..

s: bsp CI Ity Clini . II r ic IS S S Common Variable Immunodeficiency: The Disorder and Treatment

MICHAEL W. YOCUM, M.D., Division ofAllergic Diseases and Internal Medicine; JOHN M. KELSO, M.D., * Section of General Pediatrics and Pediatric Allergy and Immunology A case ofcommon variable immunodeficiency, a relatively rare disorder, is presented. This case was complicated by the presence of an anti-IgA antibody in the patient's serum and a history of a possible anaphylactic reaction to a prior intravenous infusion of y-globulin. Common variable immunodeficiency is actually a heterogeneous group of demonstrable immunoglobulin deficiencies that have in common low levels ofmost immunoglobulin isotypes, the inability to form antibodies to antigen, an absence of gross defects in cell-mediated immunity, and 'the presence of recurrent bacterial infections. The history of immunoglobulin deficiency and its treatment is reviewed. Although the primary therapy for common variable immunodeficiency is y-globulin replacement, ancillary measures such as early treatment ofinfections with antibiotics are also important. Intravenous y.globulin replacement therapy is preferred to intramuscular replacement therapy in these patients because intramuscular doses must be limited in volume to minimize local pain and take 2 to 14 days to achieve maximal blood levels, during which time in situ degradation of up to 50% of the administered dose can occur. Five intravenous y.globulin preparations are currently available in the United States. The potential adverse effects ofintravenous y-globulin infusion and the precautions currently taken to ensure safety during administration of this product are discussed.

The human immune response to infection con- immune limb, even in supposedly "pure" husists oftwo arms, the humoral antibody and the moral immunodeficient states. The incidence of cell-mediated immune systems. Patients have congenital or primary defects of the immune been described with defects limited to one of response to infection is relatively low, in comthese systems or defects in both responses. Subtle parison with the current rapid increase in acdefects are-usually present in the cell-mediated quired immunodeficiency syndrome. The incidences of primary immunodeficiency per 1 x 106 live births that have been reported from Sweden *Current address: Naval Hospital, San Diego, California. and Australia for various time periods are shown Address reprint requests to Dr. M. W. Yocum, Division of in Table 1. In addition, the diagnosis of these disorders is frequently delayed (a mean of 12 Allergic Diseases, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 66:83-96, 1991

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COMMON VARIABLE IMMUNODEFICIENCY

Table l.-Incidence of Primary Immunodeficiency in Sweden and Australia During Various Periods Country

Period

Sweden Sweden Australia Sweden Australia

1968-1978 1974-1979 1979 1979 1972-1985

Number per 1 x 106 live births Reference 26 14 89 50 24

1 2 3 4 5

years). 1,5 Because of this delay, the complications of humoral immunodeficiency such as chronic otitis, sinusitis, bronchitis, bronchiectasis, pneumonitis, and enteritis may be well established by the time of diagnosis and institution of appropriate therapy.

HISTORICAL REVIEW Agammaglobulinemia was first reported by Colonel Ogden C. Bruton" in 1952 in an 8-yearold boy. This remarkable classic article not only defined Bruton's agammaglobulinemia but also provided the first instance of effective specific replacement therapy with intramuscularly administered human y-globulin. Subsequently, in a well-controlled study, the Medical Research Council of the United Kingdom? demonstrated that intramuscular administration of y-globulin was protective in agammaglobulinemia. Currently, however, the primary humoral immunodeficiency states are known to consist of several different clinical disorders (Table 2). By 1968, reports of adverse reactions to intramuscularly administered y-globulin began to appear in the literature. Fudenberg and associates" demonstrated anti-IgA antibodies in patients who had little or no IgA in their serum but normal amounts of IgG and IgM.. They further showed that these anti-IgA isoimmune antibodies were responsible for anaphylactic transfusion reactions. The reactors possessing anti-IgA antibodies formed two discrete groups. Group 1 patients typically had no demonstrable serum IgA and had potent anti-IgA antibody titers (greater than 1:1,000). These anti-IgAs reacted with broad specificity to most myeloma IgAs and were thus class specific. They were

