gen- to 6 hours after injection (Table III). All 10 of the
eralized), angioedema(local or generalized), laryngoedema objective late reactions involving wheezing and/or
(manifestedby strider), wheezing,and/or hypotensionas- stridor began between 30 and 60 minutes after
sociatedwith tachycardia.Immediatereactionsweredefined injection.
asthoseoccurringup to 30 minutesafterinjection,andlate
reactions were defined as those occurring after 30 minutes
No late reactions were associated with injection
and up to 6 hoursafter injection. (It shouldbe notedthat errors or injections from new vials.
none of the late reactions from our initial study beganearlier
DISCUSSION
than 35 minutes after extract injections9 As a result, late
reactions in our initial study were reported as beginning Late systemic reactions account for a significant
from 35 minutesto 6 hoursafterinjection.)The following percent of the total number of systemic reactions to
dataon eachlate systemic-allergicreactionwererecorded: inhalant allergen immunotherapy. Levine* reported in
date, gender of patient, concentration of injected extract, 1979 that nearly 50% of the systemic reactions in his
useof a new or old vial, time interval betweeninjection personal experience occurred later than 30 minutes
andonsetof reaction,andthe typeof reaction(objectiveor after injection. Our findings that late reactions account
subjective and clinical characteristics). Reactionsoccurring
for approximately 40% of all reactions comparesfa-
after 30 minutes were categorizedby the patients’ descrip-
tions of signs and symptomsif a physician’s report of emer- vorably to Levine’s experience. No late reactions in-
gencytherapywas not available.Any errors, suchas in- volving hypotension were reported by Levine, and no
jection of an incorrectconcentrationof extract,werealso such reactions occurred in our study. It should be
noted. emphasized, however, that immunotherapy is elective
therapy administeredto alleviate what are, for the most
RESULTS part, nonfatal diseases. Although it is a rare event,
During the time period from July 1984 through June mortality from anaphylaxis to allergen-extract injec-
1986, 35,674 injections were administered to 712 pa- tions is well documented. Lackey et al.‘O recently
tients. Eighty-one systemic-allergic reactions oc- reported the results of questionnairessentby the Com-
VOLUME 82
Late systemic-ailergir ! ~acttons 289
WMBER 2

TABLE II. Concentration of injections related to iate systemic reactions

--..W_”
-.-_--_11__-
Objective reactians
involving the
Total reactions (%f respiratory airwiys* (%1

wtl vol n = 28 II -- :
1: 1,000,000 It (4)
1: 100,000 3 (II)
1: 10,ooo 2 (7)
l:l,OOO 6 (21)
1: 100 16 (57)

PNUiml n = 28
l-2 1$ (4)
10-20 2 (7)
1o-200 1 (4)
1,cOo-2,000 4 (14)
1o,ooo-20,ooo 20 (71) 10 ! loo)
_-..-___-___
*Evidenced by wheezing and/or strider on physical examination.
iSubjective reaction (chest tightness and generalized pruritus).
SLocalized hives at the injection site.

mittee on Allergen Standardizationto all membersof TABLE IN. Time of onset of late
the American Academy of Allergy and Immunoiogy systemic reactions
regarding fatalities that had occurred during immu-
notherapy or skin testing since 1945. Three of the 25
oeyctive
rea0tkms
fatalities for which time of onset of reaction after invoiving
injection was reported began after 30 minutes. In the the
United Kingdom, the Committee on Safety of Med- Subjwive Objathm r~8tary
icine reported that two of 20 fatalities related to reacths riMCtiOn6 siwwsf
allergen-extract injection began between 30 and 90 >30 min-60 4 18 10
minutes after injection. ‘I Therefore, careful identifi- min
cation of risk factors and a better understandingof the HO min-2 3 4
characteristics of late systemic-allergic reactions are hr
necessaryto develop precautionary measuresto en- 1>2 hr-6 hr 2 2
----
hance the safety of allergen immunotherapy.
Evidenced by wheezing and/or stridor on physicat examination.
In our series of 33 late reactions, urticaria was the
most common clinical manifestation. However, ob-
jective respiratory airway involvement, as manifested
by stridor or wheezing, occurred in 27% of all late tions provides evidencethat low concentrationsof an-
reactions. Although late reactions were related to in- tigen are usually not adequateto trigger a late systemic
jections from dilute and maintenancevials, the more reaction and that a threshold concentration of injected
severereactions involving stridor and wheezing were extract is neededto elicit a late reaction. In our study
only related to injections from vials containing population, a relatively large dose of injected extract
the highest concentration of antigen (“maintenance was required to produce a significant late reaction
vials”). None of the late reactions involving stridor involving the respiratory airways. It should be noted.
and wheezing began later than 60 minutes after in- however, that Lackey et al.” reported one late fatality
jection. Four patients experienced two late reactions, that appearedto be related to an injection from a vial
each suggestingthat a subgroup of patients are at risk of dilute antigen (1: 10,000 wt/vol).
for recurrent late systemic reactions. Finally, there No late reactionsinvolving stridor and/ or wheezing
were no confirmed errors of administration related to beganlater than 60 minutesafter injection in our study
the late reactions. population. However, as noted above, the Committee
The finding that all late reactions involving stridor on Safety of Medicines in the United Kingdom re-
and wheezing were related to maintenancevial injec- ported two fatalities that began between 30 and 90

290 Greenberg et al.
minutes after injection.” The implication from the
study is that at least one reaction began later than 1
hour after injection, although this is not clearly stated
in tbe article. It should be noted, however, that no
details regarding symptoms, signs, or treatment are
provided in this article.
Allergen immunotherapy is a safe form of therapy.
However, immunotherapy doescarry a very small but
definite risk of life-threatening late reactions and is
electively administered to alleviate what is generally
nonfatal disease. In a recent editorial, Dr. Norman’*
advocated the establishment of a working group to
draft recommendationsregarding “. . . measuresthat
demonstrate promise of reducing risk to the point
where deathsshould not occur and yet allow the many
people who can benefit by desensitizing injections to
receive a well-established method of treatment . . . .”
We feel that one measureworthy of consideration is
a lengthening of the traditional postinjection waiting
periods of 20 or 30 minutes. The British Committee
on Safety of Medicine recommendsa 2-hour postin-
jection wait. ” This would appear to be excessive
basedon the available data. To the best of our knowl-
edge, only one or two fatalities have been reported to
occur later than 1 hour after injection. (As noted
above, the exact number of fatalities occurring after
1 hour cannot be determined from the British article.)
In addition, all the more severereactions in our study
population began less than 60 minutes after injection
and were only related to injections drawn from main-
tenancevials. We believe, therefore, that it would be
reasonable to require a l-hour wait after injections
drawn from maintenancevials. In addition, it would
be prudent to ensurethat patients are informed of the
potential for late systemic reactions and understand
the importance of immediately seeking emergency
treatment at the earliest signs of such a reaction.
Large-doseallergen immunotherapy carries an un-
J. ALLERGYCLIN.IMMUNOL.
AUGUST1988
avoidable risk of late systemic-allergic reactions. Al-
though the guidelines we have outlined do not abso-
lutely ensure that all severe late systemic reactions
would occur in a physician’s office, we do believe
that they would enhance the safety of allergen
immunotherapy without making such therapy im-
practical.
We are indebtedto RichardEvansRI, MD, MPH, for
reviewing the manuscript, andto Mrs. CarolynWeaverfor
her excellent assistancein preparing the manuscript.
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