Immunoglobulin Therapy & Other Medical Therapies for

Antibody Defciencies
There are several specific medical therapies available for patients with primary
immunodeficiency diseases involving the humoral immune system. These illnesses include X-
Linked Agammaglobulinemia (XLA) and ommon !ariable "mmune #eficiency (!"#)$ among
others$ and are characteri%ed by a lack of and&or impaired antibody function. 'ffective therapies
for these disorders are a reality for most patients$ and optimi%e their health$ improve their
(uality of life and allow them to become productive members of society. "n this chapter$ therapy
for antibody disorders will be discussed. )or all of these therapies$ individual risk&benefit ratios
should be discussed with your healthcare provider.
Immunoglobulin Therapy
The term immunoglobulin refers to the fraction of blood plasma that contains
immunoglobulins, or antibodies These immunoglobulins !Ig" in the serum or plasma are Ig#,
IgM, IgA, IgD and Ig$ Indi%iduals &ho are unable to produce ade'uate amounts of Ig or
antibodies, such as patients &ith ()A, *+ID, ,yper-IgM .yndromes, /is0ott Aldrich .yndrome or
other forms of hypogammaglobulinemia, may beneft from replacement therapy &ith Ig Only
the Ig# is purifed from the plasma to produce commercial Ig products, so Ig used for treatment
contains %ery little of any of the other Ig types
As e1plained in other chapters of this handboo0, 2-lymphocytes mature into plasma cells, &hich
manufacture antibodies and release them into the bloodstream (See chapter titled The
Immune System and Primary Immunodefciency Disease.) There are literally millions of di3erent
antibodies in e%ery normal person, but because there are so many di3erent germs, no one
person has made antibodies to e%ery germ The best &ay to ensure that the Ig &ill contain a
&ide %ariety of antibodies is to combine or pool the plasma from many indi%iduals
Ig &as frst used to pre%ent infectious diseases in /orld /ar II and frst gi%en for primary
immunodefciency diseases in 4567 8ntil the early 459:;s, the only form that &as a%ailable &as
usually gi%en by deep in<ection into muscle !intramuscular or IM", although it &as also gi%en by
subcutaneous infusion rarely in the 8. but more commonly in other parts of the &orld !for
e1ample, .candina%ia" Ig products for intramuscular in<ection continue to be used to gi%e
normal indi%iduals a boost of antibodies after e1posure to some specifc diseases such as
measles or hepatitis, or before they tra%el to areas &here those diseases are pre%alent In these
instances, the amount of Ig needed to pre%ent diseases is small, generally 6-4: cc !4-7
teaspoons"
/hat is Ig =eplacement Therapy>
Ig is prepared from the plasma collected from a large number of normal indi%iduals, usually
bet&een 4:,:::-6:,:::, &ho ha%e been carefully screened to ma0e sure they are healthy and
do not harbor certain infectious diseases The plasma contains a broad range of specifc
antibodies to many di3erent types of bacteria and %iruses $ach plasma donor must be
acceptable as a blood donor according to the strict rules enforced by the American Association
of 2lood 2an0s and the 8. ?ood and Drug Administration !?DA" Donors are screened for tra%el
or beha%ior that might increase the ris0 of ac'uiring an infectious disease Only the Ig# is
purifed from the pooled plasma To commercially prepare the Ig for patients &ith primary
immunodefciency diseases, the immunoglobulin must frst be purifed !e1tracted" from the
plasma All Ig licensed in the 8. is made from plasma collected in the 8.