found in patients who had anaphylactic reactions to blood products, plasma infusions, and intramuscularly administered y-globulin. Group 2 patients consisted of multiparous or multitransfused subjects with low anti-IgA antibody titers (less than 1:256) and oflimited or isotype specificity. These patients reacted to plasma infusions with hives and other cutaneous rashes, but not anaphylaxis, and demonstrated lowered serum complement levels during these reactions.? These findings were immediately confirmed by Schmidt, Taswell, and Gleich 10 in 1969. They demonstrated precipitating IgG antibody to IgA in a patient lacking serum IgA, and this IgG anti-IgA antibody was shown to fix serum complement. Skin-sensitizing antibody (IgE) to IgA was not found in this patient, who reacted with severe anaphylaxis to infusions of as little as 10 ml of whole blood.!" Schmidt and colleagues'? postulated that an antigen (IgA)antibody (anti-IgA) reaction with fixation of serum complement resulted in the general release of mediators such as kinins to cause the anaphylactic symptoms. In 1977, Wells, Buckley, and associates!' reported severe anaphylaxis during plasma infusions given for antibody replacement therapy to two patients with common variable immunodeficiencies. Both patients had anti-IgA antibodies of class specificity and absent serum IgA. These authors pointed out the novelty of these reactions in patients not expected to form antibodies to antigens because oftheir immunodeficient status. They also described the exquisite sensitivity of those patients who possessed antiIgA antibody and pointed out that severe anaphylaxis could occur within 2 minutes after intravenous administration ofless than 1 mg of IgA-or that present in less than 0.5 ml of human plasma.!' Thus, it was clear that immunodeficient patients with absent IgA levels were at risk for anaphylaxis if given serum products that contained IgA. Intravenous therapy for immunodeficiency was first attempted in 1962 to provide higher levels of passive immunoglobulin than were obtainable through intramuscular administration of y-globulin. 12 This approach was unsuccess-

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Table 2.-Humoral Immunodeficiency States X-linked infantile agammaglobulinemia X-linked hypogammaglobulinemia with growth hormone deficiency Transcobalamin II deficiency and hypogammaglobulinemia Immunodeficiency with thymoma Immunodeficiency after a hereditary defective response to Epstein-Barr virus Common variable immunodeficiency Immunoglobulin deficiency with normal or increased levels of IgM and IgD Selective IgA deficiency Selective deficiency of other immunoglobulin isotypes Light chain deficiency Immunodeficiency caused by hypercatabolism of immunoglobulin molecules Immunodeficiency caused by excessive loss of immunoglobulins and lymphocytes

ful-14 of 15 patients with antibody deficiency were intolerant ofthis treatment. Anaphylactic shock reactions were observed, with sudden onset of dyspnea, chest oppression, emesis, flank pain, hypotension, syncope, fever, and chills. Those patients who had such a violent reaction were noted to have a pronounced decrease in all measured components ofthe serum complement system, and this phenomenon was considered to result from consumption of complement by aggregates of IgG present in the y-globulin preparations.13 Although plasma therapy for hypogammaglobulinemia has been attempted in the United States since 1966,14,15 intravenous administration of y-globulin was abandoned because of intolerance and severe anaphylactic reactions.!" Janeway and colleagues"? were able to administer a pepsin-digested y-globulin preparation in 1968 to patients with agammaglobulinemia with no adverse reactions.. This pepsin digest consisted essentially of only the' F(ab')2 fragment of intact IgG (Fig. 1) but unfortunately had a serum half-life ofonly 18 hours in comparison with a serum half-life of 17 days for intact IgG. Safe, nonaggregated, non-complement-consuming intravenous y-globulin (IVGG) preparations were finally available for the replacement therapy of humoral immunodeficiency in 1979. 18 In conjunction with the foregoing historical review of the treatment of humoral immunodeficiency, we present a case report of a patient

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with common variable immunodeficiency. This case was complicated by the fact that the patient had previously experienced an adverse reaction during an IVGG infusion and demonstrated a high titer of an IgG anti-IgA antibody in her serum. We review the disorder common variable immunodeficiency, the available IVGG preparations and their proper administration, the adverse effects of IVGG and their prevention, and the practical management of patients with this disorder.

REPORT OF CASE A 27-year-old woman was referred to the Division of Allergic Diseases at our institution for evaluation of hypogammaglobulinemia diagnosed 8 months previously. She had a history of recurrent infections since age 3 years, which had become more frequent and severe in the past 2 years. As a child, she had urinary tract infections thought to be attributable to a renal anatomic abnormality, which was surgically corrected at age 3 years. Postoperatively, however, she continued to have bladder infections. Beginning at age 4 years, she had recurrent upper respiratory infections, such as otitis media, sinusitis, pneumonitis, and bronchitis. Since adolescence, she had had six to eight yearly episodes of sinusitis associated with fever and purulent rhinorrhea. During the past 2 years, she had experienced an increase in the episodes of bronchitis and sinusitis, chronic diarrhea, a tooth abscess with complicating cellulitis, pelvic inflammatory disease, a hepatic abscess after a cesarean section, and several hospitalizations for evaluation of fevers of unknown origin. Eight months previously, serum immunoglobulin measurements had revealed decreased levels ofIgG (184 mg/dl), IgM (19 mg/dl), and IgA, (less than 4 mg/dl). Treatment with IVGG was initiated. During the first such infusion, the patient experienced shortness of breath, chills, and agitation, a reaction she described as "frightening." She was subsequently given intramuscular doses of y-globulin, which caused some minor influenza-like symptoms for a day or two after each injection but no more severe generalized symptoms.

