Further Outpatient Care
Avoid live viral vaccines for patients with agammaglobulinemia and any siblings or other children in the household because the attenuated virus is excreted and poses a threat to immunodeficient patients. The risk of vaccine-associated paralytic poliomyelitis increases 7000 times more than the normal risk of 1 case per 750,000. [79] If the patient has been exposed to a live viral vaccine, or if the live poliovirus has been given, obtain a stool culture to determine if the patient has the attenuated virus. Although most laboratories can determine the presence of an enterovirus, poliovirus identification requires sending the viral specimen to a state referral laboratory. Administer intravenous immunoglobulin (IVIG) and maintain serum immunoglobulin (Ig)G levels higher than 500 mg/dL.
Frequent monitoring of the patient's pulmonary status is important because the main long-term complication continues to be chronic lung disease. Regular measurements of pulmonary lung function should be obtained and high-resolution CT scanning of the lungs should be performed since bronchiectasis can develop (even in patients on chronic IVIG therapy). [80] If end-stage lung disease develops, lung transplantation has been performed in patients with agammaglobulinemia using intensive IVIG administration (every 48 h during the first 10 d after transplant).
Extensive diagnostic tests including cerebrospinal fluid (CSF) analyses with polymerase chain reaction (PCR) for viral genomes, neuroimaging, and electrophysiologic studies need to be pursued to evaluate for infectious or autoimmune complications.
Successful cure has been reported using stem cells from either cord blood or bone marrow from human leukocyte antigen (HLA)-matched siblings. [81]
Further Inpatient Care
Hospitalization has become unusual for patients with antibody deficiencies because home health organizations can provide intravenous antibiotics, pulmonary care, and nutritional interventions on an outpatient basis. Ig replacement therapy with either IVIG administered in outpatient clinics or SCIG at home to minimize interruptions of daily living is the mainstay of medical treatment.
The rationale for hospitalizing patients with immunodeficiency who are receiving IVIG replacement is usually to provide an adequate workup of a puzzling infection, to manage severe GI issues, to address acute pulmonary decompensation in the presence of chronic pulmonary disease, or to assess and treat severe autoimmune disorders.
Compared with others, patients who are treated have fewer acute overwhelming infections that require hospitalization.
Inpatient & Outpatient Medications
Administer IVIG to every patient with agammaglobulinemia. In rare circumstances (eg, temporary lack of venous access), intramuscular IgG can be given. Subcutaneous administration of IVIG is an option depending on individual preferences. A survey revealed that 90% of 1243 (1119) patients with primary immunodeficiencies in 16 countries receive IVIG in an inpatient setting, whereas 7% (87) are treated with subcutaneous Ig (SCIG), mainly at home. [82] However, this survey was performed before the SCIG preparation was available.
Because these patients risk developing unusual infections, attempt to identify any pathogens in either the respiratory or gastrointestinal tracts. More modern techniques using PCR helped diagnose Mycoplasma pneumoniae osteomyelitis in a patient with hypogammaglobulinemia with repeatedly sterile pus cultures.
For patients to have refractory Campylobacter jejuni infection longer than 2 years is not unusual, despite therapy with various antibiotics and IVIG preparations.
In patients with respiratory symptoms, analyzing bronchial samples obtained during bronchoscopy using traditional culture as well as PCR may help determine the various viruses and bacteria present.
Complications
Maintain IVIG and aggressively treat pneumonias with antibiotics to avoid chronic lung disease. Recurrent infections may eventually cause either obstructive disease alone or combined obstructive and restrictive lung disease. Aerosol treatments with bronchodilators and chest physiotherapy, such as postural drainage, may prevent further damage in these patients.
Although most children with agammaglobulinemia or early onset hypogammaglobulinemia develop recurrent bacterial respiratory tract infections during infancy, 20% of cases are diagnosed in children aged 3-5 years, reflecting the widespread use of antibiotics. Unfortunately, permanent damage to the lungs with bronchiectasis may have already occurred. [83]
This could be reflected in continued decline in pulmonary function testing. [84] However, increasing the dose may blunt this decline. As much as 42% of humoral or antibody deficiency may have bronchial hyperreactivity as measured by methacholine challenge testing. [85] The presence of bronchiectasis has also been found to correlate with continued risk for developing pneumonia despite immunoglobulin replacement therapy. [86]
No good studies have examined the effectiveness of aerosol treatments in these patients, although one may speculate that mobilization of secretions should help. Similarly, no good studies have examined the usefulness of prophylactic antibiotics, either systemically or topically (ie, aerosolized).
Unusual pulmonary disorders such as recurrent pulmonary alveolar proteinosis, which is not associated with any known infectious agent, have been seen in patients treated with IVIG. [87]
Chronic sinusitis may also result from repeated infections and subsequent structural changes. Chronic ear infections may result in hearing loss. A study indicated that as many as 38% of patients with primary antibody deficiency developed sensorineural hearing loss [88] and as many as 73% may have conductive hearing loss. [89] The prophylactic use of antibiotics was possibly associated with lower rates of audiological complications. Finally, watch for the development of mastoiditis.
Patients with low or absent Ig levels have increased risk of malignancy, especially in the lymphoreticular and GI organs, which may be the result of altered immune surveillance. The risk for malignancy in certain patients with immunodeficiency is estimated to be 100-300 times higher than in the general population. In one survey in Japan, approximately 2.7% of patients with primary immunodeficiency diseases developed malignant disorders. [90] Most are diagnosed when the patient is younger than 10 years, except for those whose immunodeficiencies developed later in life (eg, common variable immunodeficiency disease [CVID]).
Multiple neoplasms in the GI tract have been described in XLA. [91] Gastric adenocarcinoma has been described in one 15-year old male with autosomal recessive agammaglobulinemia. [92]
The association of hypogammaglobulinemia with thymoma is well recognized and is known as Good syndrome.
