Human Normal Immunoglobulins
Human Normal Immunoglobulin (Ph. Eur.) (Normal 1m-
munoglobulin Injection: Normal Immunoglobuirn (BP 1998):
Immunoglobulinlim Humanum Normale) is a liquid or
freeze-dried preparation containing immunoglobulins. main-
ly immunoglobulin 0 (lgG) antibodies, of normal subjects.
Other proteins may be present; it contains not less than 10 and
not more than 18% of total protein. It is intended for intra-
muscular injection. It is obtained from the pooled plasma col-
lected from at least 1000 donors who must be healthy, must
not have been treated with substances of human pituitary ori-
gin, and as far as can be ascertained be free from detectable
agents of infection transmissible by transfusion of blood or
blood components. No antibiotic is added to the plasma used.
It is prepared as a stabilised solution and passed through a
bacteria-retentive filter. Multidose, but not single dose, prep-
arations contain an antimicrobial preservative. The pH of a
solution in sodium chloride 0.9% containing 1% of protein is
6.4 to 7.2. The liquid preparation should be stored, protected
from light, in a sealed, colourless, glass container. The freeze-
dried preparation should be stored, protected from light, un-
der vacuum or under an inert gas.
Human Normal Immunoglobulin for Intravenous Admin-
istration (Ph. Eur.) (Normal Immunoglobulin for Intravenous
Use (BP 1998); Immunoglobulinum Humanum Normale ad
Usum Intravenosum) is a liquid or freeze-dried preparation
containing immunoglobulins. mainly immunoglobulin 0
(lgG). Other proteins may be present and the total protein con-
tent is not less than 3%. It contains lgG antibodies of normal
subjects: the standard does not apply to products intentionally
prepared to contain fragments or chemically modified lgG. It
is prepared as a stabilised solution and passed through a bac-
teria-retentive filter. It does not contain an antimicrobial pre-
servative. The pH of a solution in sodium chloride 0.9%
containing 1%of protein is 4.0 to 7.4. Storage requirements
are similar to those for Human Normal Immunoglobulin, ex-
cept that the freeze-dried preparation is stored at a tempera-
ture not exceeding 25Β°.
Immune Globulin (USP 23) is a sterile solution of globulins
that contains many antibodies normally present in human
adult blood. It is prepared from pooled material (approxi-
mately equal quantities of blood, plasma, serum, or placentas)
from not fewer than 1000 donors. It contains 15 to 18% of
protein, of which not less than 90% is gamma globulin. It con-
tains glycine as a stabiliser, and a suitable preservative. It
contains antibodies against diphtheria, measles, and
poliomyelitis. It should be stored at 2Β° to 8Β°.
Adverse Effects and Precautions
As for immunoglobulins in general.
Antibody titres for some common pathogens can
vary widely not only between products from differ-
ent manufacturers, but also from lot to lot. Formula-
tions of intravenous immunoglobulins should
therefore not be regarded as equivalent.
Reviews.
Effects on the blood. Adverse effects on the blood have
occasionally been reported following intravenous administra-
tion of normal immunoglobulin to increase the platelet count
in patients with idiopathic thrombocytopenic purpura. Re-
duced platelet adhesiveness with multiple subcutaneous hae-
matomas occurred in one patient. Thrombotic events in 4
elderly subjects (fatal in 3) suggested that a rising platelet
count during normal immunoglobulin treatment may repre-
sent a risk in patients with severe atherosclerotic diseased A
review in Scotland of 34 patients over 60 years of age treated
with normal immunoglobulin could not, however, confirm the
association.)
Passive transfer of anti-A, anti-B. or anti-D antibodies or ac-
tive immunisation by blood group substances from normal
immunoglobulin preparations has been implicated in the pro-
duction of haemolytic reactions including a case of haemolyt-
ic disease of the newbom.Nicholls et al. suggested that
blood phenotyping be earned out before treatmeni with nor-
mal unmunoglobulin is commenced.
Transient neutropenia has been observed after administration
of normal immunoglobulin to patients with thrombocytopen-
ic purpura, but the clinical significance of this effect has been
disputed.