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positive at 1,055% of the negative control. She was treated with an IVGG preparation low in IgA content (Gammagard), 400 mg/kg, given at an infusion rate of 0.5 ml/kg per hour. A physician and emergency resuscitation equipment were present at the bedside, and vital signs were monitored frequently. The infusion rate was gradually increased to 1 ml/kg per hour and then to 2 ml/kg per hour. At this last rate, the patient had chills and nausea but demonstrated stable vital signs and denied having any respiratory distress or cutaneous symptoms. The chills and nausea resolved spontaneously before completion of the infusion. A serum IgG level determined after the infusion was 936 mg/dl. A serum sample obtained before the infusion was mailed to Dr. Rebecca H. Buckley at Duke University, who subsequently reported negative results of an IgE anti-IgA antibody test on this specimen. Fig. 1. Diagram of a prototypic immunoglobulin monomer. Each rectangle represents an immunoglobulin domain, with the extended polypeptide strands connecting the domains into complete heavy (dark shading) and light chains. The interchain disulfide bonds (88) between the hinge regions of the heavy chains are represented as black bars. Intrachain and interchain disulfides between heavy and light chains are not shown. Carbohydrate groups are shown connected to both the hinge regions and the second constant region domain of each heavy chain. The boundaries ofthe major proteolytic fragments are indicated by the bars to the left and right ofthe diagram. Note that the FabFc division occurs above the interchain disulfides, whereas the F(ab')2 division is below. V and C = variable and constant regions of the light (L) and heavy (H) chains. (From Hasemann CA, Capra JD: Immunoglobulins: structure and function. In Fundamental Immunology. Second edition. Edited by WE Paul. New York, Raven Press, 1989, pp 209-233. By permission.)

Physical examination revealed an afebrile patient with no abnormal physical findings. The immunoglobulin levels were as follows: IgG, 165 mg/dl; IgM, 18 mg/dl; IgA, less than 4 mg/dl; and IgE, less than 12 U/ml. The leukocyte count was 9.1 x 1Q3/m m 3 with a normal differential. Numbers ofT cells and B cells, as well as T-cell subset quantitations, were normal. Serum specimens demonstrated an IgG anti-IgA antibody, quantitated by a solid-phase radioimmunoassay technique.!" The anti-IgA antibody was strongly

CHARACTERISTICS OF THE DISORDER Common variable immunodeficiency has been referred to as an idiopathic, congenital non-Xlinked, acquired, or late-onset disorder, but experts generally agree that the defect most likely exists at birth. This very rare disorder has an incidence of 6 to 12 cases per 1 x 106 live births. 1-5 ,20 Although Bruton's agammaglobulinemia is Xslinked," common variable immunodeficiency is equally represented in both sexes. Excellent reviews of this subject have been published recently.i':" Rarely, common variable immunodeficiency may develop after a fetal rubella infection or a postnatal Epstein-Barr virus infection. This disorder is actually a heterogeneous group of demonstrable immunoglobulin deficiencies that have in common low levels of most immunoglobulin isotypes, the inability to form antibodies to antigen, an absence of gross defects in cell-mediated immunity, and the presence of recurrent bacterial infections. Infections may not manifest as unusual or as unduly frequent until late childhood or early adulthood. The involved organisms are typically virulent encapsulated extracellular pathogens, such as Haemophilus influenzae, Streptococcus pneumoniae, group A streptococci, and Staphylococcus aureus. The infections occur because

Mayo Cltn Proc, January 1991, Vol 66

these patients lack the major heat-stable opsonin of the extracellular fluid, IgG. Occasional infections with Mycobacterium tuberculosis, fungal pathogens, andPneumocystis carinii may occur. In addition, echovirus infections are particularly virulent in these patients, and a fatal dermatomyositis-like syndrome may develop." H. influenzae is a major cause of recurrent bronchitis in these patients, but Helicobacter pylori and Mycoplasma infections also occur." The respiratory system is predominantly involved with sinusitis, otitis, pharyngitis, bronchitis, pneumonitis, and bronchiectasis. The gastrointestinal system is affected with cholecystitis, ascending cholangitis, enteritis, jejunal villous atrophy, malabsorption syndrome, and H. jejuni as well as Giardia lamblia infections. Resultant lactase and gluten intolerance may occur. Noncaseating granulomas may form in the lungs, spleen, and liver, and the gutassociated lymphoid tissue may hypertrophy and appear as nodules on a small bowel x-ray film. Germinal center enlargement in greatly expanded Peyer's patches, spleen, and lymph nodes is thought to represent uncontrolled proliferation ofB cells, which are driven by antigen without the normal terminal differentiation of plasma cells and production of antibody to provide negative feedback to discontinue proliferation. The incidence of malignant lesions, especially the non-Hodgkin lymphomas, is increased in these patients." Chronic infections may lead to eventual amyloidosis. Studies of lymphocytes from these patients show either normal or decreased numbers of B cells. Lymph node biopsy specimens reveal minimal plasma cell differentiation. Suppressor T cells develop in 15% of these patients and block the helper T-cell function from driving Bcell differentiation into plasma cells, but this is thought to be a secondary phenomenon rather than a primary pathogenetic mechanism.P Defects in cell-mediated immunity may later develop in as many as 30% of patients or may be disclosed earlier in their course if sophisticated laboratory studies are performed. Helper T cells, CD4+, are usually present in normal numbers. Most authorities believe that this

