Pediatric Bruton Agammaglobulinemia 

Updated: Mar 18, 2019
Author: Terry W Chin, MD, PhD; Chief Editor: Harumi Jyonouchi, MD 

Overview

Background

Bruton agammaglobulinemia (see the image below) was the first primary immunodeficiency disease to be described. In 1952, Colonel Ogden Bruton noted the absence of immunoglobulins (Ig) in a boy with a history of pneumonia and other bacterial sinopulmonary infections.[1] Bruton was also the first physician to provide specific immunotherapy for this X-linked disorder by administering intramuscular injections of IgG. The patient improved but succumbed to chronic pulmonary disease in his fourth decade of life. Several historical reviews have been recently written.[2, 3]

This patient presented with recurrent otitis and a 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.

This disorder is now formally referred to as X-linked agammaglobulinemia (XLA), and the gene defect has been mapped to the gene that codes for Bruton tyrosine kinase (Btk) at band Xq21.3. The BTK gene is large and consists of 19 exons that encode the 659 amino acids that form the Btk cytosolic tyrosine kinase. Mutations can occur in any area of the gene. Btk is required for the proliferation and differentiation of B lymphocytes.[4, 5, 6]

In the absence of functional Btk, mature B cells that express surface Ig and the marker CD19 are few to absent. The absence of CD19 is readily detected with fluorocytometric assays, and this finding usually easily confirms the diagnosis of XLA in a male. As Bruton originally described, XLA manifests as pneumonia and other bacterial sinopulmonary infections in 80% of cases.[1] Such infections that begin in male infants as maternal IgG antibodies, acquired transplacentally, are lost. Thus, XLA is most likely to be diagnosed when unusually severe or recurrent sinopulmonary infections occur in a male infant younger than 1 year.

In some individuals, the diagnosis is delayed into adulthood. In some cases, this delay can be explained by the variable severity of XLA, even within families in which the same mutation is present. However, a significant contributing factor is the deceptively poor inflammatory response seen in the absence of antibodies. Delayed diagnosis puts patients at risk for chronic pulmonary disease and poor growth, leading to mortality at a younger age. Encapsulated bacteria, most commonly Streptococcus pneumoniae, followed by Haemophilus influenzae type b and staphylococcal species, are the typical pathogens.

Pathophysiology

In the absence of mature B cells, patients lack lymphoid tissue and fail to develop plasma cells, the cells that manufacture antibodies. Germinal centers where B cells proliferate and differentiate are poorly developed in all lymphoid tissue, including the spleen. Tonsils, adenoids, peripheral lymph nodes, and Peyer patches in the intestines are all small or absent. The lungs and the lamina propria of the gut lack the normal pattern of lymphocyte distribution. However, biopsy of lymphoid tissue and bone marrow examination are not currently performed in the workup of most cases of XLA.

Animal models of human BTK mutations are confined to mice at this time. Mouse models have milder disease than humans. However, murine models, including knockout and transgenic mice, have been useful in understanding the mechanisms of B lymphopoiesis, B-cell differentiation, and antibody formation. Murine gene mutations in human counterparts may be associated with a clinical illness different from the illness seen in mice.

Bruton's tyrosine kinase (Btk) is a member of the Tec family of kinases. Activation of Btk results in a cascade of signaling events resulting in calcium mobilization and fluxes, cytoskeletal rearrangements, and transcriptional regulation involving nuclear factor-kappaB (NF-kappaB) and nuclear factor of activated T cells (NFAT). Its activation is tightly controlled by numerous other signaling proteins including protein kinase C (PKC), Sab/SH3BP, and caveolin-1.[7]

Although defects may occur in many steps in B-cell development and maturation, resulting in agammaglobulinemia, the most common and well-described defect is the impaired maturation of the pro–B cells to pre–B cells. In the fetal bone marrow, the first committed cell in B-cell lineage is the early pro–B cell, which is identified by its ability to proliferate in the presence of interleukin (IL)-7. These cells develop into late pro–B cells, in which rearrangement of the heavy chain occurs. This rearrangement process requires the recombination-activating genes (ie, RAG1 and RAG2); their enzymatic activities are controlled by IL-7 and, perhaps, by other factors.

