History
All patients with Bruton agammaglobulinemia, now formally termed X-linked agammaglobulinemia (XLA), are males. More than 90% of affected males present with unusually severe or recurrent sinopulmonary infections. Meningitis, osteomyelitis, sepsis, and GI tract infectious (eg, gastroenteritis or diarrhea) are less common initial manifestations of XLA. [26]
The images below depict patients diagnosed with Bruton agammaglobulinemia.
This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.
Bruton agammaglobulinemia (ie, X-linked agammaglobulinemia [XLA]) in brothers. XLA was diagnosed in the less-robust younger brother when he presented with neutropenia and typhlitis. The older brother, with a history of 7 episodes of pneumonia, was then evaluated and diagnosed with XLA. In both brothers CD19- B cells were less than 1%; this finding is consistent with XLA.
Infants typically develop recurrent otitis media, pneumonia, and sinusitis before age 1 year but after 3 months. By mid childhood, chronic sinusitis becomes prevalent, and the prevalence of otitis media decreases.
Infectious agents involved are usually S pneumonia or H influenzae type b. Both are extracellular encapsulated bacteria. As patients become older, encapsulated bacteria continue to be the most common sources of infection, although staphylococcal infections must also be considered. Neisseria meningitidis and Moraxella catarrhalis, which is not encapsulated, are other bacteria whose portal of entry is the respiratory tract.
A chronic cough in a patient may indicate a risk for chronic pulmonary disease, which may be restrictive, obstructive, or both.
Infections due to Mycoplasma and Ureaplasma species have been reported in both adolescents and adults. In addition, organisms usually thought of as indicating T-cell immunodeficiency may be present, such as Pneumocystis jirovecii. [27]
The child may also have diarrhea that is not completely explained by frequent antibiotic use. Many patients have diarrhea caused by Giardia or Campylobacter species, and management of the diarrhea is difficult, even with appropriate therapy. [28]
Four types of gastrointestinal diseases can be described: infectious, malignancy, inflammatory, and autoimmune. [29]
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 with enteroviruses such as poliovirus, echovirus, and coxsackievirus.
Chronic bacteremia and skin infections caused by Helicobacter and related species (eg, Flexispira,Campylobacter) in patients with XLA are now appreciated. [30] Campylobacter infection can also be associated with a reactive arthritis in patients with XLA. [31]
Patients may present with vaccine-related poliomyelitis after immunization with the live poliovirus vaccine. [32] Although prolonged secretions of a virus have been described (up to 637 days postvaccination), based on 3 separate studies, poliovirus carrier status among people with primary immune deficiency appears to be rare and may not manifest with disease. Conversely, enteroviral infections are potentially fatal, irrespective of route of acquisition (ie, community acquired or acquired via the live poliovirus vaccine).
Katamura et al (2002) described nonprogressive viral myelitis in a patient with XLA and suggested that the prognosis of CNS infections in agammaglobulinemia is not based on the Ig level alone and that they are not always progressive or fatal. [33]
The use of intraventricular infusion of Ig has been well documented in XLA patients with CNS viral infection. However, the infusions have not been documented to prevent death caused by chronic enteroviral infection of the CNS.
Invasive fungal and other opportunistic infections remain rare, even in older patients with XLA and debilitating chronic lung or GI disease.
Autoimmune disorders may be associated with infections at the patient's initial presentation or may develop in older patients. Inflammatory bowel disease is particularly common. Other autoimmune disorders include cytopenias. Arthritis indistinguishable from juvenile rheumatoid arthritis (JRA) may be the presenting manifestation in patients with XLA. [34] Overall, 7-22% of patients with agammaglobulinemia develop joint manifestations. Reactive arthritis with Campylobacter coli infections is common. Enthesitis-related arthritis has also been described in a boy with XLA. [35] Other autoimmune disorder such as Kawasaki disease has been described in XLA. [36]
Evaluating for chronic infectious processes is essential. Mycoplasmal infection is a common cause of severe chronic erosive arthritis. Patients with mild cases rapidly respond to antimicrobial therapy, such as tetracycline. In more severe cases, arthritis may improve following treatment with IVIG. The need to always consider infectious etiology is further indicated by a case of XLA with JRA who developed invasive Klebsiella septic arthritis. [37]
Interestingly, malignancies are rare and are not currently a significant cause of mortality. The risk for XLA appears to be much less than the other immunodeficiency syndromes. Multiple neoplasms in the GI tract have been reported. [38]
A family history of other affected males should be sought because approximately one third of affected patients have an affected family member. [21] However, female carriers have no clinical manifestations related to their mutated allele.