COMMON VARIABLE IMMUNODEFICIENCY

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disease represents an inherent B-cell defect with a blockin their normal differentiation into plasma cells after antigenic stimulation (Fig. 2).23 Investigators have postulated that the B cells in patients with common variable immunodeficiency perhaps lack receptors for B-cell stimulation and differentiation factors such as the interleukins 4, 5, and 6. 27 It is known that IgAdeficient patients have an increased frequency of particular combinations of major histocompatibility alleles rather than individual or specific HLA alleles per se. 28 These combinations of major histocompatibility alleles are called"supratypes," viewed more properly as conserved ancestral haplotypes. Specific ancestral haplotypes have been associated with IgA deficiency" and also with common variable immunodeficiency.30 Furthermore, these ancestral haplotypes in IgAdeficient patients were found to possess a high frequency of null alleles for the gene that encodes the A isotype of complement component C4. Thus, these ancestral haplotypes had deleted, duplicated, or defective C4 genes." Rare complement component C2 alleles or C4 alleles (or both) as well as deletions have also been found in common variable immunodeficiency." Complement component genes are clustered in the central or class III major histocompatibility area between the HLA-B and HLA-DQ areas, along with genes coding for factor B and tumor necrosis factors a and ~. 28 Thus, defects or deletions ofgenes in the C4 major histocompatibility class III area may be in linkage dysequilibrium with other defective alleles that affect plasma cell maturation and antibody secretion. Peripheral blood lymphocytes of patients with common variable immunodeficiency have also been found to produce less interleukin 2, interleukin 4, and interferon-y than such lymphocytes from normal subjects.P These cytokines are necessary for B-cell growth and differentiation. T cells from patients with common variable immunodeficiency produce lower levels of interferon-y and interleukins 2, 4, and 5 than do normal T cells but still retain the ability to proliferate with mitogens." Investigators have postulated that patients with common variable immunodeficiency may have defects in the gen-

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COMMON VARIABLE IMMUNODEFICIENCY

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- - - - - Antigen-Independent --~>1..- --Antigen-Dependent--> SlemCelJ I

Pre B Cells

I Plasma Cell

B Cells Memory

Immatur. Motur. Activated

~ ~

c::5 /

rQ-~/'!"

0'4:"'U-''-V-+0td...u~ )//) I

SCID

I

XLA

I

YYy

':@v

CVI

Fig. 2. Hypothetical model ofthe comparative levels ofB-cell arrests that may characterize severe combined immunodeficiency (SC/D), X-linked agammaglobulinemia (XLA), and common variable immunodeficiency (CVI). (From Cooper and Butler." By permission of Raven Press, Ltd.)

eration of nuclear transcription factors common to both their T and B cells. Surprisingly, several autoimmune disorders and autoantibodies have been described in these patients. The concomitant occurrence of rheumatoid arthritis and agammaglobulinemia was described by Good and associates" in 1957. These authors related that adequate y-globulin replacement ameliorated the rheumatoid arthritis-like syndrome present in their patients. Studies for rheumatoid factor in these patients were negative. Pernicious anemia with gastric atrophy, achlorhydria, and absent intrinsic factor production but negative demonstration of parietal cell and intrinsic factor autoantibodies can occur, as can Coombs-positive hemolytic anemia, thyroid autoantibodies, and clinical thyroid disease. Splenomegaly from germinal center hypertrophy or from noncaseating granulomas (or both factors) may cause secondary hypersplenism, as reflected by leukopenia and thrombocytopenia.

and IgA antibody. Thus, even with y-globulin replacement, most patients continue to have chronic respiratory and gastrointestinal infections because oftheir continued lack of secretory IgA. Ampicillin and trimethoprim-sulfamethoxazole are helpful for H. influenzae infections. If this organism is resistant, cefaclor or ampicillin in combination with clavulanate potassium should be administered." Diarrhea is most frequently due to G. lamblia, but other enteropathogens and also bacterial overgrowth must be ruled out. Giardia responds to quinacrine hydrochloride or, as a second choice, to metronidazole, and metronidazole is also recommended for Clostridium difficile infections. Baseline pulmonary function tests, including lung volumes, flow rates, and diffusion capacity, should be performed in order to gauge the adequacy of y-globulin replacement. Deterioration in these variables has been shown to correlate with inadequate replacement and continued severe pulmonary inflammation. 1,4 Intramuscularly administered y-globulin is GENERAL THERAPY infrequently used for immunodeficient patients Although the primary therapy for common vari- because the volume is limited to 10 ml per able immunodeficiency is y-globulin replacement, injection site (to minimize local pain) and the ancillary measures for practical management minimal requirement for replacement is 100 mg/ are extremely important. y-Globulin replace- kg; thus, a typical 70-kg patient will require ment essentially provides only IgG antibody and 7,000 mg present in up to 43 ml ofthe y-globulin clinically insignificant amounts of passive IgM preparation. This volume limits the total prac-