Effects on the kidneys. Barton el al. reported the develop-
ment of acute renal failure after intravenous administration
of normal immunoglobulin to a patient who had demonstrable
serum rheumatoid factor associated with lymphoma. They
recommended that normal immunoglobulin should not be
given to such patients. Schifferii et al. noted a symptom
less, transient rise in plasma-creatinine concentrations in 6
patients
with nephrotic syndrome after administration of intravenous
normal immunoglobulin. A similar rise in plasma creatinine
was observed in two other patients with pre-existing renal im-
pairment but no nephrotic syndrome. More recently.' an eld-
erly patient with lymphoproliferative disorder and idiopathic
thrombocytopenic purpura received normal immunoglobulin
and developed acute renal failure within 48 hours, with sub-
sequently fatal heart failure and pulmonary oedema.
Effects on the nervous system. Reports of aseptic men-
ingitis after intravenous administration of normal immu-
noglobulin.
Migraine was associated with intravenous immunoglobulin
therapy in a patient on two occasions. Migraine did not recur
after prophylaxis with propranolol was instituted.
Effects on the skin. A report of 3 women experiencing dif-
fuse alopecia within I to 4 weeks of treatment with intrave-
nous normal immunoglobulin. There have been reports of
severe and extensive eczema in elderly patients up lo 3 weeks
after receiving normal immunoglobulin intravenously. There
has also been a report of cutaneous Vasculitic rash on the face
of a woman receiving intravenous normal immunoglobulin.
For mention of a patient with AIDS who developed erythema
characteristic of fifth disease following intravenous normal
immunoglobulin, see Infection, below.
Hypersensitivity. Hypersensitivity reactions may occasion-
ally occur after intramuscular or intravenous administration
of normal immunoglobulins particularly in hypogammaglob-
ulinaemic or agammaglobulinaemic patients. Both immediate
and late reactions have occurred,
The IgA content of normal immunoglobulins can result in the
development of lgE and lgG anti-lgA antibodies in immuno-
deficient patients with igA deficiency. Burks et aV have sug-
gested that the lgE anti-lgA antibodies are responsible for
anaphylaxis although others have disagreed. The two pa-
tients reported by Burks et al. who had reactions to conven-
tional normal immunoglobulin preparations tolerated
preparations with a low content of igA. Some manufacturers
of normal immunoglobulin preparations recommend that they
not be used in patients with selective igA deficiencies who
have known antibody against igA.
The lgE content of some preparations has also been suggested
as causing hypersensitivity reactions although this has been
disputed,- Complement-activating lgG aggregates may also
be involved although the anticomplementary activity of the
products does not appear to be related to the incidence of
sideeffects.
Infection. An association between administration of certain
intravenous immunoglobulin preparations and hepatitis C in-
fections has led to changes in manufacturing procedures and
withdrawal of the affected products from the market.
In addition, there has been a report of a patient with AIDS
who developed fifth disease (erythema infectiosum) follow-
ing intravenous normal immunoglobulin treatment for infec-
tion with parvovirus.
Interactions
Administration of normal immunoglobulin may in-
terfere with the immune response to live viral vac-
cines. Such vaccines should therefore be given at
least 3 weeks before or 3 months after normal im-
munoglobulins. This does not apply to yellow fever
vaccine for immunoglobulins prepared in the UK,
nor for booster doses of oral poliomyelitis vaccines.
Where such an interval is impractical for immunisa-
tion preceding foreign travel it may have to be
ignored.