Physical
Infants and older patients with XLA typically appear healthy. In healthy infants, lymphoid tissues such as tonsils and peripheral lymph nodes are poorly developed; therefore, the absence of these tissues is not noted until patients are toddlers. A poor local inflammatory response also compromises the usefulness of physical examination findings. For example, patients may have hypoplastic tonsils and lymph nodes that fail to undergo normal hypertrophy in response to infection. Therefore, physicians should suspect XLA in male infants who have unusually severe pneumonias associated with bacteremia or who have unusually frequent otitis media, chronic cough, or congestion. The last 2 symptoms typically respond to antibiotic therapy in a timely fashion but may soon recur.
In a study by Sikora and Lee (2003), up to 48% of patients developed sinusitis. Upon examination, patients may have hypoplastic tonsils and lymph nodes that fail to undergo normal hypertrophy in response to infection. [39]
Staphylococcal conjunctivitis and skin infections are less common than sinopulmonary infections, but they may also be part of the initial presentation in patients with XLA. These staphylococcal infections are less useful for discriminating XLA from other illnesses because they are frequently present in immunocompetent individuals and in individuals with other primary immunodeficiencies such as hyperimmunoglobulin E (hyper-IgE) syndrome and other antibody deficiencies.
Diarrhea caused by Giardia species is part of the classic presentation in any patient with antibody deficiency disease. Patients with XLA have an increased risk for other infectious etiologies of diarrhea, including Campylobacter jejuni, Shigella species, and Salmonella species. Infections due to these organisms seem to respond less well to medical therapy and also seem to become chronic more often in patients with antibody deficiency diseases than in others.
Rarely, patients with XLA also have a short stature caused by a deficiency in growth hormone. [40] A newly discovered mutation in myeloid elf-1–like factor may be responsible for the disease. [41] These patients must be distinguished from patients with XLA who have poor growth secondary to malnutrition.
Causes
As discussed in Pathophysiology, the disease is caused by impaired function of Btk. More than 600 mutations have been identified, ranging from single base pari substitutions to small insertions or deletions to gross deletions. [42] If a mutation in BTK cannot be found, the absence of BTK RNA or protein is considered the criterion standard for validating a diagnosis of XLA. Mutations of BTK account for 85-90% of patients with early-onset agammaglobulinemia and an absence of B cells.
Mutations in BTK are found in all areas of the gene. The pleckstrin homology region, the tyrosine kinase region, and areas referred to as Src homology domains (SH1, SH2, and SH3) are all important for gene function. Defects in these exons are most common. Splice defects that involve introns account for fewer than 20% of the abnormalities. Rare mutations in the promoter upstream region have been described. In some milder cases of XLA, the Btk protein is still present, although in a mutated form and in lesser amounts . However, no genotype-phenotype correlation has been found. Some studies suggest a genotype-phenotype correlation, specifically between genotype and age of disease onset as well as occurrence of severe infections [43] but other studies fail to find a correlation. [44, 45]
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This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.
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Bruton agammaglobulinemia (ie, X-linked agammaglobulinemia [XLA]) in brothers. XLA was diagnosed in the less-robust younger brother when he presented with neutropenia and typhlitis. The older brother, with a history of 7 episodes of pneumonia, was then evaluated and diagnosed with XLA. In both brothers CD19- B cells were less than 1%; this finding is consistent with XLA.
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 |
0.25 M 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 and sucrose- 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 |