Reports of progressive neurodegeneration in patients with primary immunodeficiency on IVIG treatment are concerning. [93, 94] Extensive diagnostic tests including CSF analyses with PCR for viral genomes, neuroimaging, and electrophysiologic studies need to be pursued to evaluate for infectious or autoimmune complications.
Autoimmune diseases (eg, inflammatory bowel disease, atrophic gastritis, pernicious anemia) are also observed in patients with agammaglobulinemia or hypogammaglobulinemia. Their occurrence suggests that the altered immune system, with its low resistance to infectious pathogens, may cause an inappropriate hyperfunction toward self-antigens that cause autoimmune disorders.
Treatment of autoimmune complications may consist of increasing the dose of immunoglobulin replacement and/or steroids or rituximab. [95]
Prognosis
The outcome of patients with agammaglobulinemia or hypogammaglobulinemia depends on the underlying disease.
For patients with agammaglobulinemia, overall prognosis is good when patients comply with their IVIG or SCIG therapy and attend to the possible complications of chronic infections in the upper and lower respiratory tracts.
In a 10-year prospective study of children younger than 4 years with hypogammaglobulinemia, Dalal et al identified 3 groups: (1) those who developed normal Ig levels with specific antibody production, (2) those who developed normal IgG levels but only transient antibody production, and (3) those with persistently low IgG levels. [96] In a similar study with 8-year follow-up, Kidon et al (2004) found that 75% of children with hypogammaglobulinemia normalized their serum Ig levels (and were therefore diagnosed with transient hypogammaglobulinemia of infancy). [97] Finally, Kutukculer and Gulez followed a group of 37 patients with hypogammaglobulinemia and found 49% spontaneously corrected their immunoglobulin abnormalities with IgG or IgM levels reaching normal levels at about 5 years of age and IgA levels by about 6 years of age.
Cases of so-called "reversible hypogammaglobulinemia" have been reported in which adult patients on IVIG therapy resume immunoglobulin production. [98]
In studies of patients before IVIG treatment was developed, 75% of patients older than 20 years had developed chronic lung disease, and 5-10% had cor pulmonale.
Patient Education
Patients can be expected to attend school and hold jobs.
Two organizations offering scholarships to patients with immune disorders are the Immune Deficiency Foundation and the Jeffrey Modell Foundation. They are also excellent resources for the parents of a child with an immune deficiency disorder.
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Early stages of B-cell differentiation can be identified by the status of the immunoglobulin genes and by the cell surface markers CD34, CD19, and surface immunoglobulin (sIg). From: Conley ME. Genes required for B cell development. J Clin Invest. 2003;112: 1636-8. Reproduced with permission of American Society for Clinical Investigation via Copyright Clearance Center.
Tables
Brand(Manufacturer) |
Manufacturing Process |
pH |
Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].) |
Parenteral Form and Final Concentrations |
IgA Content (mcg/mL) |
Carimune NF (ZLB Behring) |
Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration |
6.4-6.8 |
6% solution: 10% sucrose, < 20 mg NaCl/g protein |
Lyophilized powder 3%, 6%, 9%, 12% |
Trace |
Flebogamma (Grifols USA) |
Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization |
5.1-6 |
Sucrose free, contains 5% D-sorbitol |
Liquid 5% |
< 50 |
Gammagard Liquid 10% (Baxter Bioscience) |
Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation |
4.6-5.1 |
0.25M glycine |
Ready-for-use liquid 10% |
37 |
Gammar-P IV (ZLB Behring) |
Cohn-Oncley fraction II/III; ultrafiltration; pasteurization |
6.4-7.2 |
5% solution: 5% sucrose, 3% albumin, 0.5% NaCl |
Lyophilized powder 5% |
< 20 |
Gamunex (Talecris Biotherapeutics) |
Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation |
4-4.5 |
Contains no sugar, contains glycine |
Liquid 10% |
46 |
Gammaplex (Bio Products) |
Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation |
4.8-5.1 |
Contains sorbitol (40 mg/mL); do not administer if fructose intolerant |
Ready-for-use solution 5% |
< 10 |
Iveegam EN (Baxter Bioscience) |
Cohn-Oncley fraction II/III; ultrafiltration; pasteurization |
6.4-7.2 |
5% solution: 5% glucose, 0.3% NaCl |
Lyophilized powder 5% |
< 10 |
Polygam S/D Gammagard S/D (Baxter Bioscience for the American Red Cross) |
Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated |
6.4-7.2 |
5% solution: 0.3% albumin, 2.25% glycine, 2% glucose |
Lyophilized powder 5%, 10% |
< 1.6 (5% solution) |
Octagam (Octapharma USA) 9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events |
Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization |
5.1-6 |
10% maltose |
Liquid 5% |
200 |
Panglobulin (Swiss Red Cross for the American Red Cross) |
Kistler-Nitschmann fractionation; pH 4 incubation, trace pepsin, nanofiltration |
6.6 |
Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl |
Lyophilized powder 3%, 6%, 9%, 12% |
720 |
Privigen (CSL Behring) |
pH 4 incubation; octanoic acid fractionation, depth filtration, and virus filtration |
4.6-5 |
10% solution; Preservative-free, sucrose-free, and maltose-free |
Ready-to-use solution 10% |
< 25 |
Brand(Manufacturer) |
Manufacturing Process |
pH |
Additives |
Parenteral Form and Final Concentrations |
IgA Content mcg/mL |
Vivaglobin (ZLB Behring) |
Cold ethanol fractionation, pasteurization |
6.4-7.2 |
2.25% glycine, 0.3% NaCl |
Liquid 16% (160 mg/mL) |
< 50 mcg/mL |