The blood, or plasma, from each donor is carefully tested for e%idence of transmissible diseases,
such as AID. or hepatitis, and any plasma sample that is e%en suspected of ha%ing one of those
%iruses is discarded The frst step in Ig production is to remo%e all the red and &hite blood cells
This is fre'uently done right as it comes out of the donor;s arm by a process called
plasmapheresis, &hich collects the plasma and then returns the red and &hite cells directly bac0
to the donor @lasmapheresis is done at centers specifcally designated for this purpose Then,
the immunoglobulins are chemically purifed from the plasma in a series of steps This process
results in the purifcation of antibodies of the Ig# classA only trace amounts of IgA and IgM, and
other plasma proteins remain in the fnal product
In the early 459:;s, ne& manufacturing processes &ere de%eloped to ma0e Ig preparations that
could be safely in<ected intra%enously, that is directly into the %ein Bo& multiple Ig preparations
are licensed in the 8. for intra%enous use @roducts de%eloped for intra%enous use ha%e also
been used successfully subcutaneously, &hich is administered under the s0in, and in recent
years products for subcutaneous use ha%e been licensed ?or the most part, the products are
e'ui%alent in antibody acti%ity ,o&e%er, there are some di3erences, &hich may ma0e one
particular preparation more suitable than another for a gi%en indi%idual Most products contain
some type of sugar or amino acid that help preser%e the Ig# molecules and pre%ent them from
stic0ing together to form aggregates If aggregates &ere present, they could cause se%ere side
e3ects Although these sugar and protein additi%es are harmless for most people, some of them
may cause problems for specifc indi%iduals Cour prescriber is your best source of information
about &hich product is best for you
@urifed Ig has been used for nearly 6: years and has an e1cellent safety record During the
purifcation process and &ith the fnal product, there are se%eral steps that destroy or remo%e
many types of %iruses, including ,I+, to ensure that the fnal Ig product cannot transmit any
0no&n infectious diseases to the patient Thus, the fnal Ig product contains highly purifed
plasma Ig# that has a broad range of specifc antibodies to many types of bacteria and %iruses
It is also e3ecti%e in helping the &hite cells in the body 0ill bacteria, %iruses and other germs
that may be in the tissues or blood of the patient being treated, and is safe to administer
Administration of Ig =eplacement Therapy
It is important to understand that the Ig that is gi%en partly replaces &hat the body should be
ma0ing, but it does not stimulate the patient;s o&n immune system to ma0e more Ig In
addition, the Ig only pro%ides temporary protection Most antibodies, &hether produced by the
patient;s o&n immune system or gi%en in the form of Ig replacement, are used up or
metaboliDed by the body and must be constantly replenished
Appro1imately half of the infused antibodies are metaboliDed o%er three to four &ee0s, so repeat
doses of Ig are re'uired at regular inter%als Depending on the route of administration, this may
be done by gi%ing small infusions under the s0in !subcutaneous immunoglobulin or .*I#" &ee0ly
or as often as e%ery one to three days, or by gi%ing larger intra%enous immunoglobulin !I+I#"
infusions once e%ery three or four &ee0s .ince Ig only replaces the missing end product, but
does not correct the patient;s defect in antibody production, Ig replacement is usually necessary
for the patient;s lifetime
I+I# infusions are usually gi%en once e%ery three or four &ee0s This results in a %ery high
pea0 Ig# le%el in the blood right after the dose is gi%en and a lo&er Ig# le%el in the blood at
the trough <ust before the ne1t dose is due
Another route for gi%ing immunoglobulin is to in<ect it relati%ely slo&ly, directly under the s0in,
&hich is .*I# 2ecause small amounts of Ig are gi%en fre'uently and the Ig is absorbed slo&ly,
the pea0 and trough associated &ith I+I# are eliminated &hen gi%ing .*I# @atients &ho ha%e
side e3ects from high pea0s of Ig# or feel &ashed out or &ea0 before their ne1t I+I# dose is
due may prefer .*I#
.*I# therapy may be an alternati%e for those patients &ho ha%e diEculty getting %enous access
andFor &ho ha%e systemic ad%erse reactions to I+I# *ollaborating &ith their healthcare
pro%ider, patients ha%e the Ge1ibility to de%elop a dosing regime that is tailored to their lifestyle
The number of infusions per &ee0, &hen the infusions are done, the number of needles used,
using an infusion pump or manually pushing the drug, and the rate of infusion are all %ariables