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tical intramuscular dose ofy-globulin that can be administered to patients and hence effectively "underdoses" them. Furthermore, maximal blood levels of intramuscularly administered y-globulin may take from 2 to 14 days to achieve, during which time substantial in situ degradation of up to 50% of the administered dose can occur. 34,35 The plasma from at least 1,000 donors is extracted to obtain the y-globulin preparation, and it is initially screened to be negative for hepatitis A and B viruses as well as human immunodeficiency virus. Although its IgG subtype distribution is normal and the Fc function is intact, it has high anticomplement activity because of the presence of immunoglobulin aggregates. 13,35

Intravenous Administration of y-Globulin.-An IgG molecule is depicted in Figure 1. Total serum IgG consists of the following subclass percentages: IgG1, 70%; IgG2, 15%; IgG3, 10%; and IgG4, 5%.35 The hinge region (the area between CH1 and CH2) of IgG is most susceptible to degradation during processing and manufacture. Passively administered IgG depends on an intact hinge region and Fab segment to combine with antigen and an intact Fc segment to fix serum complement, retain a normal catabolic rate, effect placental transfer, and interact with neutrophils, macrophages, lymphocytes, and natural killer cells." The different IgG subtypes have predominant functions for host defense, although considerable overlap exists between subclasses: IgG1 = antibody to heterologous protein antigens, toxins, and viruses; IgG2 = antibody to bacterial polysaccharides; IgG3 =antibody to viruses and streptococcal M protein; and IgG4 = antibody to bacterial carbohydrates and antibody raised by repeated immunization.I" The World Health Organization has published minimal recommendations for IVGG preparations used in humans." The IVGG should be free of prekallikrein activator, kinins, prostaglandins, platelet-activatingfactor, leukotrienes, and plasmin. Ninety percent of the IgG1 subclass shouldbe intact, and the preparation should have little IgA and be free of aggregates. Furthermore, all subclasses should be represented, and levels of antibody to at least two bacteria or

COMMON VARIABLE IMMUNODEFICIENCY

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bacterial toxins and to viruses should be demonstrable, including 0.1 IU/ml of antibody to hepatitis B virus. Three major groups of IVGG are available, varying with the method of preparation: enzymatic modification, such as with pepsin or plasmin; chemical modification with ~-pro­ piolactone; and reduction and alkylation or sulfonation and unmodified but purified with diethylaminoethyl or polyethylene gycol-hydroxyethyl starch." Enzyme-treated preparations vary considerably in their content of IgG1 and IgG3 fragmentation and aggregation, which may result in a shortened half-life. Five IVGG preparations are available in the United States (Table 3).38 Gammagard has been extensively studiedv" and is prepared in unmodified form by ionexchange chromatography. Each lot is obtained from 2,000 to 10,000 donors and screened for hepatitis B surface antigen, antibodies to hepatitis B core antigen, aspartate aminotransferase level, and human immunodeficiency virus antibody. This preparation contains much less IgA at Lfi ug/ml than do Sandoglobulin and Gamimmune N.39 Therapy with y-globulin should be given to any patient with demonstrable low IgG levels, absence of antibodies to pathogens known to have caused infections, and a history of recurrent bacterial infections. It is not indicated for a pure isolated IgA deficiency unless an IgG deficiency coexists (which, most typically, is absent IgG2, IgG4, or both of these subclassesl.s'v'? If normal subjects receive IVGG preparations, the half-life averages 21 days, whereas the half-life is 26 to 28 days in patients with immunodeficiency.'! IgG catabolism is thought to be somewhat dependent on the serum concentration; thus, patients with hypogammaglobulinemia experience slower IgG catabolism. Serum IgG levels in the range of 200 to 400 mg/dl 4 weeks after infusion are recommended'v" because this level protects against progressive respiratory infections and most systemic infections. The survival curve ofIVGG is constant in an individual patient but varies among patients (Fig. 3).34 The IgG subclass survivals in patients with hypogammaglobulinemia typically demonstrate the following half-lives (in days): IgG, 26 to 32;

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Table 3.-Available Intravenous y-Globulin Preparations Product name

Manufacturer

Method of preparation

Gammonativ

KabiVitrum AB, Stockholm, Sweden

GamimmuneN (Polyglobin N) Sandoglobulin Gammagard

Cutter Biological, Emoryville, California

Globulin N Intraglobin F Venimmune Venoglobulin-I Iveegam

Sandoz AG, East Hanover, New Jersey Baxter Healthcare Corp., Hyland Division, Glendale, California Armour, Tarrytown, New York Biotest Pharma GmbH, Frankfurt, Germany Behringwerke AG, Marburg, Germany Alpha Therapeutic Corp., Los Angeles, California Immuno AG, Vienna, Austria

Diethylaminoethyl-Sephadex adsorption, albumin stabilization Formulation at pH 4.25 Treatment at pH 4 with porcine pepsin Diethylaminoethyl-Sephadex adsorption Precipitation with hydroxyethyl starch and polyethylene glycol Treatment with propiolactone Sulfonation Polyethylene glycol, diethylaminoethylSephadex adsorption Immobilized trypsin treatment, purification by polyethylene glycol precipitation

From Berkman and associates." By permission of the American College of Physicians.

