**8. Choosing a commercial brand for IVIG therapy**

There are several factors required for selection of an IVIG brand:


Regarding lyophilized or liquid forms, sugar content, amount of IgA (varies between <0.4 μg/mL and 720 μg/mL), used antimicrobial processes and stabilizing agent, an appropriate commercial immunoglobulin preparation should be selected for treatment of immunodeficient patients(Table 1). The patients with diabetes may have high blood glucose levels due to maltose-containing products therefore they have to adjust doses of insulin [5, 8, 21, 23, 49].

Patients with selective IgA deficiency carry the risk of anaphylaxis due to production of anti-IgA antibodies. Selective IgA deficient patients having high anti-IgA (>1/1000) titers should not be treated with IVIG or a IgA-free immunoglobulin product should be chosen for the treatment [8, 21, 50, 51]. Since IVIG administration is a life-saving therapy, the treatment should be supported by scientific clinical evidence regardless the economic impact of therapy [52]. Therefore considering scarcity of resource for IVIG, its judicious use must be promoted for the diseases FDA approved.

#### **9. Dose**

100 Immunodeficiency

patients.

[10, 25, 48].

infections.

syndrome (XLP)(Table 5).

2. Safety and tolerability

3. Price

significant lower IgG trough levels than patients without pneumonia, with the exception of patients whose IgG trough levels were persistently <400 mg/dL. In addition, in XLA comorbidity risk factor identified for pneumonia was the presence of bronchiectasis [10,23].

Studies have shown that 10 years survival of CVID patients receiving IVIG treatment was

Patients with severe combined immunodeficiency(SCID) syndromes are also agammaglobulinemic and have significant inability to produce antibody against antigens. Hematopoietic stem cell transplantation is choise of therapy for these patients, but functional B-cell reconstitution often fail following marrow engraftment and these patients could not produce antibodies. Regular replacement therapy with IVIG is indicated for these

Hyper IgM syndromes are usually defined with reduced levels of IgG and IgA, but high or normal IgM. These patients have normal B cell counts, but defective class switching do not allow to generate specific antibodies, thus these children experience frequent infections like agammaglobulinemic individuals. Adequate replacement of IVIG has been shown to reduce the incidence of pneumonia from 7.6% to 1.4% per year and patients did not have meningitis

Selective antibody deficiencies or normogammaglobulinemia with impaired specific antibody production are group of disorders characterized by impaired production of specific antibody with normal serum IgG levels. Evidence of recurrent infection and absent or reduced specific antibody production against polysaccharide antigens after vaccination, are requirements for IVIG therapy. Therapy can be stopped after clinical improvement and the immune response of patient should be re-evaluated at least 5 months later. Usually antibody response to antigens, improve in growing children, but in conditions of unresponsiveness to antigens, restart to IVIG treatment is appropriate due to recurrence of

Immunoglobulin treatment is not commonly recommended to patients with selective IgA

Replacement therapy is also recommended in patients with combined immune deficiencies, other well-defined immunodeficiency syndromes and X-linked lymphoproliferative

1. To obtain enough information about the IVIG product: lyophilized powder or premixed solution, amount of sodium, IgG and IgA, stabilizing sugar, preservative, viral

deficiency unless poor specific antibody or IgG2 subclass deficiency exists [21].

**8. Choosing a commercial brand for IVIG therapy** 

There are several factors required for selection of an IVIG brand:

inactivation methods, concentration, osmolarity

78%; while expected survival in the general population at ten year was 97% [28].

The common recommended dose of IVIG treatment for antibody replacement is between 0.3 and 0.6 g/kg, administered every 2 to 4 weeks via the intravenous route. The first dose of IVIG infusion usually results more frequently in adverse reactions compared to the following second or third doses. Thus, the first IVIG infusion to a patient with antibody deficiency must be given slowly as a 5% solution, starting with a rate of 0.5 to 1.0 mg/kg per minute. Patient should be monitored closely for any adverse reactions during infusion. If the patient tolerates well, the infusion rate may be increased to 1.5 to 2.5 mg/kg per minute after 15 to 30 minutes. The maximal infusion rate is 4 mg/kg per minute. Infusion of an IVIG product should last 2 to 4 hours. For subsequent infusions IVIG concentrations of 10% and 12% can be used, with rates 4 mg/kg per minute. The aim of IVIG therapy in patients with PID is to maintain serum IgG levels between 350 mg/dl and 500 mg/dl [7,10,16,17,25,42,43,45,48,51].

Since, there is large variation in individual IgG elimination rates, periodic measurement of serum IgG concentration is critical to monitor the adequacy of replacement during therapy.