that can be considered to design an indi%idual patient;s .*I# regimen @atients must be
committed to this therapy and should not s0ip doses or change their regimen &ithout
consulting their pro%ider
.ide $3ects from Ig =eplacement Therapy
Most patients tolerate I+I# %ery &ell Infusions can be administered either in an outpatient clinic
or, after tolerability and safety is demonstrated in a controlled setting, in the patient;s o&n
home A typical I+I# infusion &ill ta0e t&o to four hours from start to fnish .ome patients may
tolerate more rapid infusion &hile others may re'uire longer times 8se of intra%enous products
allo&s physicians to gi%e larger doses of Ig at one time than could be gi%en subcutaneously In
fact, doses can be gi%en that are large enough to 0eep the Ig# le%els in the patient;s serum in
the protecti%e range, e%en <ust before the ne1t infusion &hen the le%el &ould be lo&est
There is a potential for some side e3ects associated &ith I+I# These can include lo&-grade
fe%er, aching muscles or <oints or post-infusion headaches occur These symptoms can usually
be alle%iated or eliminated by infusing the immunoglobulin at a slo&er rate andFor by gi%ing
acetaminophen, non-steroidal anti-inGammatory drugs li0e ibuprofen, or e%en small amounts of
short-acting systemic steroids .ometimes saline infusions may be gi%en before I+I#, andFor
infusions may be run more slo&ly to help minimiDe side e3ects )ess often, patients e1perience
hi%es, chest tightness or &heeDing These symptoms usually respond to antihistamines such as
diphenhydramine !2enadrylH" andFor asthma medications li0e albuterol
,eadaches associated &ith I+I# are not uncommon and may occasionally be se%ere, especially
in patients &ith a history of migraine headaches These headaches may occur during the
infusion or as long as three days later .ome patients &ith se%ere and persistent headaches ha%e
been found to ha%e an increase in the number of &hite blood cells in the cerebral-spinal Guid
This condition is 0no&n as aseptic meningitis The cause of this apparent inGammation is not
0no&n, but it is not an infection and patients ha%e not had permanent in<ury It is important to
note that e%ery patient &ho de%elops a post-infusion headache does not necessarily ha%e
aseptic meningitis Cou should notify your prescriber if you e1perience headaches that do not
respond to standard medications such as acetaminophen or non-steroidal anti-inGammatory
drugs li0e ibuprofen
It may ta0e se%eral infusions to de%elop a tolerable specifc I+I# regimen for each patient
+ariables include the product used, the rate of infusion, and the need for any pre-medications
Once a regimen that is &ell tolerated has been found, it should be follo&ed &ith $+$=C infusion
/hile all Ig products pro%ide necessary antibody replacement, each has subtle di3erences and
thus are BOT interchangeable .&itching from one brand to another is one of most common
causes for side e3ects @atients need to 0no& &hat their product is, the dose, and their specifc
infusion protocol The ID? e,ealth=ecord is a good place to 0eep this information
!&&&idfehealthrecordcom"
@atients &ho e1perience signifcant side e3ects from I+I# infusions may beneft from changing to
.*I# 2ecause the doses gi%en at any one time are small, and the Ig is slo&ly absorbed, there
are fe&er systemic side e3ects associated &ith .*I# .ide e3ects associated &ith .*I#, tend to
be localiDed s0in reactions, &hich tend to decrease o%er time *hanges to the indi%idual infusion
regimen, including the number of sites used, the length of the subcutaneous needle!s" used, the
amount of drug gi%en into each site and the rate of infusion are all things that can be modifed to
decrease the incidence of localiDed reactions to .*I#
Iualifying for Ig =eplacement Therapy and Appropriate Dosage
2efore starting Ig replacement therapy, it is important that your physician completes all the
immune studies to demonstrate that your immunoglobulins are not only lo& but that you do not
ma0e specifc antibodies normally follo&ing natural infections or immuniDation &ith %accines An
e1ception to this rule is those patients that ha%e e1tremely lo& serum immunoglobulins, li0e a
serum Ig# of 7:: mgFdl or less The immunologists generally use tetanus to1oid and
pneumococcal %accines li0e @neumo%a1 to test the ability of the patient to ma0e specifc
antibodies Another blood sample is dra&n four to si1 &ee0s after immuniDation to determine
ho& &ell specifc antibodies are made to these %accines It is important that you follo& through
&ith this second blood dra& to determine your response to %accines &ithin this four to si1 &ee0