When the heavy chain is produced, it is transported to the cell surface by IgA (CD79a) and IgB (CD82) heterodimers or by the surrogate light chain. Progression from this late pro–B-cell stage to the pre–B-cell stage involves the rearrangement and joining of the various segments of the heavy chain. The completion of light- and heavy-chain rearrangement and the presence of surface IgM results in an immature B cell, which then leaves the bone marrow.

Increasing levels of IgD in the transitional cells finally results in the mature B cell, with both IgM and IgD expressed. The mature B cells circulate between secondary lymphoid organs and migrate into lymphoid follicles of the spleen and lymph nodes in response to further stimuli and various chemokines. T cells stimulate B cells to undergo further proliferation and Ig class switching, leading to the expression of the various isotypes of Ig (ie, IgG, IgA, or IgE). Activation of the B-cell receptor (BCR) induces the recruitment of Syk, which phosphorylates BLNK, a contributor to the activation of BTK that affects other intracellular signaling events.

Murine B-cell proliferation and differentiation is under the control of BTK, as well as SYK; PAX5; and genes that code for l5, Ig-a, Ig-b, g chain of IL-2 receptor (IL-2Rg), lyn, and bcl-2. Mutations in these mouse genes and in the mouse gene for Btk lead to milder forms of B-cell deficiency compared with that of humans with BTK, m heavy-chain (µH), or l5 mutations.

Mutations in the murine IL receptor common g chain also cause mild B-cell deficiency in mice. In contrast, mutations in the human IL common g chain cause X-linked severe combined immunodeficiency (SCID), with normal-to-high levels of B cells expressing CD19. These findings indicate that a defect in any of the steps in B-cell development may be clinically important. Approximately 85% of patients with defects in early B-cell development have XLA.

The vital role of Btk in Toll-like receptor (TLR) signaling has been supported by several lines of evidence. Although patients with XLA have normal numbers of circulating dendritic cells, a profound impairment of IL-6 and tumor necrosis factor (TNF)-a production is observed in response to the TLR8 agonist ssRNA.[8, 9] This may provide an explanation for their increased susceptibility to enteroviral infections. Others have also found defective TLR2, TLR4, and TLR7/8–induced TNF-a production.[10] Btk is involved in TLR9 activation and expression[11] and TLR-induced IL-10 production.[12] Subsequent involvement of other immune cells such as NK may be effected by Btk regulation of IL-12 and IL-18 production.[13] It may be that Btk is required for hem oxygenase-1 gene activation by major TLR pathways.[14]

On the other hand, mutations in the Btk gene do not always result in X-linked agammaglobulinemia, and measurements of actual Btk protein blood levels and/or measurements of B-cell numbers, as well as more advanced genetic assays, may be needed to confirm the diagnosis.[15]

More than 600 patients with mutations in Btk involving all functional domains have been reported, and additional new disease-causing variants continue to be discovered. Insertions and deletions of less than 5 bp and single-base-pair substitutions are responsible for more than 90% of documented mutations.

Epidemiology

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Frequency

United States

The estimated birth rate of XLA in the United States was calculated to be 1 case per 379,000 live births. A prevalence of 1 case per 250,000 individuals has been estimated in the United States. However, this number was reviewed prior to the availability of mutational analysis and is generally considered to be an underestimate. New mutations are believed to cause 30-50% of XLA cases.

International

Geneticists believe that the prevalence of XLA is similar among most ethnic groups. The prevalence of XLA in Eastern and Central Europe is 1 per 1,400,000.[16] Data from France have suggested a prevalence of 1 case per 70,000-90,000 population. The greater frequency in France may well be related to more accurate acquisition of statistics. Black, Japanese, and Malaysian populations have lower reported frequencies of clinical XLA, but whether these frequencies are accurate is debatable because of the genetic mechanisms that cause XLA.