IgG1,30 to 35; IgG2, 27 to 40; IgG3, 16 to 24; and IgG4, 34 to 36. 42.44 The mean maintenance dose is 400 mg/kg, but this must be adjusted to the individual patient's half-life and prior experience based on monitoring postinfusion serum IgG levels. 21 The mean infusion time at this dose is usually 4 hours. Serum IgG levels have been measured at 15 minutes, 72 hours, 7 days, 14 days, 21 days, and 28 days after infusion through two to three therapeutic cycles to obtain individual decay curves." The day 7 measurement is crucial because thereafter the IgG decay rate is exponential; thus, the day 7 level will decrease by 50% at day 28. Therefore, preinfusion IgG and day 28 levels are almost identicaL43 Homeostasis is usually attained after six monthly infusions; by this time, the peak and trough levels become predictable in an individual patient.v' This amount of time is necessary to normalize the Fc receptors of the patient's monocyte-macrophage system, which have been down-regulated before replacement therapy. Studies reveal that specific antibody levels such as to hepatitis B surface antigen, pneumococcal polysaccharide, and tetanus antitoxin mirror the half-life of IgG in an individual patient. 42,43 Patients first begun on IVGG replacement therapy or those actively infected will require higher initial doses." Furthermore, in the pregnant patient with hypogammaglobulinemia, higher

maintenance dosages (in the range of 800 mg/kg per month) are necessary because of a physiologic extracellular fluid volume expansion plus an active placental transfer of IgG. Cord blood levels average 81% of maternal blood levels." Adjustments of loading doses yield fairly predictable serum IgG levels; thus, a dosage of 100 mg/kg will result in an IgG level of 200 mg/dl, and a dosage of 500 mg/kg will result in a 1,000 mg/dllevel by 72 hours after infusion." Adequate y-globulin replacement therapy will diminish serious clinical infections and prevent progressive bronchiectasis, emphysema, and pulmonary fibrosis." AdverseEffects ofIVGG.-Although adverse effects to IVGG most frequently occur if the recipient has preexisting anti-IgA antibody, as previously described, other adverse effects do occur. Reactions are most frequent in newly treated or currently infected patients, perhaps because of the union of passive antibody and antigen.s- In addition, prekallikrein activator and ~-lipoproteinas well as some IgG aggregates are present in IVGG.38 Typical symptoms that may occur are vasomotor flushing, myalgias, headache, nausea, emesis, chest constriction, chills, and fever experienced during the first 30 minutes of infusion. Slowing the infusion rate and premedication with aspirin or corticosteroids usually control these symptoms.

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1000

COMMON VARIABLE IMMUNODEFICIENCY

r

900t I

80 01 700 600 500

200

100 l--L---'----'-_-'-----"----L'_-1...10 12 14 2 4 6

J

16

I

18

20

22

I

I

,

24

26

28

Days Post -Infusion Fig. 3. Serum IgG values before and at various days after intravenous infusion of 150 mg/kg of serum y-globulin. Note rapid decline in serum IgG levels from immediate postinfusion level through third postinfusion day. Thereafter, reduction of serum IgG values followed an exponential pattern, reflecting the half-life of the infused IgG. (From Pirofsky.s" By permission of Reed Publishing USA.)

If the IVGG recipient has demonstrable anti-IgA antibody, more frequent adverse effects may occur during infusion. The frequency of anti-IgA antibody is particularly high if the immunodeficient patient has a very low or absent serum IgA level. Large numbers of blood donors have been screened for the absence of serum IgA and the presence of anti-IgA antibody. IgA deficiency has a frequency in the general population of 1 in 650, and of these IgAdeficient patients, 1 in 886 has no measurable serum IgA.47 Of these patients with unmeasurable serum IgA, 22% may have high titers of anti-IgA antibody. Vyas and colleagues." however, showed that if some IgA is measurable in

