Intravenous Immunoglobulin Replacement Research Articles

Infectious complications in chronic lymphoid malignancy.

Taking steps to minimize, prevent, and treat infection in patients with chronic lymphoid malignancies, especially chronic lymphocytic leukemia, has always been a challenge. As more patients with these diseases live longer and lead productive lives upon successful initial treatment, strategies for preventing infections have become more important. Distinguishing patients at low risk for infection from those at high risk is a crucial but challenging issue. Unfortunately, there are hardly any data on the use of prophylactic antibiotics for patients with chronic lymphoid malignancy (CLL). If patients cannot be enrolled in a clinical trial, antibiotics with co-trimoxazole should be administered when steroids are warranted. They should also be administered in patients who have had a documented infection early in the treatment course and during neutropenia. Viral infections remain another controversial issue in patients with CLL receiving treatment, especially a purine analogue. Very low CD4 counts (less than 50 cells/mL) might predict for reactivation for herpes zoster. Outside of depleted CD4 counts, there are no other means of identifying a high-risk group. Based on limited data, it would be reasonable to administer herpes zoster prophylaxis to patients with CD4 counts that are severely depleted or to patients with a prior episode of zoster. Controversial issues still remain regarding immunoglobulin treatment, specifically cost, scarcity of the product, and adequate dose, which has not yet been established. We would consider intravenous immunoglobulin (Ig) replacement in patients with marked hypogammaglobulinemia (IgG less than 400 mg/dL) with more than two recent severe infections [1]. Lower Ig doses (240 mg/kg) have been shown to be equivalent to higher ones in this trial [1].

Respiratory disorders in common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and various immunologic abnormalities. The clinical presentation is generally that of recurrent pyogenic sinopulmonary infections.Our objectives were to study the prevalence of lung involvement and the response to intravenous immunoglobulin replacement therapy in 19 patients with CVID. Nineteen patients (12 men) with a mean age (SD) of 33¶1 (17¶1) years had a previous diagnosis of CVID and were treated with intravenous immunoglobulin replacement. All patients underwent complete pulmonary function tests and high-resolution computed tomography (HRCT) examination. Bronchiectasis was diagnosed in 11 (58%) patients and eight (42%) were multi-lobar bronchiectasis. Chronic airflow limitation (CAL) was present in 10 (53%) patients and a restrictive pattern was seen in one case. Eleven patients (58%) presented a decrease in single-breath carbon monoxide diffusing capacity of the lung (DLco). Before intravenous immunoglobulin replacement therapy (INIRT), 84% of patients had suffered from at least one episode of pneumonia. Episodes of lower respiratory tract infection decreased significantly from 0¶28 per patient and year before replacement therapy to 0¶16 per patient and year after treatment. The mean duration of replacement therapy was 7¶5 years.In conclusion lung involvement was frequent in patients with CVID. Long-term administration of intravenous gammaglobulin resulted in a substantial reduction of pneumonic episodes.

Transient hypogammaglobulinemia of infancy: clinical and immunologic features of 40 new cases.

Transient hypogammaglobulinemia of infancy (THI) results from a delay in the maturation of immunoglobulin production. The clinical and immunologic data of 40 patients with THI are presented. Clinically, the majority of patients presented with recurrent respiratory infections and otitis media, bronchitis and/or bronchial asthma and recurrent gastroenteritis. Ten of 40 children had isolated low IgG; isolated low IgA and isolated low IgM were detected in one and three patients, respectively. At initial evaluation, levels of all three immunoglobluins were low in nine patients. Ten patients had diminished IgG and IgA levels, six had diminished IgA and IgM levels and one had low IgG and IgM levels. Two patients were given intravenous immunoglobulin replacement therapy for 1 year. None of the patients has experienced serious infections during their follow-up period. Prospective evaluation of patients (age range 5-60 months) revealed that immunoglobulin levels in 33 patients recovered before 36 months of age. Seven patients still had low immunoglobluin levels at 40-57 months of age. Three of these patients had low levels of both IgG and IgA, while two patients had low IgM levels and a further two patients had low IgA levels.