Uses and Administration
Normal immunoglobulin is available as two distinct
preparations and formulations. One type of injection
generally containing 16% of protein is used for pas-
sive immunization, and sometimes also for primary
antibody deficiencies, and should only be given in-
tramuscularly; Human Normal Immunoglobulin
(Ph. Eur.) and Immune Globulin (USP 23) are in-
tended for intramuscular use only. The second type
of preparation is formulated for intravenous admin-
istration (Human Normal Immunoglobulin for Intra-
venous Administration (Ph. Eur,)) and is used in
disorders such as primary antibody deficiencies and
idiopathic thrombocytopenic purpura; solutions
generally contain about 3 to 6% of protein, although
some may contain up to 12%. Doses of normal im-
munoglobulin often appear confusing, being ex-
pressed variously in terms of weight (protein or
immunoglobulin G content) or in terms of volume to
be administered; the two do not always appear to
correspond. It should be remembered that there may
be differences between intravenous preparations of
normal immunoglobulin including differing IgA
content and lgO subclass distribution,
Normal immunoglobulin, being derived from the
pooled plasma of blood donors, contains antibodies
to bacteria and viruses currently prevalent in the
general population; in the UK. and also in some oth-
er countries, typical antibodies present include those
against hepatitis A, measles, mumps, rubella, and
varicella. Normal immunoglobulin, therefore, may
be used to provide passive immunisation against
such diseases.
For the pre-exposure prophylaxis against hepatitis
A in travelers going to endemic areas doses recom-
mended in the UK for intramuscular injection are
for short-term exposure of up to 2 months, 125 mg
for children under 10 years of age and 250 mg for
older children and adults; for longer-term exposure
250 mg for children under 10 years of age and
500 mg for older children and adults. Alternative
doses, expressed in terms of volume administered
have been 0.02 to 0.04 mL per kg body-weight for
short-term exposure in both adults and children and
0.06 to 0.12 mL per kg for longer-term exposure
Hepatitis A vaccine may be preferred in
adults visiting endemic countries frequently or stay-
ing for over 3 months or hepatitis A immunoglobu
lin for shorter or less frequent journeys
Normal immunoglobulin may also be used to con-
trol outbreaks of hepatitis A. the recommended dose
for close contacts being 250 mg in those under 10
years of age and 500 mg in older children and
adults.
Normal immunoglobulin may be used to prevent or
possibly modify an attack of measles in children
and adults at special risk (such as those who are im-
munocompromised) but should be given as soon as
possible after contact with measles. In dK,UK rec-
ommended doses, administered intramuscularly, for
the prevention of an attack are 250 mg for those un-
der I year of age, 500 mg for those aged I to 2 years,
and 750 mg for those aged 3 years and over: to mod-
ify an attack, recommended doses are 100 mg for
those under I year of age and 250 mg for older chil-
dren. Alternatively, doses (expressed in terms of
volume) of 0.2 mL per kg have been suggested to
prevent an attack and 0.04 mL per kg to modify an
attack. The dose should be repeated after 3 weeks in
the case of continued exposure to measles.
Normal immunoglobulin may reduce the likelihood
of a clinical attack in pregnant women exposed to
rubella but should be given as soon as possible after
exposure. The recommended dose is 750 mg by in-
tramuscular injection. A dose of 20 mL has also
been suggested.
Normal immunoglobulin may be used in the man-
agement of patients with primary antibody defi-
ciencies such as congenital agammaglobulinaemia,
hypogammaglobulinemia, or immunocompro-
mised patients including those with immunodefi-
ciency syndromes: the immunoglobulin is given to
provide protection against infectious diseases that
such patients may suffer. The intramuscular prepa-
ration may be used but the intravenous route is usu-
ally preferred since administration is less painful for
the doses required. For intravenous infusion, the
dose, expressed in terms of weight (protein or im-
munoglobulin G content), is usually 400 to 800 mg
per kg body-weight initially, then 200 mg per kg
every 3 weeks adjusted as necessary according to
trough-immunoglobulin concentrations: the mainte-
nance -dose is usually 200 to 800 mg per kg per
month. In patients with secondary immunodeficien-
cy syndromes doses of 200 to 400 mg per kg every
3 to 4 weeks have been recommended. Other dosage
regimens have been used. When infused intrave-
nously, normal immunoglobulin should always be
given very carefully and slowly with gradual in-
creases in the rate of administration. For the intra-
muscular type of preparation the usual initial dose,
expressed in terms of volume, is 1.3 to 1,8 mL per
kg in divided doses over 48 hours: the maximum
recommended total initial dose is 60 mL. For main-
tenance, doses of 0.6 to 0.65 mL per kg (maximum
30 mL) may be given every 3 to 4 weeks.