91

the serum, then anti-IgA antibody is usually absent. The consequences of a recipient possessing anti-IgA antibody when given blood that contains IgA have been studied.t" No difference was found in the frequency of anaphylactic reactions whether the recipient had anti-IgA antibody (26 of 54) or did not (28 of 54). This early study raised the question of whether anti-IgA antibody independently was of critical pathogenetic importance in anaphylactic reactions that occur in recipients ofIVGG. In a population of patients with hypogammaglobulinemia, an anti-IgA antibody is demonstrable in 6.2% of serum samples." This incidence increases considerably, however, ifthe patient with hypogammaglobulinemia has unmeasurable serum IgA (to a frequency of 20 to 60%).50 The highest frequency of anti-IgA is seen in selective IgA deficiency and in patients with coexistent IgA and IgG2 deficiencies. Again, even in patients with hypogammaglobulinemia, if some serum IgA is measurable, an anti-IgA antibody is rarely found." An enzyme-linked immunosorbent assay can detect serum IgA to a level of 0.001 ug/ml; therefore, this procedure is much more sensitive for the detection of serum IgA than the single radial immunodiffusion technique (which is sensitive to only 20 f.lg/ml).50 Even in patients with absent serum IgA and the presence of antiIgA antibody who received IVGG replacement, only 1 of40 recipients was unable to tolerate this treatment.P! Thus, the actual pathogenicity of anti-IgA antibody in patients who receive IVGG is questioned, and other mechanisms for adverse effects must be considered. In 1979, Ropars and associates'" first detected an IgE antibody to immunoglobulins in a study of 43 renal dialysis workers who received 5 ml of intramuscularly administered y-globulin every 2 months for hepatitis B prophylaxis.52 Their method involved an inverse-radioallergosorbent technique, which was used in only 11 workers. They detected an IgE anti-immunoglobulin antibody in 8 of these 11 employees, which was of limited specificity to a panel of monoclonal immunoglobulins. Only two of these workers, however, seemed to have experienced an adverse IgE immediate-type reaction to intramus-

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COMMON VARIABLE IMMUNODEFICIENCY

cularly administered y-globulin. Homburger and co-workers'? used a solid-phase immunoradiometric assay to search for IgG and IgE antiIgA antibody in 101 patients who had a nonhemolytic urticarial transfusion reaction. Although IgG anti-IgA was found in 7.9% of patients, no IgE anti-IgA was found. In 1986, Burks and colleagues" published a seminal report of IgE anti-IgA antibodies demonstrable in patients with common variable immunodeficiency who experienced anaphylactic reactions to IVGG.39 An enzyme-linked immunosorbent assay was used to demonstrate an IgE anti-IgA of more than 1 ng/ml in 9 of 18 patients who had an anaphylactic reaction to blood products.w-"? These authors pointed out that true anaphylaxis, although rare, manifests as flushing, urticaria, angioedema, dyspnea, anxiety, emesis, cyanosis, hypotension, and syncope." They also showed that Gammagard contains less than 1.6 ug/ml ofIgA in comparison with levels ofIgA up to 15 Ilg/ml in other IVGG preparations and the more than 700 ug/ml ofIgA present in the intramuscularly administered form of y-globulin. 39 Other investigators have also found IgE antiIgA antibodies in patients with common variable immunodeficiency.52 Another major concern with use of IVGG is the ensurance of safety from transmissible infectious agents, particularly the viruses that cause hepatitis B and acquired immunodeficiency syndrome. IVGG is obtained from plasma subjected to the Cohn-Oncley cold ethanol fractionation method, as shown in Figure 4. 53 In 1978, Trepo and associates'< reported that the e antigen and also DNA polymerase are reliable markers for the presence of infective 43-nm Dane particles and that they are retained in Cohn fraction III. Moreover, the bulk of hepatitis B surface antigen 22-nm particles are distributed into fraction IV, and no hepatitis B surface antigen is found in fraction II (from which IVGG is obtained). Most immunoglobulin preparations contain antibodies to hepatitis B surface antigen in titers of 100 or greater by radioimmunoassay quantitation, a finding that strongly suggests that no transmission of viable virus could occur.I" Nevertheless, hepatitis B core

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IMMUNOGLOBULIN Fig. 4. Schematic diagram of Cohn-Oncley fractionation process studied for effects on infectivity with human T lymphotropic virus type III. (From Wells and associates." By permission ofthe American Association of Blood Banks.)

antibody and aspartate aminotransferase enzyme elevations in the y-globulin final product may be "surrogate" markers for hepatitis C virus.P! If human immunodeficiency virus is treated with 19% ethanol for 5 minutes, as is done during Cohn-Oncley fractionation, its reverse transcriptase activity is reduced to 1% of the pretreatment level.?" The human immunodeficiencyvirus infectious titers are decreased 10 5- to lOB-fold during Cohn-Oncley fractionation into fraction II. Another 10 3_ to 10 5-fold reduction in infectious titer occurs during incubation at pH 4, and another 10 4-fold reduction occurs during incubation of the pure liquid immunoglobulin at 27°C.57 Because large plasma pools have been reported to contain up to 2,000 infectious particles/ml of human immunodeficiency virus, a worst-case scenario is that IVGG purification methods must be able to fractionate

