History
History in patients with agammaglobulinemia, or hypogammaglobulinemia, is similar to that for Bruton agammaglobulinemia because the patient is unable to produce functional humoral immunity. Patients may have problems with recurrent upper and/or lower respiratory tract infections or with chronic diarrhea. However, patients with mutations in the μ heavy chain and non-Btk mutations tend to develop symptoms earlier and are more likely to have severe symptoms.
Encapsulated bacteria with Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and pseudomonal species (in that order) cause most infections. Other bacteria, such as Salmonella and Giardia species, may also cause problems. Chronic bacteremia and skin infections by Helicobacter and related species such as Flexispira and Campylobacter in patients with X-linked agammaglobulinemia (XLA) are now appreciated. [19]
Almost three fourths of patients with agammaglobulinemia have infections occurring in the upper respiratory tract with otitis and sinusitis. Lower respiratory tract infections (eg, pneumonia, bronchiolitis), GI tract infections (eg, gastroenteritis), or both occur in more than two thirds of patients. Some have suggested obtaining immunoglobulin levels in all children with community-acquired pneumonia who require hospitalization may be cost effective. [20]
Other bacterial infections, such as pyoderma, sepsis, meningitis, osteomyelitis, and septic arthritis occur less frequently. Lower-grade pathogens, such as Pneumocystis carinii pneumonia, have also been reported. Additionally, sites of infection may be unusual with the encapsulated pyogenic bacteria, such as H influenzae lymphadenopathy or pneumococcal meningitis.
Although patients with agammaglobulinemia are usually able to handle viral infections, they are susceptible to certain viruses that replicate in the GI tract and then spread to the CNS. This indicates the importance of antibody production in limiting the spread of infections by enteroviruses such as poliovirus, echovirus, and coxsackievirus.
Patients may present with vaccine-related poliomyelitis after immunization with the live poliovirus vaccine. [21, 22] Although prolonged secretions of a virus have been described (up to 637 days after vaccination), poliovirus carriers among people with primary immune deficiency appears to be rare, based on 3 separate studies, and may not manifest with disease.
Alternately, echovirus infection of the CNS may cause chronic encephalomyelitis or meningoencephalitis. In 13 patients with primary hypogammaglobulinemia, Rudge et al (1996) described 3 clinical pictures: (1) progressive myelopathy in 1 patient, (2) myelopathy progressing to an encephalopathy in 4 patients, and (3) pure encephalopathy in 8 patients. [23] Enteroviral infection was found in 7 patients by either culture or polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF). However, Katamura et al (2002) described a nonprogressive viral myelitis in a patient and suggested that the prognosis of CNS infections in agammaglobulinemia is not determined by the immunoglobulin (Ig) level alone and that they are not always progressive or fatal. [24]
The use and potential efficacy of interventricular infusion of Ig have been well-documented in these patients. The use of an antiviral agent Pleconaril with intravenous immunoglobulin (IVIG) in these patients has been described. [25]
In addition, rare CNS disorders such as progressive multifocal leukoencephalopathy may present in patients with hypogammaglobulinemia. [26]
GI disorders such as chronic or acute diarrhea, malabsorption, abdominal pain, and inflammatory bowel diseases can all indicate immune deficiency. [27, 28]
Virus-induced autoimmune diseases such as a dermatomyositislike syndromes and chronic arthritis may also occur. These diseases suggest an element of dysregulated antibody production in their pathogenesis. In some cases, enteroviruses have been isolated from skin or joints. Therefore, any joint symptom should be suspected to be caused by various infectious agents in patients with humoral immunodeficiencies. Conversely, noninfectious arthritis may indicate an underlying autoimmune disorders such as lupus or rheumatoid arthritis. [29]
Mycoplasma or Ureaplasma organisms may play a role in other cases of chronic arthritis. In a survey of 358 patients with primary antibody deficiency, mycoplasmal infection was the most common cause of severe chronic erosive arthritis. Patients with mild cases rapidly respond to antimicrobial therapy, such as tetracycline. In more severe cases, arthritis improved following treatment with intravenous Ig. Overall, 7-22% of patients with agammaglobulinemia develop joint manifestations. Reactive arthritis with Campylobacter coli infections is also common. Various types of arthritis such as psoriatic, enthesitis-related, septic, and relapsing polychondritis have all been described. [30, 31]
Always consider that infections may mimic autoimmune arthritis in patients with hypogammaglobulinemia (eg, Mycoplasma). [32]
Enthesitis-related arthritis has also been described in a boy with XLA. [33]
The constellation of symptoms in a family of brothers with leukoencephalopathy, arthritis, colitis, and hypogammaglobulinemia prompted some to label this the LACH syndrome. [34]
Other associated autoimmune disorders most commonly include hematological manifestations (eg, thrombocytopenia, hemolytic anemia, neutropenia), alopecia totalis, glomerulonephritis, protein-losing enteropathy, malabsorption with disaccharidase deficiency, and amyloidosis.