For prophylaxis of infection after bone marrow
transplantation, normal immunoglobulin is given
intravenously in a dose of 500 mg per kg weekly,
adjusted according to response.
Intravenous infusion of normal immunoglobulin is
also employed to raise the, platelet count in patients
with idiopathic thrombocytopenic purpura.
Doses of 400 mg per kg are given daily for 2 to 5
consecutive days. Alternatively doses of 800 to
1000 mg per kg may be given on day I and repeated
on day 3 if necessary. Further doses may be given as
necessary.
For Kawasaki disease, normal immunoglobulin is
given intravenously in a dose of 1.6 to 2 g per kg in
divided doses over 2 to 5 days, or 2 g per kg given as
a single dose. Similar doses of intravenous normal
immunoglobulin have been tried in a range of disor-
ders believed to have an auto-immune origin. The
precise mode of action of normal immunoglobulin
Normal immunoglobulin is also given intramuscu
larly as an adjunct to plasma and blood in the treat-
ment of bums.
Administration. In order to overcome some of the prob-
lems associated with ensuring regular venous access neces-
sary for long term intravenous immunoglobulin therapy,
administration by rapid subcutaneous infusion has been eval-
Mated. Subcutaneous infusion of approximately 16% preserv-
ative-free solutions or solutions not containing a mercurial
preservative were administered to adults through 2 pumps at
a rate of 17 to 20 mL per hour at each pump and to children
at a rate of 10 to 20 mL per hour. Adequate immunoglobulin
concentrations were achieved and this route of administration
was generally well tolerated. A subsequent review* of subcu-
taneous infusion therapy in 165 patients receiving doses of
between 80 and 800 mg per kg body-weight per month in di-
vided doses supported these results.
Oral administration of normal immunoglobulins has been
proposed to reduce the incidence and severity of gastro-intes-
tinal infections," particularly in patients with defective im-
mune systems including neonates. Although the predominant
immunoglobulin secreted into the gastro-intestinal tract in
subjects with a normal immune system is IgA, a species not
present in large quantities in commercial normal immu-
noglobulins. beneficial responses, especially in viral infee-
tions, have been reported following oral administration.
Preparations of immunoglobulin A are available in some
countries and have been tried, mainly in bacterial gastro-in-
testinal infections.
Blood disorders. Intravenous normal immunoglobulins are
used in the treatment of symptomatic severe acute and chron-
ic idiopathic thrombocytopenic purpura . Other
blood disorders in which normal immunoglobulins have been
tried include agranulocytosis and haemolytic disease of the
newborn , aplastic and haemolytic anaemias ,
red-cell aplasia caused by parvovirus B 19 infections (below),
thrombotic thrombocytopenic purpura and haemolytic-urae-
mic syndrome (see Thrombotic Microangiopathies,
and thrombocytopenia with a variety of causes.
Epilepsy. Normal immunoglobulins have sometimes been of
benefit in the treatment of children with epilepsy unrespon-
sive to conventional therapy . More recently, 13 of 15
children with intractable Lennox-Gastaut syndrome or West's
syndrome' responded to high doses of intravenous immu-
noglobulins.
Hypogammaglobulinemia. See underprimary Antibody
Deficiency, below.
Immunocompromised patients. Immunodeficiency
states may arise from primary disorders of the immune sys-
tem, or, more commonly, they are secondary to immunosup-
pressive therapy, HIV infection, or haematological
malignancies. Premature neonates may have deficits in their
immune systems due to their immaturity; placenta) transfer of
maternal antibodies usually occurs after about 32 weeks of
gestation. Such immunodeficient patients and neonates may
be deficient in gammaglobulins which increases their suscep-
tibility to infections, and they could potentially benefit from
the administration of normal immunoglobulins. For informa-
tion on the use of immunoglobulins in specific conditions, see
the following sections and under Neonatal Sepsis, below.
