Immunotherapy Safety for the Primary Care ... - U.S. Coast Guard

S54 Cox et al
J ALLERGY CLIN IMMUNOL
SEPTEMBER 2007
mixtures of allergens that can be used alone as a concentrated
dose of single allergen or combined with other
concentrated allergens to prepare an individual patient’s
customized allergen mixture. This is designated as the
patient’s maintenance concentrate.
Nonstandardized manufacturer’s extracts usually are
available at concentrations of between 1:10 and 1:50 wt/
vol or 20,000 and 100,000 PNU. Standardized extracts are
available with biologic potencies of 10,000 and 100,000
BAU for grasses; 5000 and 10,000 BAU for cat allergen;
5000, 10,000, or 30,000 AU for dust mite; and 100,000
AU or 1:10 and 1:20 wt/vol for short ragweed, with the
Amb a 1 concentration listed in FDA units on the label of
the wt/vol extracts (Table IX). The main factor that limits
how concentrated an allergen immunotherapy extract can
be is the tendency of highly concentrated antigen solutions
to develop precipitates. This is an unpredictable and
poorly understood phenomenon. Although there is no evidence
that such precipitates adversely affect the extract,
the FDA does not permit a manufacturer to ship an extract
that has a precipitate.
Summary Statement 36: The highest-concentration allergy
immunotherapy vial (eg, 1:1 vol/vol vial) that is used
for the projected effective dose is called the maintenance
concentrate vial. The maintenance dose is the dose that
provides therapeutic efficacy without significant adverse
local or systemic reactions and might not always reach the
initially calculated projected effective dose. This reinforces
that allergy immunotherapy must be individualized. D
The highest concentration of an allergen extract mixture
that is projected to be used as the therapeutically effective
dose is called the maintenance concentrate. This should be
prescribed individually for each patient by an allergist/
immunologist. The maintenance concentrate (if a mixture
of extracts) should either be obtained from the manufacturer
as a customized mixture or should be prepared by
the physician under sterile conditions by adding an
appropriate volume of individual manufacturer’s extracts.
Some patients might be unable to attain the projected
therapeutically effective dose of the maintenance concentrate
because of local reactions, systemic reactions, or both
(eg, cat, 1000 BAU [highest tolerated dose] vs 2000 BAU
[projected effective dose]; see Table X for probable effective
therapeutic dose range). Such patients might need
weaker dilutions of their maintenance concentrate. Even
so, the original projected maintenance concentration of
the allergen immunotherapy extract is still referred to as
the maintenance concentrate, and the specific patient’s
therapeutic dose is referred to as the maintenance dose.
The consistent use of this nomenclature system is essential
because errors in choosing the correct vial are a common
cause of systemic reactions, especially when the patient
transfers from one physician to another. Therefore it is
important that standard terminology be adopted by all
physicians who prescribe allergen immunotherapy.
Recommended doses
Summary Statement 37: The maintenance concentrate
should be formulated to deliver a dose considered to be
therapeutically effective for each of its constituent components.
The projected effective dose is referred to as the
maintenance goal. Some individuals unable to tolerate the
projected effective dose will experience clinical benefits at
a lower dose. The effective therapeutic dose is referred to
as the maintenance dose. A
The effective maintenance dose of immunotherapy for a
particular patient must be individualized. To do this, the
allergist/immunologist who prepares the allergen immunotherapy
extract must balance the dose necessary to
produce efficacy and the risk of reactions if such a dose is
reached. The allergist/immunologist might need to prepare
more than one maintenance concentrate to provide
a therapeutic dose of each of the allergens for the
polysensitized patient. Therapeutically effective doses
for immunotherapy have been reported for some allergen
extracts. 22,24,25,128,134,135,149,246,260,261 Effective doses
have been determined for Hymenoptera venom, dust
mite, cat allergen, dog, grass, and short ragweed (Table X).
Controlled studies demonstrate that the content of
particular allergens in allergen immunotherapy extracts
can be used to predict a therapeutic dose for those
allergens, particularly when the extracts are standardized.
For antigens that have not been standardized, the effective
dose must be estimated and individualized. It is important
to keep a separate record of the contents of each extract,
including final dilutions of each of the constituents. The
therapeutically effective doses used in the most recent
controlled clinical studies are the basis of the recommended
dosage range of standardized extracts presented in
Table X. Although early improvement in symptoms has
been documented with these doses, long-term benefit appears
to be related not only to the individual maintenance
dose but also the duration of time that it is administered. 14
Because a full dose-response curve has not been
determined for most allergens, it is possible (and supported
by expert opinion) that therapeutic response can
occur with doses lower than those that have been shown to
be effective in controlled studies. In general, however, low
doses are less likely to be effective, and very low doses
usually are ineffective. 27 Although administration of a
higher maintenance dose of immunotherapy increases
the likelihood of clinical effectiveness, it also increases
the risk of systemic reactions. In particular, highly sensitive
patients might be at risk of systemic reactions to immunotherapy
injections with higher maintenance doses.
The maintenance concentrate should be formulated to
deliver a full therapeutic dose of each of its constituent
components. However, some sensitive patients might
not tolerate the targeted therapeutic dose, and their maintenance
dose would be lower. Individuals who have
systemic reactions with doses that are less than the projected
effective dose should be maintained on the highest
tolerated dose, providing this dose is effective. The highest
tolerated effective therapeutic dose is referred to as the
maintenance dose.
Regardless of dose schedule, some patients are unable
to progress to the predetermined maintenance dose because
of large local or systemic reactions to the allergen