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and inactivate 2 x 104 infectious particles/ml of human immunodeficiency virus. 57 Studies of the transmissibility of' 'the acquired immunodeficiency virus have been performed with plasma "spiked" with human immunodeficiency virus.53 Cohn-Oncley fraction II requires six precipitations, as shown in Figure 4. The ratio of residual live virus in plasma fractions to live virus in starting plasma was 1 x 10-15 for precipitate II, from which IVGG is manufactured. A further calculation relevant to human immunodeficiency virus infectivity is that the geometric mean infectivity titer of plasma from 43 patients with human immunodeficiency virus was reported as 0.02 infectious unit/ml.P Studies by the American Red Cross revealed that 3.8 per 10,000 plasma donors demonstrate anti-human immunodeficiency virus antibody by the Western blot method, and screening is 98 to 99% sensitive. Thus, a 1,000liter plasma pool from screened donors might contain a maximum of 0.13 infectious unit/ml, and the foregoing IVGG purification efficacy would ensure the absence of human immunodeficiency virus infectivity.P-" Because human immunodeficiency virus is not fractionated into Cohn fraction II, no cases of human immunodeficiency virus infection from IVGG have been reported. 59 Furthermore, the final IVGG product is tested in chimpanzee studies or by in vitro studies of viral inactivation by using, as internal standards, marker viruses that are culturable. Gamimmune, Sandoglobulin, and Gammagard are all safe, in that no risk for hepatitis C transmission has been found in phase II clinical trials."? Isolated rare reports suggested that hepatitis C may have occurred With one or more lots ofIVGG obtained from the Scottish National Blood Transfusion Service.61 No proven cases of hepatitis or human immunodeficiency virus infection from IVGG have been reported in the United States."

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IgA, the presence of an IgG anti-IgA antibody is most unlikely." If the patient has no measurable serum IgA, a sensitive method such as enzyme-linked immunosorbent assay should be used to search for an anti-IgA antibody. (Although an IgE anti-IgA antibody may be demonstrable by such sensitive methods, these assays are not generally available.) Rarely, an IgE antiIgA antibody may be present in the absence of coexistent IgG anti-IgA antibody (Buckley RH: Personal communication). If the patient has an anti-IgA antibody, it is best to administer IVGG that is low in IgA content. Even in patients who have very high titers of anti-IgA antibodies, these "IgA-poor" IVGG products are safely tolerated. 62 The use of diethylaminoethyl-Sephadex A50 removes most IgA from Cohn fraction II down to a level of 3 to 23 ug/ml, In one report, a patient who had an anaphylactic reaction to an IVGG preparation that contained an IgA concentration of720 Ilg/ml safely tolerated an IVGG preparation with an IgA content of less than 20 ug/ml.63 When commercial IVGG preparations are assayed for IgA content by a competitive binding solid-phase radioimmunoassay, they vary from 0.441lg/ml to . 3.5 x 1031lg/m1.64

CONCLUSION Common variable immunodeficiency is a rare disorder. If it is suspected, immunoglobulin levels in the patient's serum should be measured and compared with age-, race-, and sex-adjusted normal laboratory levels. This comparison is crucial because normal immunoglobulin levels vary from laboratory to laboratory and with the type of methods used, such as radial immunodiffusion, rate nephelometry, or enzyme-linked immunosorbent assay. The patient's serum should also be tested for a lack of functioning antibody by Epstein-Barr, antistreptolysin, rubella, or isohemagglutinin titers. It is particularly important to search for antibodies to pathoPRACTICAL MANAGEMENT gens known to have caused infection. In addiWhen a physician suspects that a patient may tion, preimmunization and postimmunization have common variable immunodeficiency, quan- titers to vaccines such as influenza, rubella, H. titative immunoglobulin levels should be ob- influenzae, and pneumococcal or tetanus toxoid tained. If the patient has measurable serum can be measured. Patients should not be treated

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with IVGG if they have isolated IgA or IgG subclass deficiency, unless the inability to form specific antibodies in a patient with serious recurrent infections is clearly substantiated. Thorough medical follow-up and early treatment of infection with antibiotics are as important as IVGG. Serial pulmonary function tests should be monitored, and the adequacy ofIVGG replacement should be determined through the initial.two or three treatment cycles by day 7 and day 28 postinfusion IgG levels. If the prospective IVGG recipient has unmeasurable IgA levels, one should test for anti-IgA antibody. If an anti-IgA is demonstrated, an IgE anti-IgA antibody may coexist, and particular care must be exercised during IVGG infusion. In such situations, an IVGG preparation with low IgA content should be used.

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9. 10.

11.

12. 13. 14. 15. 16.

ACKNOWLEDGMENT

We thank Dr. Rebecca H. Buckley for personal assistance, Dr. Charles E. Reed and Dr. John W. Yunginger for their helpful critique and comments, and Colleen A. Wiginton for preparation of the submitted manuscript. REFERENCES

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