BONE-MARROW TRANSPLANTATION. In patients undergoing allo-
geneic bone-marrow transplantation , intravenous nor-
mal immunoglobulin has decreased the incidence of both
bacterial infections and of symptomatic cytomegalovirus in-
fection, particularly interstitial pneumonia. Overall
survival or overall incidence of cytomegalovirus infection
was not decreased. A combination of normal immunoglobu-
lin and ganciclovir appears to improve the outcome of cy-
tomegalovirus pneumonia subsequent to bone-marrow
transplantation. No patients treated with normal immu-
noglobulin alone survived. Cytomegalovirus immunoglobu-
lins may be more appropriate for the specific
prophylaxis and treatment of cytomegalovirus infections.
Intravenous immunoglobulin therapy has been found to be in-
effective in preventing infections in patients receiving
autologous bone-marrow transplants and may have contributed
to an increased incidence of fatal hepatic veno-occlusive dis
ease.
Normal immunoglobulin administration has been associated
with a reduced frequency of acute graft-versus-host disease.
possibly as a result of a direct immunomodulatory effect,
HIV INFECTION AND AIDS. Immunoglobulin levels are typically
raised in patients with AIDS, but hypogammaglobulinemia
has been observed and. even in the presence of hypergamma-
globulinaemia, patients behave as though they were hypo-
gammaglobulinaemic. Normal immunoglobulin has therefore
been administered to some symptomatic HIV-positive chil-
dren. A significant improvement was noted in 8 children giv-
en intravenous normal immunoglobulin, in terms of weight
gain. number of infectious episodes, and diarrhoea. HIV core
antigen was detected in 4 children before treatment. All be-
came core-antigen negative after treatment was commenced
although the effect was only maintained in 3. The validity of
these results was questioned. Larger studies have reported
improvements in the rate of decline of the CD4+ T lym-
phocyte count) and the incidence of serious bacterial
infections but could not demonstrate improved survival.
However, a further controlled study in adult patients with
AIDS given intravenous normal immunoglobulin demonstrat-
ed both an increase in the time free from bacterial or viral
infection and also an improvement in survival rate after 31
weeks, and a small study in 24 patients has reported im-
proved survival at up to 12 months in patients who received
normal immunoglobulin.
MALIGNANCIES. Hypogammaglobulinemia and the effects of
treatment may increase the susceptibility to infection of pa-
tients with chronic lymphocytic leukaemia. In a study of 81
patients with chronic lymphocytic leukaemia considered to
be at an increased risk of infection, intravenous normal immu-
noglobulin 400 mg per kg body-weight given every 3 weeks
for one year reduced the incidence of bacterial infection com-
pared with saline placebo. The incidence of viral and fungal
infections was not affected. A study in 34 patients suggested
that a dose of normal immunoglobulin 250 mg per kg per
month was adequate for routine prophylaxis in most patients.
Beneficial effects on infection rates have been reported in pa-
tients with multiple myeloma receiving normal immunoglob-
ulins.
PRIMARY ANTIBODY DEFICIENCY. There are three major forms of
primary antibody deficiency: X-linked agammaglobulinae-
mia (XLA. Bruton's agammaglobulinaemia), common varia-
ble immunodeficiency (CVID) which includes lgG subclass
and specific antibody deficiencies, and selective IgA deficien-
cy. The disease is characterised by a wide range of infective
complications as well as auto-immune disorders. Manage-
ment is by replacement therapy with normal immunoglobulin
accompanied by appropriate antimicrobial therapy for break-
through infections. Immunization against infection is of no
value and is contra-indicated for live viral vaccines.
Normal immunoglobulin was traditionally administered by
[he intramuscular route. However, the maximum dose that can
be reasonably given by this route is 25 mg per kg body-
weight weekly, and it is therefore only satisfactory for pa-
tients with mild disease, The introduction of intravenous
preparations of normal immunoglobulin allows high doles to
be given to those with severe disease. This route should there-
fore be used for all patients with XLA and for patients with
CVID who have more than mild disease. The use of intrave-
nous normal immunoglobulin in lgG subclass deficiency,
with or without igA deficiency, or in specific antibody defi-
ciency is successful, though less well established. The dose
and frequency of administration of intravenous normal immu-
noglobulin.is variable and should be adjusted to prevent
breakthrough infection. Most patients require 200 to 600 mg
per kg every 2 or 3 weeks to maintain optimum protection.
