**7. Treatment of primary immunodeficiencies**

Primary antibody deficiencies [25], account for approximately 65-50% of primary immunodeficiencies (PID) [3,40]. Due to defects in critical stages of B cell development, B cells areabsent/reduced and B cell functions are impaired in patients with PAD [41]. B cell defects are a heterogeneous group of disorders consisting of patients presenting a wide variety of clinical conditions ranging from asymptomatic to severe and recurrent infections. Patients with selective IgA and IgG subclass deficiencies are often asymptomatic, while children with agammaglobulinemia present encapsulated bacterial infections initiating at 6 months of age. Reduced immunoglobulin concentrations and lack of antibody response against protein antigens (diphtheria, tetanus toxoids) or polysaccharide antigens (pneumococcal polysaccharide) are well defined in patients with agammaglobulinemia or hypogammaglobulinemia [40-42]. Although these patients have frequent or recurrent bacterial infections, they could not mount IgG antibody responses against antigens and this condition is a clear indication for immunoglobulin replacement therapy (Table 5) [21, 42].

Therefore, the aim of replacement therapy is to avoid acute infections, respiratory complications such as bronchiectasis, gastrointestinal complications, to improve quality of life and to increase life expectancy of patients [17, 22]. The delay in diagnosis of primary immunodeficiencies remains a significant problem, as a consequence of delay recurrent pneumonias results in structural lung damage such as bronchiectasis, pulmonary hypertension and finally cor pulmonale [10].


**Table 5.** Primary Immunodeficiencies benefit IVIG treatment

Definitely beneficial

Probably beneficial

Might provide benefit

Unlikely to be beneficial Primary immune defects with absent B cells

Chronic lymhpocytic leukemia with reduced

hypogammaglobulinemia and impaired

Prevention of bacterial infection in HIV

normogammaglobulinemia and impaired

**Table 4.** Recommendation of IVIG in primary and secondary immunodeficiencies [17]

Prevention of neonatal sepsis Ia A

Primary antibody deficiencies [25], account for approximately 65-50% of primary immunodeficiencies (PID) [3,40]. Due to defects in critical stages of B cell development, B cells areabsent/reduced and B cell functions are impaired in patients with PAD [41]. B cell defects are a heterogeneous group of disorders consisting of patients presenting a wide variety of clinical conditions ranging from asymptomatic to severe and recurrent infections. Patients with selective IgA and IgG subclass deficiencies are often asymptomatic, while children with agammaglobulinemia present encapsulated bacterial infections initiating at 6 months of age. Reduced immunoglobulin concentrations and lack of antibody response against protein antigens (diphtheria, tetanus toxoids) or polysaccharide antigens (pneumococcal polysaccharide) are well defined in patients with agammaglobulinemia or hypogammaglobulinemia [40-42]. Although these patients have frequent or recurrent bacterial infections, they could not mount IgG antibody responses against antigens and this condition is a clear indication for immunoglobulin replacement therapy (Table 5) [21, 42].

Therefore, the aim of replacement therapy is to avoid acute infections, respiratory complications such as bronchiectasis, gastrointestinal complications, to improve quality of life and to increase life expectancy of patients [17, 22]. The delay in diagnosis of primary immunodeficiencies remains a significant problem, as a consequence of delay recurrent pneumonias results in structural lung damage such as bronchiectasis, pulmonary

Primary immune defects with

specific antibody production

IgG and history of infection

Primary immune defects with

specific antibody production

Isolated IgA deficiency Isolated IgG4 deficiency

**7. Treatment of primary immunodeficiencies** 

hypertension and finally cor pulmonale [10].

infected children

category recommendation

B

B

A

A C

D D

IIb

IIb

Ib

Ib III

IV IV

> Evaluation of IVIG use in patients lacking immunoglobulin has demonstrated reduction of acute and chronic bacterial infections frequency, pneumonia, days of antibiotic usage, days of fever and hospital admission [16]. Retrospective studies in patients with XLA revealed that severity and number of infections are decreased depending on IVIG dose. Serious bacterial illnesses and enteroviral meningoancephalitis were prevented when maintained IgG levels were above 800mg/dL [16,21,42,43].

> Bars S et al. evaluated the efficacy of IVIG treatment (500 mg/kg every 3 weeks) in 29 children diagnosed with CVID. During therapy, median serum IgG levels increased from 410 to 900 mg/dL. The mean number of respiratory infections per patient per year decreased significantly from 10.2 to 2.5. The annual number and length of hospital stays decreased significantly from 1.36 to 0.21 and 16.35 to 6.33 days per patient, respectively. The mean annual number of antibiotics used decreased significantly from 8.27 to 2.50 per patient. Twelve patients had developed bronchiectasis before initiation of IVIG [44].

> Intravenous immunoglobulin therapy has to be started without any delay in patients with CVID predisposed to chronic lung diseases. Appropriate replacement therapy in these patients, reduced the incidence of pneumonia and prevent progression of lung involvement [17, 42-47].

> A 5-year multicenter prospective study on 201 patients with CVID and 101 patients with XLA was conducted to identify the effects of long-term immunoglobulin treatment and the IgG trough level to be maintained over time required to minimise infection risk. Overall, 21% of the patients with CVID and 24% of patients with XLA remained infection free during the study. Pneumonia episodes had been reduced. Patients with pneumonia did not have

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].

Immunoglobulin Treatment of Immunodeficient Patients 101

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,

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

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

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.

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

21, 23, 49].

**9. Dose** 

promoted for the diseases FDA approved.

[7,10,16,17,25,42,43,45,48,51].

**10. Adverse effects of IVIG** 

Studies have shown that 10 years survival of CVID patients receiving IVIG treatment was 78%; while expected survival in the general population at ten year was 97% [28].

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 patients.

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 [10, 25, 48].

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 infections.

Immunoglobulin treatment is not commonly recommended to patients with selective IgA deficiency unless poor specific antibody or IgG2 subclass deficiency exists [21].

Replacement therapy is also recommended in patients with combined immune deficiencies, other well-defined immunodeficiency syndromes and X-linked lymphoproliferative syndrome (XLP)(Table 5).