The specific mutations of Btk have been examined in Mexican,[17] Brazilian,[18] Iranian,[13] and Chinese[19] populations. The experience of a single center in India has been published.[20]

Mortality/Morbidity

Patients who received intravenous IgG (IVIG) before age 5 years have lower morbidity and mortality rates than previously identified patients who were treated only with fresh-frozen plasma (FFP) and intramuscular Ig (IMIG); achieving IgG levels near normal or even above 200 mg/dL is difficult using FFP or IMIG. Patients who receive IVIG or subcutaneous IgG (SCIG) therapy regularly may have a near-normal lifestyle. Patients are known to survive into their seventy's year of life.

Viral and pulmonary infections cause more than 90% of mortalities.

Chronic enteroviral infections are the most common etiology for early morbidity. High-dose IVIG or Ig administered intrathecally has slowed, but not stopped, the progression of CNS deterioration. Dementia, ataxia, and paresthesias are the common clinical features of meningoencephalitis due to enteroviruses. Other viral causes of death are sporadic. Adenoviruses are well-recognized causes of morbidity and mortality in any patient with immunocompromise. Hepatitis viruses are also a risk; hepatitis C has been transmitted by IVIG preparations with inadequate viral inactivation processes. Overall, viral infections resulted in one half of the deaths that occurred in 3 series.

Pulmonary infections, both acute and chronic, account for most other deaths. Recurrent pulmonary infections frequently lead to bronchiectasis. Common causative agents include S pneumoniae, H influenzae type b, and Staphylococcus aureus. Burkholderia cepacia and coagulase-negative staphylococci are other significant bacterial agents.

If present, inflammatory bowel disease is usually chronic in XLA and leads to malnutrition and cachexia and further increases the risk of infection. Other autoimmune disorders such as arthritis can be especially disabling. In patients with these complications, examining for involvement of microbial pathogens is important because treatment with immunosuppressive medications may complicate their management.

Race

Most investigators have studied northern European populations. Although black, Japanese, and Malaysian populations are reported to have lower risks for XLA, geneticists doubt the accuracy of these statistics. Recently, more reports have detailed Asian[21, 22] and Arabic populations.[23]

Sex

XLA is a disorder that affects only males. No carrier female with any clinical illness related to the mutated allele has been identified. Girls with absent mature B cells may have autosomal recessive mutations that affect gene products other than those of BTK (see Agammaglobulinemia).

Age

Because XLA is a genetic disorder, male infants can be identified with prenatal diagnosis when the mother has been identified as a carrier. Chorionic villus sampling (CVS) can be performed early in pregnancy, and DNA analysis can be used when the family's exact mutation is known. Amniocentesis can be performed later in gestation. Collection of fetal lymphocytes through in utero umbilical cord sampling can be used to enumerate CD19+ B cells and mature T cells using fluorocytometric analysis, although this procedure places the fetus at some risk for mortality (ranging from < 1-5%). At birth, cord blood can be sent for fluorocytometric analysis of lymphocyte populations. Quantitative IgG levels are not useful; cord and fetal IgG levels largely reflect maternal IgG transported across the placenta.

Because of passive transplacental acquisition of maternal IgG, newborns have normal serum IgG levels and may not have problems until the IgG is catabolized. Because newborns cannot produce their own Ig, increased susceptibility to infections usually develops in infants older than about 6 months. Therefore, patients with XLA can clinically present when they are aged 3 months to 5 years. Most cases of XLA are now identified in patients younger than 1 year, depending on the rate of maternal-derived IgG loss and occurrence of infections. The average age of diagnosis is younger in patients with a family history (2.6 y) than in those without (5.4 y).