Surgical procedures should be covered with additional nor-
mal immunoglobulin and appropriate prophylactic antibacte-
rials. Home treatment with intravenous normal
immunoglobulin has been used successfully in several coun-
tries in both adults and children. Adverse reactions have
been few and generally mild. They are most likely to occur
during the first infusion and during intercurrent illness, and
may be precipitated by a high infusion rate. Long-term treat-
ment of children with antibody deficiencies with intravenous
normal immunoglobulin has been shown to lead to normal
growth and similar rates of infection to those found in non-
immunodeficient children. Some patients have been successfully
treated with subcutane-
ous infusion of normal immunoglobulin (see Administration,
above) and the intraventricular route may be of benefit to
some patients with echovirus encephalitis.
In a pilot study, normal immunoglobulin given subcutaneous-
ly to 10 patients with selective igA deficiency was safe and
reduced the rate of respiratory-tract infections.
Inflammatory bowel diseases. High-dose intravenous
normal immunoglobulin may be beneficial in inducing re-
mission of Crohn's disease and ulcerative colitis and has been
tried in antibiotic-associated colitis.
Kawasaki disease. Kawasaki disease, also known as muco-
cutaneous lymph node syndrome of childhood, occurs mainly
in children under 5 years of age. It is epidemic and endemic
worldwide but is a particular problem in Japan. Kawasaki dis-
ease presents with high fever which persists for at least 5 days
and may be followed by bilateral conjunctival injection,
changes in the oropharyngeal mucosa, signs of vasculitis in
the extremities, rash. and cervical lymphadenopathy. The ma-
jor complications of Kawasaki disease are cardiac effects in-
cluding coronary artery aneurysm, aortic or mitral
incompetence, myocarditis, and pericarditis with effusion,
The cause of the disease is unknown, although an infective
aetiology has been suggested. Early diagnosis, expert cardiac
assessment, and immediate treatment are essential for im-
proved outcome.
Initial treatment aims to reduce inflammation, particularly in
the coronary arterial wall and myocardium, and therefore pre-
vent the development of cardiac complications. Long-term
treatment is given as necessary to prevent coronary thrombo-
sis.
Initial treatment is with aspirin and normal immunoglobu-
lin. Newburger et al. demonstrated a decreased incidence of
coronary-artery abnormalities after such a combination as
compared with aspirin alone. Normal immunoglobulin has
generally been given by intravenous infusion in divided doses
over 2 to 5 days. although administration as a single dose is
recommended as an alternative, and has been associated
with a lower incidence of coronary abnormalities after 30
days than multiple-dose treatment. The optimum dosage and
duration of treatment with aspirin is not yet established, but
the usual practice is to use an anti-inflammatory regimen until
the fever has settled and then to convert to an antithrombotic
regimen. Some recommend an anti-inflammatory regimen
until the fourteenth day of illness, A few patients fail to re-
spond to treatment with aspirin and normal immunoglobulin.
A small study' suggested that re-treatment with normal im-
munoglobulin may be considered for those with persistent or
recurring fever. Oxpentifylline, which may moderate the in-
flammatory response, is being investigated as adjunctive ther-
apy to aspirin and normal in;munoglbbulin.7 Corticosteroids
are not routinely used in Kawasaki disease as there is,a risk
that they may exacerbate coronary artery aneurysms.
Long-term management. Aspirin should be continued for 6
to 8 weeks after the onset of illness and then discontinued if
there are no coronary abnormalities. Some practitioners use
aspirin and dipyridamole as antithrombotic therapy although
it is not known whether this combination provides benefit
over aspirin alone.2 Dipyridamole may be used as an alterna-
tive antithrombotic agent for patients who cannot tolerate
aspirin. Aspirin is usually continued for at least one year if
coronary abnormalities are present and should be continued
indefinitely if coronary aneurysms persist. Anticoagulation
with warfarin or heparin in addition to aspirin may be neces-
sary in some patients such as those with giant or multiple an-
eurysms.