529 The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy

529 The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy

Pulmonary abnormalities in patients with primary hypogammaglobulinemia

Background: Pulmonary complications are common in patients with primary hypogammaglobulinemia. Intravenous immunoglobulin replacement therapy has been thought to reduce the occurrence of pulmonary complications, yet they do occur. Objective: The purpose of this study was to evaluate pulmonary abnormalities in 22 patients with primary hypogammaglobulinemia (18 with common variable immunodeficiency, 4 with X-linked agammaglobulinemia) and to conduct a prospective 3-year follow-up study to assess the possible progression of pulmonary abnormalities. Methods: Pulmonary changes were evaluated with use of pulmonary imaging (chest radiographs, high-resolution computed tomography), and pulmonary function testing. Results: High-resolution computed tomography revealed pulmonary abnormalities in 21 patients. Bronchiectasis was present in 16 patients, whereas chest radiographs revealed bronchiectasis in only 3 patients. Pulmonary function testing showed obstruction in 5 patients. A prospective 3-year follow-up was conducted in 14 patients. It showed silent progression of bronchiectasis in 5 of the 14 patients, all of whom were receiving intravenous immunoglobulin replacement therapy and had preinfusion serum IgG concentrations of 5 g/L or more. Conclusions: Pulmonary abnormalities develop in most patients with primary hypogammaglobulinemia. A new finding is that silent and asymptomatic progression of pulmonary changes may occur in patients despite an adequate immunoglobulin replacement therapy. High-resolution computed tomography is the method of choice in monitoring pulmonary changes. (J Allergy Clin Immunol 1999;104:1031-6.)

Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: A retrospective survey of 31 patients

Objective: To evaluate the outcome of children who received prolonged intravenous immunoglobulin (IVIg) replacement therapy early in life for X-linked agammaglobulinemia (XLA). Study design: We performed a retrospective study of the clinical features and outcome of patients with genetic and/or immunologic results consistent with XLA. Patients receiving IVIg replacement therapy within 3 months of the diagnosis and for at least 4 years between 1982 and 1997 were included. Results: Thirty-one patients began receiving IVIg replacement therapy at a median age of 24 months and were followed up for a median time of 123 months. IVIg was given at doses >0.25 g/kg every 3 weeks, and mean individual residual IgG levels ranged from 500 to 1140 mg/dL (median, 700 mg/dL). During IVIg replacement, the incidence of bacterial infections requiring hospitalization fell from 0.40 to 0.06 per patient per year ( P < .001). However, viral or unidentified infections still developed, including enteroviral meningoencephalitis (n = 3) causing death in one patient, exudative enteropathy (n = 3), and aseptic arthritis (n = 1). At last follow-up, 30 patients were alive at a median age of 144 months (range, 58 to 253 months). Among 23 patients who were evaluated by respiratory function tests and computed tomography, 3 had an obstructive syndrome, 6 had bronchiectasis, and 20 had chronic sinusitis. Conclusion: Early IVIg replacement therapy achieving residual IgG levels >500 mg/dL is effective in preventing severe acute bacterial infections and pulmonary insufficiency. More intensive therapy may be required to fully prevent the onset of bronchiectasis, chronic sinusitis, and nonbacterial infections, particularly enteroviral infections, in all cases. (J Pediatr 1999;134:589-96)

Clinical utility of high-resolution pulmonary computed tomography in children with antibody deficiency disorders.

To assess the value of high-resolution computed tomography (HRCT) in determining the extent and significance of lung disease in children with antibody deficiency states. Seventy HRCT scans performed on 37 children with various antibody deficiency disorders over a 5-year period were retrospectively scored using a previously described demerit scoring system (0-25 with 0 = worst, 25 = best). Points are subtracted from 25 with increasing severity of disease. The potential correlations between CT scores and clinical factors, including age at diagnosis, age at CT, type of immunoglobulin deficiency, length of respiratory symptoms before diagnosis, number of pneumonias before diagnosis, type, length and success of therapy, patient compliance and pulmonary function tests (PFTs), were assessed. Of the 37 children, a demonstrated 22 abnormal scans (CT score < or = 22). All nine demonstrated bronchiectasis with a lower lobe and right middle lobe predominance. Statistically significant correlations were seen between severity of lung disease (CT score) and length of respiratory symptoms before diagnosis (p = 0.01), success of therapy (P = 0.001) and PFTs (P = 0.0008). Of seven children who were followed with repeated scans, 4 of the 7 demonstrated CT scores which improved on high-dose intravenous immunoglobulin replacement therapy. HRCT is a useful adjunct to demonstrate the extent and severity of lung disease at diagnosis and during therapy. Correlation with clinical factors suggests a higher risk group needing more aggressive management.