Hypogammaglobulinemia has also been described in the immediate period following transplantation of intestines, kidneys, liver, and lungs. [35, 36, 37] Most likely it is secondary to the immunosuppressive therapy required for transplantation, and restoration of humoral immunity with IVIG decreases the number of infectious complications [38]
Other patients in whom measurements of Ig may be helpful include those with renal dialysis and patients in pediatric ICUs. In the former, IgG and IgG subclass deficiency were found in 8 out of 12 children undergoing continuous ambulatory peritoneal dialysis. [39] Similarly, total IgG levels were below the reference range for age in 14 of 20 patients admitted to a pediatric ICU. [40] However, these studies included a small number of subjects.
A new syndrome has been described warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome. These patients also have neutropenia and a tendency to develop B-cell lymphoma.
Physical
Patients with agammaglobulinemia appear to be healthy between bouts of infections. Patients usually do not fail to thrive, although chronic diarrhea, if present, could cause some dehydration and malabsorption. Any abnormal physical findings indicate presence of various infections for which patients have increased susceptibility. Concomitant short stature in a male suggests X-linked hypogammaglobulinemia with growth hormone deficiency syndrome.
Most patients with agammaglobulinemia were recognized to have immunodeficiency during or shortly after their first hospitalization for infection. Most of the patients had a history of recurrent otitis or upper respiratory tract infection at the time of diagnosis, which when combined with the physical finding of markedly small or absent tonsils and cervical lymph nodes, should alert physicians to the diagnosis of agammaglobulinemia.
Some patients have cutaneous manifestations representing several unique syndromes. One of these is known as WHIM syndrome, consisting of warts, hypogammaglobulinemia, infections, and myelokathexis. The gene responsible for this syndrome has been identified as a chemokine receptor CXCR4. [41]
The concomitant occurrence of hypogammaglobulinemia and thymoma is known as Good syndrome. [42] These patients appear to have more severe cellular deficiency with the possibility of opportunistic infections.
Causes
Genetic factors have included mutations of Btk only (accounting for 85-90% of patients with early onset agammaglobulinemia and absence of B cells). The remaining cases in males and females are clinically similar to XLA and represent mutations affecting the IGHM, CD79AA, and IGLL1 genes involved in the composition of the pre-BCR or the BLNK gene involved in pre-BCR signal transduction. Patients who do not have XLA may have other defects that result in an arrest of B-cell differentiation at a pro–B-cell level (before the onset of Ig gene rearrangements) or defects in an adjacent gene to the Btk gene responsible for growth hormone production (XLA with growth hormone deficiency).
Other genetic factors do not involve the Btk gene (which would be Bruton’s X-linked agammaglobulinemia) but involve other genes for the µ heavy chin, Igα, Igβ, λ, B-cell linger (BLNK), leucine-rich repeat-containing 8 (LRRC8), CD79a, transcription factor E47 or the p85α subunit of phosphoinositide 3-kinase (PL13K).
A female has been described with a translocation involving a new gene in chromosome 9 (LRRC8) that resulted in a block in B-cell differentiation at pro–B-cell to pre–B-cell transition. [43] She had minor facial anomalies and congenital agammaglobulinemia and absent B cells in peripheral blood.
Patients with mutations in the μ heavy chain usually present initially around 4 months of age with pneumonia, otitis, gastroenteritis, chronic enterovirus encephalitis, and septic shock with Pseudomonas aeruginosa infection. One 15-month-old child presented with fever, weakness, rash, and neutropenia 2 weeks after an oral poliovirus vaccine.
One newborn girl with mutation in the Ig-α gene developed recurrent diarrhea and failure to thrive in the first month of life. By age 1 year, she had chronic bronchitis.
One infant boy with mutation in the λ light chain had recurrent otitis media at age 2 months. At age 3 years, he had H influenzae meningitis with arthritis.
Three cases of Igβ deficiency have been reported, the most recent presenting with neutropenia, ecthyma, and mild respiratory infections. [44]
One boy with a BLNK defect presented with overwhelming sepsis during childhood. With intravenous immunoglobulin (IVIG) treatment, he survived to adulthood without any growth or developmental delay.
Five cases of autosomal recessive agammaglobulinemia involving a mutation in CD79a have been described, one presenting with an invasive CNS infection. [45]
Four patients with decreased number of peripheral B cells and mutation in the transcription factor E47 and possible autosomal dominant form of agammaglobulinemia have been described. [46]
Other patients have been described with reduced pro-B cells but no identifiable molecular defect. One was a 4-month-old infant girl with failure to thrive, recurrent otitis, candidiasis, H influenzae arthritis, and herpes simplex stomatitis. Another girl had microcephaly, persistent diarrhea, failure to thrive, and recurrent respiratory and gastrointestinal infections. This patient eventually developed pancytopenia with progressive bone marrow failure.