Kidney disorders. Treatment with normal immunoglobulin
has been of benefit in some patients with haemolytic-uraemic
syndrome (see under Blood Disorders, above.) and with lupus
nephritis (see under Musculoskeletal and Nerve Disorders,
below). For mention of the use of normal immunoglobulin in
IgA nephropathy see Glomerular Kidney Disease.
Musculoskeletal and nerve disorders. High-dose intra-
venous normal immunoglobulin has been tried with some
benefit in various disorders of the nerves, muscles, joints,
and connective tissues which may have an auto-immune basis.
These include multiple sclerosis, chronic inflammatory de-
myelinating polyneuropathy, polymyositis and dermatomy-
ositis, myasthenia gravis, stiff-man syndrome, chronic
systemic juvenile arthritis, systemic lupus
erythematosus including lupus nephritis, Guillain-Barre
syndrome (see below), and motor neuron disease (see also
below).
GUILLAIN BARRE SYNDROME. Guillain-Barre syndrome (acute
idiopathic inflammatory polyneuropathy: acute idiopathic de-
myelinating neuropathy; acute infectious polyneuropathy)
may follow an infection or, more rarely, immunisation, but
very often no predisposing factor can be identified. There
may be an association with infection with Campylobacter je-
juni. Reversible demyelination results in pain and progres-
sive flaccid paralysis. An autoimmune aetiology seems
likely. Severely affected patients require cardiovascular
monitoring and respiratory support if respiratory muscles are
affected or autonomic instability is present. Corticosteroids
have been given but are generally considered to be of little
value . Plasma exchange is effective if given early, but is not
universally available and is not suitable for all patients Adminis-
tration of immunoglobulins has been shown to be at least as
effective as plasma exchange in a study of 150 patients" al-
though the response to plasma exchange in this study was
lower than would be expected. A more recent study" has
confirmed the equivalent efficacy of plasma exchange and im-
munoglobulins and has also demonstrated no advantage from
combining the two forms of treatment. Deterioration has also
been noted in some patients following immunoglobulin
therapy and farther evaluation of the use of immunoglob-
ulins is awaited.
MOTOR NEURONE DISEASE. Normal immunoglobulins have been
tried in the treatment of motor neurone disease, in particular
multifocal motor neuropathy.
NEONATAL SEPSIS. Sepsis is a serious problem in premature in-
fants despite appropriate antimicrobial therapy. Preterm
infants are born with low serum-immunoglobulin concentra-
tions which decrease over the next several weeks of life.
There is also a deficiency of antibodies to specific organisms
such as group B streptococci. Staphytococcus epidermidis,
and Escherichia coli.
Some, but not all studies, suggest that prophylactic adminis-
tration of intravenous normal immunoglobulin to premature
infants shortly after birth can decrease the incidence of septi-
caemia. Aspects of the methodology of these studies have,
however, been criticized. Some benefit has been observed af-
ter administration of intravenous immunoglobulin to treat in-
fants ill with suspected sepsis, and may improve the response
to antibacterials.
The optimum effective dosage of intravenous immunoglobu-
lin is not established. A prophylactic dose of 500 mg per kg
body-weight on admission repeated every one to two weeks
has been suggested for units where infection is common in
very low birth-weight infants. Others have suggested adjust-
ing the dose to maintain a specified serum-immunoglobulin
concentration. Alternatively, normal immunoglobulin
could be administered only to infants with immunoglobulin
concentrations below a certain level, or be reserved for imme-
diate use in those who become ill with suspected sepsis.
Normal immunoglobulin cannot protect against all types of
infection. Givner has shown that normal immunoglobulin
preparations from different manufacturers demonstrate, for a
specific pathogen (group B streptococcus), differing levels of
specific antibody and differing levels of functional activity
both in vim and in animals. Lot-to-lot variability in function-
al activity was also observed for normal immunoglobulin
from a specific manufacturer. Such variability, resulting in
low concentrations of functional antibodies in the 4 batches
of immunoglobulins used in the National Institute of Child
Health Study was held responsible for the lack of demon-
strable effectiveness of immunoglobulins in that study, one of
the largest to date. Kohl elal. considered that normal immu-
noglobulin would probably not be effective for the prevention
of serious Herpes simplex virus infection in neonates at risk.