RECURRENT SINUSITIS AND IMMUNODEFICIENCY

Recurrent sinusitis may be due to an underlying primary immunodeficiency disorder. The immune system evaluation entails analysis of the lymphocytic (antibody and cellular), phagocytic, and complement components of the immune system. This workup needs to be coupled with a detailed history and physical examination. With appropriate screening of the patient with recurrent sinusitis, the diagnosis of an underlying primary immunodeficiency can be established. The immune workup may include evaluations of serum immunoglobulins; isohemagglutinins; complete blood count; IgG subclasses; delayed hypersensitivity skin testing with Candida , tetanus, and PPD; humoral immune assessment-baseline and postimmunization blood specimens to assess for functional humoral immunity; chest and sinus roentgenograms; and serum C3, C4, and CH 50 determinations. If indicated, special white blood cell studies, such as nitroblue tetrazolium testing, myeloperoxidase staining, chemotaxis, and chemiluminescence assessments, and surface glycoprotein measurements can be performed. If a patient has received gamma globulin injections or infusions, the true extent of functional humoral immunity may be difficult to ascertain objectively. In this setting, bacteriophage ФX-174 can be used. Because ФX-174 is a potent T cell–dependent antigen found only in bacteria, primary and secondary responses can be determined as a function of antigen clearance. In this way, functional humoral immunity can be assessed. When the clinician establishes primary immunodeficiency as part of the diagnosis in the patient who presents with recurrent sinusitis, treatment regimens can be instituted in a more efficacious manner. The immunodeficiency diseases most commonly associated with chronic sinusitis are antibody deficiency states, such as Bruton’s (X linked) congenital agammaglobulinemia, common variable immunodeficiency, IgG subclass deficiency, and selective IgA deficiency. Patients with cellular immune defects that permit survival also suffer from chronic sinusitis, e.g., ataxia telangiectasia. Treatment of antibody-deficient patients with intravenous immunoglobulin replacement therapy is rewarded by at least partial relief of symptoms when administered in conjunction with appropriate antimicrobial treatment. Identifying the patient with primary immunodeficiency disorder is the first step to successful treatment of underlying sinusitis. Understanding that recurrent sinopulmonary infection may be secondary to underlying immunodeficiency should guide therapeutic options and comprehensive management.

Sinus computerized tomography in primary hypogammaglobulinaemia.

Thirteen patients suffering from primary hypogammaglobulinaemia receiving intravenous immunoglobulin replacement therapy underwent computerized tomography of the paranasal sinuses. The CT scans were evaluated and related to clinical data from the patients, who were selected for study on the basis of having symptoms of rhinosinusitis. The scans varied from normal to demonstrating widespread sinus abnormality. There was no relationship between the scan findings and duration of ENT symptoms, range of current symptoms, or the interval between the onset of ENT symptoms and the start of intravenous immunoglobulin replacement therapy. It is nevertheless possible that prompt institution of replacement therapy, after correct diagnosis early in the course of the disease, may prevent the development of sinus disease refractory to such treatment.

Long-term follow up of patients with common variable immunodeficiency treated with intravenous immunoglobulin: reevaluation of intravenous immunoglobulin replacement therapy. IVIG therapy in CVID.

Five patients with common variable immunodeficiency treated in our hospital between December 1979 and December 1990 were given six kinds of intravenous immunoglobulin preparations (pepsin treated, S-sulfonated, polyethylene glycol treated, pH4 treated, alkylated, and pH4.25 formulation preparation) for replacement therapy. Duration of the therapy ranged from 7.6 to 11 years. Incidences of fever and acute infections were variable among patients, but no significant differences were seen in the incidences among periods given each preparation. Three cases revealed abnormal pulmonary functions in tests. Adverse reactions were rarely seen in our study periods, and no severe reactions were observed. No significant differences were seen in incidences of adverse reactions. Postinfusion levels of serum complement slightly decreased from preinfusion levels. However, the decrease in complement was not related to any adverse reaction. No long-term complications such as transmission of hepatitis have been observed. Our data suggest that no obvious differences exist between the efficacy and safety of each IVIG preparation. Differences of efficacy of IVIG replacement therapy may be due to the variable pathophysiology of each patient.

IgG antibody reactive with five serotypes of Streptococcus pneumoniae in commercial intravenous immunoglobulin preparations.