#### **10. Adverse effects of IVIG**

There are two main risks of immunoglobulin treatment: Infusion related adverse effects and transmission of blood–borne viruses [5,7,22,23]. Incidence of adverse reactions, have been found 44% in more than 1.000 patients with PID, in a study done by Immune Deficiency Foundation (IDF) [16]. This rate was surprisingly higher than those observed in licensing studies (Table 6). The IDF survey showed that 34% of patients experienced adverse reactions during the first administration of IVIG and who has had a recent bacterial infection. Reactions may develop 1 to 15% in the first 30 minutes of IVIG infusions. After second or third doses of the same IVIG product additionial infusion dependent reactions become less likely. Most IVIG reactions are mild, however anaphylaxis may occur occasionally. Adverse reactions are characterized by chills, headache, low grade fever, back or abdominal pain, nausea, vomiting, myalgias, rhinitis, asthma, flushing on face, vertigo, anxiety, conjunctival congestion, occasional rash and drop of arterial pressure. Varying rates of adverse events have been reported (Table 6) [53-56]. Thus, close monitoring of a patient during infusion is essential to identify and manage reactions [8,24,53]. Recently, manufacturing processes of immunoglobulins have been improved and new IVIG products have been developed. Several trials with these products demonstrated that the infusion related adverse reactions were reduced [24,53]. IVIG infusions have to be done at hospital or home by professionally educated staff if possible. Local anesthetic cream (EMLA Cream) could be applied on skin prior infusion to reduce pain in small children. Administration IVIG via indewelling venous catheter is not encouraged because of additional adverse events such as thrombotic and infectious complications.

Immunoglobulin Treatment of Immunodeficient Patients 103

**11. Late-onset side effects of IVIG** 

Central nervous system: rarely aseptic menengitis

intravascular coagulation and changes in blood rheology

25,27,28,57]:

A variety of side effects due to IVIG therapy have been reported in different tissues [7-11,21-

Hematologic: hemolytic anemia, leukopenia, neutropenia, monocytopenia, disseminated

Cardiovascular system: rarely heart attack, most commonly, drop in arterial blood pressure Urogenital system: During the period between June 1985 and November 1998, 88 cases of kidney injuries had been reported to FDA. Acute renal failure occured with IVIG preparations stabilized with sucrose, where as those stabilized with D-sorbitol did not cause such an effect. Patients whose urinary output decreases, who suddenly gain weight with edeme on feet and

Liver Disease: The risk of Hepatitis C, Hepatitis B, HIV infection, prion disease disappeared after the initiation of viral inactivation (solvent-detergent or pasteurization) methods and PCR studies which took place after CDC's confirmation of 88 infections among 137 suspected

Other: Life threatening parvovirus B19 has occured due to IVIG, hyperproteinemia, increased serum viscosity, pseudo-hyponatremia during infusions, transient serum sickness.

An expert monitoring is necessary for prompt diagnosis and treatment of adverse reactions. Most side effects resolve by themselves and are usually due to the speed of infusion. Infusion should temporarily be stopped 15 to 30 minutes if the symptoms appear or should be continued with slower rate once the symptoms disappear. Since the side effects are usually non-IgE dependent, the use of antihistamines is controversial, but diphenhydramine, acetaminophen or ibuprofen may be helpful. More severe reactions can be treated with 50 to

Those who are reactive to IVIG should receive premedication. Thirty minutes prior to IVIG administration, oral nonsteroid anti-inflamatory agent (acetaminophen 15 mg/kg), antihistaminic agent (Benadryl 1mg/kg) or one hour prior to infusion intravenous

As an alternative to intravenous immunoglobulin treatment, immunoglobulins can be administered subcutaneously to patients with primary immunodeficiencies, Subcutaneous infusion of IgG was introduced more than 20 years ago but has gained ground in recent

hepatitis C cases (occuring after IVIG) in 1994. Therefore they are reliable preparations.

ankles and those who experience dyspnea should be monitored very closely.

Skin: severe cutaneus vasculitis, dermatitis (egzema) and hair loss

100 mg of hydrocortisone in adults and intravenous hydration is helpful.

hydrocortisone (6 mg/kg) should be administered [8,24].

**13. Subcutaneos immunoglobulin** 

**12. How to manage adverse reactions?** 


AE:Adverse event, infect/subj/y: infections per subject per year, NF:nanofiltration, SAE:serios adverse event a) 0-48 h postinfusion, b) 0-430 min postinfusion, c) 0-72 h postinfusion

**Table 6.** Clinical trials in patients with primary immunodeficiency disorders [22]