timeframe Insurance companies often re%ie& this information before appro%ing Ig therapy
The dose of Ig %aries from patient to patient In part, the dose is determined by the patient;s
condition and &eight The dose by the intra%enous route generally starts at J::-K:: mgF0g per
month, and 4::-4L6 mgF0gF&ee0 by the .* route ,o&e%er, some patients re'uire higher doses,
especially those &ith chronic lung disease =ecent studies ha%e sho&n that an optimal trough
le%el !if gi%en by the intra%enous route" or steady state Ig# plasma le%el !if gi%en by the
subcutaneous route" is appro1imately 96: mgFd) to insure ade'uate prophyla1is !infection
protection" Cour prescriber &ill measure your Ig le%els and monitor your clinical status !such as
ho& you are feeling, if you are ha%ing infections" to insure that you are recei%ing an ade'uate
dose of replacement therapy
*hoice of =oute
The choice of route of administration of Ig therapy !I+I# or .*I#" should be a decision based on
discussions bet&een the patient and pro%ider This decision is usually based on a number of
factors including the clinical characteristics of each patient, the patient;s preferences for
therapy, appropriate site of care !home, hospital, infusion center", and sometimes, e%en
insurance co%erage
.ome patients &ith chronic sinusitis and chronic lung diseases, such as bronchitis, do better
&hen gi%en higher doses of Ig .ome patients, &ho lose Ig# molecules from their digesti%e tracts
or 0idneys, may re'uire more fre'uent doses andFor higher doses
=emember that although our current Ig products are %ery good, they do not duplicate e1actly
&hat nature normally pro%ides The manufactured Ig is almost pure Ig#, so no IgA or IgM is
transferred to the patient The specifc protecti%e functions of these immunoglobulins are
therefore not replaced The IgA on the mucosal surfaces of the respiratory tract is not being
replaced, &hich may be part of the reason that antibody defcient patients remain some&hat
more susceptible to respiratory infections, e%en though they are recei%ing enough
immunoglobulin to maintain normal or near-normal blood le%els of Ig#
@rophylactic Antibiotic Therapy
.ome pro%iders may prescribe prophylactic antibiotics for patients &ith a history of sinus or
pulmonary disease in order to co%er against bacterial infections of the sinuses and lungs
@rophylactic doses of antibiotics are lo& dose antibiotics generally gi%en at about half the daily
full dose *ommon prophylactic antibiotics are amo1icillin, 2actrimF.eptra
!trimethoprimFsulfametho1aDole" or aDithromycin
#enerally, antibiotics used for treatment of acti%e infection are not used as prophyla1is .ome
pro%iders rotate prophylactic antibiotics &ith the goal of reducing the de%elopment of bacterial
resistance, although there is no true e%idence that this approach is necessary .ome prefer to
treat &ith a single drug Depending on the specifc circumstances of the indi%idual case and the
type of antibiotic and the microbe needing prophyla1is, the prophylactic antibiotic may be
stopped temporarily during the treatment of an acti%e infection &ith a di3erent antibiotic and
resumed after the resolution of the infection and completion of the ne& treatment There is no
true e%idence that this approach is necessary .ome prefer to treat &ith a single drug There is
some contro%ersy regarding the use of prophylactic antibiotics, as some pro%iders belie%e that
the potential for de%eloping drug resistant pathogens is a ris0 that out&eighs the beneft The
decision needs to be discussed &ith a specialist
In patients &ith sinus infections the pro%ider may also recommend a topical nasal steroid andFor
saline nasal &ashes
.ummary of Immunoglobulin Therapy and Other Medical Therapies
for Antibody Defciencies
The goal of Ig therapy for antibody disorders is to pro%ide protection from infection @atient
compliance &ith therapy is paramount to achie%ing this goal Any barriers to therapy, real or
potential, need to be addressed appropriately It is also important to remember se%eral thingsM
Bot all infections can be pre%ented After starting Ig therapy, you may still get
infections ,o&e%er, it is hoped that the fre'uency and se%erity of infections &ill be
signifcantly decreased so that permanent organ damage, li0e bronchiectasis can be
pre%ented
One siDe does not ft all An indi%idualiDed regimen must be de%eloped for each
patient and modifed as necessary to achie%e treatment goals and the needs of each person
Once a diagnosis has been made, therapy &ill probably be needed life long In some
instances, ree%aluation of the diagnosis may be underta0en This &ill be done by ta0ing the
patient o3 of therapy and ree%aluating humoral immunity