Finally, hypogammaglobulinemia (with almost absent B cells) has been described in several patients with specific dysmorphic features, and limb anomalies and labeled as Hoffman syndrome. [47]
In a detailed study performed in China of 21 children with congenital agammaglobulinemia, mutations of in Btk was identified in 18 patients. [48] A compound heterozygote mutation in the IGHM gene was found in one patient. No molecular etiology was found in the other two.
Also, certain infections and drugs may result in low or absent Ig levels. In a survey of laboratory values indicating hypogammaglobulinemia, patients with IgG levels less than half of the lower limit for age revealed 33% with a primary immune deficiency. [49] Secondary hypogammaglobulinemia was found most often due to chemotherapy or from complex cardiac anomalies, malignancy, or autoimmune disorders.
Certain viral infectious have been shown to cause transient or permanent immune deficiency.
Congenital rubella infection can cause hypogammaglobulinemia. Although infection with human immunodeficiency virus (HIV) usually causes hypergammaglobulinemia, hypogammaglobulinemia has been reported in some pediatric cases.
Patients with X-linked lymphoproliferative syndrome (ie, Duncan disease, Purtilo syndrome) may develop overwhelming disease with infection by Epstein-Barr virus with subsequent agammaglobulinemia and a decrease in B cells. Therefore, any male with persistent hypogammaglobulinemia following mononucleosis should be closely monitored for X-linked lymphoproliferative disease.
Drug-induced hypogammaglobulinemia has been described with immunosuppressive agents (eg, corticosteroids, rituximab [50, 51] ), epilepsy medications (eg, phenytoin, carbamazepine [52] ), and antipsychotic medications (eg, chlorpromazine). Recurrent infections and reduced serum Ig levels resolved when the medication was stopped. However, this may take some time and require IVIG in the interim. [53]
IgG levels should be determined in patients with drug rash with eosinophilia and systemic symptoms (DRESS). [54]
Oral prednisone at a dose of at least 12.5 mg/d for patients with asthma has been shown to be able to cause hypogammaglobulinemia. [55] Hypogammaglobulinemia is also frequently seen in steroid-sensitive nephrotic syndrome. Therefore, in patients with autoimmune diseases such as systemic lupus erythematosus who are being treated with prednisone and other immunosuppressive medications, the hypogammaglobulinemia could be due to either medication use or could reflect the underlying autoimmune process.
Some have speculated on the association between anticonvulsant hypersensitivity syndrome (a life-threatening, drug-induced, multiorgan system reaction) with herpesvirus reactivation and hypogammaglobulinemia.
Speculation that phenytoin-induced suppressor T-cell activity and subsequent antibody deficiency has found some support with in vitro experiments.
Malignancies such as leukemias, multiple myeloma, and neuroblastoma may also manifest hypogammaglobulinemia.
The association of hypogammaglobulinemia associated with thymoma is known as Good syndrome. [56] The most common autoimmune disorder associated with hypogammaglobulinemia is systemic lupus erythematosus. [57, 58] As noted above, antibody deficiency must be distinguished from an underlying condition versus drug-induced or renal losses.
Body losses of protein may result in hypogammaglobulinemia. A case was reported of agammaglobulinemia due to protein losses through the skin in a patient with exfoliative dermatitis. [59] Excessive protein loss from the GI tract may result in hypogammaglobulinemia; however, primary antibody deficiency may also cause chronic diarrhea. Therefore, any protein-losing enteropathy should be considered in patients presenting with hypogammaglobulinemia. In these situations, specific antibody responses are intact, and circulating B cells are normal. About 4% of patients with malabsorption syndrome have been found to have hypogammaglobulinemia. [60] Concomitant infections such as with Giardia have been described and need to be treated. [61]
On the other hand, GI protein loss may also occur from lymphatic obstruction in diseases such as intestinal lymphangiectasia. Concomitant loss of lymphocytes into the intestinal tract may result in lymphopenia.
Similarly, patients with chylothorax also have hypogammaglobulinemia (IgG = 179 ± 35 mg/dL) and lymphopenia (985 ± 636 cells/μL). [62]
Cow's milk allergy may also result in hypogammaglobulinemia, possibly due to immunoglobulin leakage through inflamed GI mucosa. [63] Avoidance of the allergen resulted in normalization of immunoglobulin levels.
Hypogammaglobulinemia has also been described in the immediate period following transplantation of intestines, kidneys, liver, and lungs. [35, 36, 37] Most likely it is secondary to the immunosuppressive therapy required for transplantation and restoration of humoral immunity with IVIG decreases the number of infectious complications in these patients. [38]
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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 |