The use of fresh frozen plasma as an alternative to normal
immunoglobulin could not be recommended following a
study which showed that it did not produce the beneficial ef-
fects on humoral immune markers seen with normal immu-
noglobulin.
Human immunoglobulin preparations hyperimmune for a
specific pathogen or human monoclonal antibody prepara-
tions against common perinatal pathogens are possible fu-
ture strategies.
Passive Immunization. CYTOMEGALOVIRUS INFECTION. See
under Bone Marrow Transplantation, above,
HEPATITIS. Hepatitis A. With the decreasing incidence of hepa-
titis A in the UK, a reduction in the concentration of
hepatitis
A antibodies in normal immunoglobulin has been observed.
In the future, normal immunoglobulin could become unsuita-
ble for hepatitis A prophylaxis.l2 However, hepatitis A vac-
cines have been developed and specific hepatitis A
immunoglobulins are available in some countries.
Hepatitis C. In a randomised, placebo-controlled study' in se-
ronegative sexual partners of patients positive for antibody
to hepatitis C, normal immunoglobulin administered intramus-
cularly every 2 months was found to significantly reduce the
incidence of subsequent seroconversion. One of 450 subjects
who received normal immunoglobulin became seropositive
during follow-up compared with 6 of 449 who had received
placebo.
PARVOVIRUS B19 INFECTION. Persistent infection with human
parvovirus B 19 can cause red-cell aplasia with resultant anae
mia particularly in immunocompromised patients. Kurtzman
et al. reported resolution of anaemia and clearance of parvo-
virus B 19 from the circulation after administration of normal
immunoglobulin to a patient who had had red-cell aplasia for
10 years.' Normal immunoglobulin was given by intravenous
infusion in a dose of 400 mg per kg body-weight daily for 10
days and then periodically for several months. Ramage et al.
have described successful treatment of anaemia due to parvo-
virus B19-induced red-cell aplasia with plasmapheresis and
intravenous immunoglobulin in a liver transplant recipient.
Clearance of parvovirus B19 from the circulation has been
reported in patients who also have AIDS. but the presence of
concomitant opportunistic infections may prevent resolution
of the anaemia.
Beneficial responses to intravenous immunoglobulin have
also been reported in a few patients with parvovirus B19 in-
fections associated with Vasculitic syndromes.
RUBELLA One of the uses of normal immunoglobulin involves
the administration to pregnant women recently exposed to ru-
bella. It does not prevent infection in non-immune contact
but may reduce the risk to the fetus and may be used when
termination of pregnancy is unacceptable.
TOXIC SHOCK SYNDROME. For a discussion of toxic shock syn
drome and its treatment, including reference to clinical in
provement in one patient after administration of intravenous
normal immunoglobulins.
Skin disorders. Normal immunoglobulins have been tried
in a few patients with blistering skin diseases. The usual
treatment for pemphigoid is with systemic corticosteroids:
normal immunoglobulins in high doses have produced generally
transient improvement when used alone, although steroid-spar
ing effects have been reported.2 A patient with severe
epidermolysis bullosa responded to therapy with high-dose
intravenous immunoglobulins. Clinical benefit was noted in
9 of 10 patients with auto-immune chronic urticaria who were
given a 5-day course of intravenous immunoglobulins, 2 of
whom experienced prolonged remission over 3 years of fol-
low-up.
Spontaneous abortion. Fetal loss has been attributed in
some cases to the presence of antiphospholipid antibodies (lu-
pus anticoagulant and anticardiolipin) in the mother. Success-
ful pregnancy outcome has been reported after administration
of intravenous normal immunoglobulin during pregnancy to a
few such women.
RECURRENT SPONTANEOUS ABORTIONS DUE TO ANTI-PHOSPHOLIPID ANTIBODY SYNDROME - 1 VIAL OF 16.5% ( BHARGLOB ) EVERY 21 DAYS TILL 36 WEEKS ( MAT START THE INJ FROM PRECONCEPTION PERIOD )