Intravenous immunoglobulin replacement is recommended for immunoglobulin deficiency, but comparison of the efficacy of intravenous immunoglobulin preparations (IVIGs) has been hindered by the lack of standardized assays to measure immunoglobulin levels against important bacterial pathogens. IgG reactive with five commonly isolated serotypes of Streptococcus pneumoniae in four commercially available IVIGs was measured by ELISA. Specific antibody to capsular polysaccharide was quantitated before and after adsorption with cell wall polysaccharide (CWPS). All IVIGs contained measurable levels of antibody to the five pneumococcal serotypes, although the levels against an individual serotype varied by as much as sevenfold from one preparation to another. Each IVIG also contained substantial concentrations of IgG reactive with CWPS. The amount of each IVIG that protected mice was nearly identical after the doses were adjusted on the basis of specific IgG measured by ELISA, thereby providing proof in vivo of the validity of this in vitro assay system.

High- vs low-dose immunoglobulin therapy in the long-term treatment of X-linked agammaglobulinemia.

The data of 29 patients with X-linked agammaglobulinemia, who received immunoglobulin replacement therapy between 1965 and 1990, were analyzed for dose-dependent long-term results concerning infectious complications. Patients who received high-dose intravenous immunoglobulin replacement (greater than 400 mg/kg every 3 weeks) showed a significant increase in trough serum IgG levels and a significant decrease in the incidence of pneumonias and the number of days spent in the hospital compared with patients receiving intravenous immunoglobulin low-dose (less than 200 mg/kg every 3 weeks) or intramuscular immunoglobulin (less than 100 mg/kg every 3 weeks) treatment. Improvements in therapeutic outcome were particularly evident when high-dose intravenous immunoglobulin replacement therapy was started before the age of 5 years. Bacterial meningitis, chronic pulmonary disease, and bronchiectasis occurred in the intramuscular immunoglobulin group but did not occur in either of the intravenous immunoglobulin groups. High-dose intravenous immunoglobulin therapy may have a positive impact on the clinical course and may prevent severe complications in patients with X-linked agammaglobulinemia.

Penetration of Administered IgG into the Maxillary Sinus and Long-term Clinical Effects of Intravenous Immunoglobulin Replacement Therapy on Sinusitis in Primary Hypogammaglobulinaemia

The influence of long-term intravenous immunoglobulin (i.v. IgG) replacement therapy on the clinical course of chronic sinusitis in patients with primary hypogammaglobulinaemia has not previously been reported. We have analysed the efficacy of i.v. IgG therapy and the penetration of administered i.v. IgG into the maxillary sinus. Seventeen patients with primary hypogammaglobulinaemia received i.v. IgG replacement therapy to maintain pre-infusion serum IgG concentrations above 4 g/l for periods of 12 to 58 (mean 36.7) months. Cases with established chronic sinusitis prior to therapy did not have symptomatic or radiological improvement at this dose, although no sinusitis developed de-novo in the 3 previously unaffected patients. The administered IgG penetrated into maxillary sinus antral lavage fluid in 3 patients from whom secretions were obtained at antroscopy. This indicates that poor clinical responses are not due to lack of penetration of antibodies to the required sites of action. Larger doses of i.v. IgG may be more effective in this situation, but the addition of antibiotics at high dosage may be a more economical therapeutic alternative. These findings highlight the importance of diagnosis of hypogammaglobulinaemia by measurement of serum IgG concentrations in patients who suffer from recurrent sinusitis, as the early institution of i.v. IgG therapy may prevent the development of sinusitis refractory to i.v. IgG therapy.

Serum ALT levels in patients with primary hypogammaglobulinaemia receiving replacement therapy with intravenous immunoglobulin or fresh frozen plasma.

The intravenous immunoglobulin (IV. IgG) preparation used in this study is manufactured by the Scottish National Blood Transfusion Service (SNBTS) by the pH 4/mild pepsin method. Recent reports suggest that non-A, non-B hepatitis may be transmitted by certain intravenous immunoglobulin preparations. Serum ALT levels were therefore measured prospectively in 16 patients with primary hypogammaglobulinaemia who received an intravenous immunoglobulin replacement therapy (SNBTS IV IgG) over a period ranging from 6 to 25 months. Retrospective analysis of serum ALT levels was also carried out in 8 patients with primary hypogammaglobulinaemia who received fresh frozen plasma (FFP) for periods ranging from 8 months to 13 years. There was no evidence of non-A, non-B hepatitis transmission by either SNBTS IV IgG or by FFP in all the patients studied.