Patients may also present in the second or third decade of life, although this is uncommon. The oldest age at diagnosis was 51 years. These patients may have milder disease related to the presence of mutated Btk protein rather than complete absence of the protein. Rarely, the individual has mild disease while others with the same mutation have more severe clinical illness.

New content

Primary Agammaglobulinemia is a rare disorder that occurs almost exclusively in males although some females have been affected by certain types of this disorder. The incidence of XLA in the United States has been estimated to be at least 1/190,000 male births. The age of onset of symptoms for most patients is between 3 months and 3 years, with over 50% of patients becoming symptomatic by 1 year of age and more than 90% of patients becoming symptomatic by 5 years of age.[24, 25]

 

Presentation

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 a 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 agammaglob 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]

 

DDx

Diagnostic Considerations

Diagnosing Bruton agammaglobulinemia, formally termed X-linked agammaglobulinemia (XLA), in male infants requires the determination of a mutation in the Btk protein. However, in clinical practice, in a male with low IgG levels, combined T-lymphocyte and B-lymphocyte deficiency needs to be excluded. Diagnosis of severe combined immunodeficiency requires immediate intervention to allow stem cell transplantation or even gene therapy. Therefore, flow cytometric measurement of T-lymphocyte and B-lymphocyte populations and T-cell function assays are essential to rule out a broader defect of cell-mediated immunity.

Usually, absent CD19+ B cells in a male with hypogammaglobulinemia is sufficient to make the diagnosis, especially if there is a positive family history. However, some estimates suggest approximately 30% of patients who have a Btk mutation have normal protein expression. This is related to the position of the mutation in the gene and the antibody used for flow cytometric analysis. In addition to clinical correlation, genetic testing is recommended to confirm the diagnosis of XLA.

Most clinical laboratories can now perform both (BTKFP/89742 Bruton's Tyrosine Kinase (BTK) Genotype and Protein Analysis, Full Gene Sequence and Flow Cytometry). If a familial mutation has already been identified, then a limited panel can be ordered (BTKMP/89740 Bruton's Tyrosine Kinase (BTK) Genotype and Protein Analysis, Known Mutation Sequencing and Flow Cytometry).

In patients with no other affected family members, autosomal forms of agammaglobulinemia must be considered when the CD19 expression on B cells is minimal in a male patient (although 30-50% of XLA cases are believed to arise from new mutations). Mutations in the genes for the 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) are unusual etiologies for agammaglobulinemia with absent CD19+ B cells. For more information, see Agammaglobulinemia.

Other primary immunodeficiency diseases occasionally need to be considered, but assessment of B- and T-lymphocyte markers almost always allows the distinction of XLA from other disorders. Patients with X-linked hyper-IgM or common variable immunodeficiency (CVID) may appear clinically similar to patients with XLA.

Growth hormone deficiency associated with absent B cells is rare. Mutations in BTK may or may not be found in these patients.

Differential Diagnoses

 

Workup

Laboratory Studies

Measurement of IgG using quantitative techniques such as nephelometry supports the diagnosis of X-linked agammaglobulinemia (XLA) when the IgG level is less than 100 mg/dL. Confirmation of XLA requires low (< 1%) or absent expression of CD19+ lymphocytes with of normal-to-increased numbers of mature T lymphocytes.

Quantitative measurements of IgG, IgM, IgA, and IgE are readily available and inexpensive and require little blood.

IgG levels are less than 100 mg/dL in most patients with XLA who are aged 6 months or older. However, in some patients with XLA, IgG levels may be as high as 200-300 mg/dL. Unlike IVIG, IMIG administration does not significantly affect this level.

IgM and IgA are usually undetectable in patients of any age. In patients with XLA, levels are usually far below age-related reference ranges; however, in mild cases of XLA and in other antibody deficiencies, Ig levels must be carefully compared with age-related reference ranges.

IgG subclass levels are not usually required because the total IgG is severely deficient. Determination of functional antibody levels as noted below is more appropriate in the rare case in which the total IgG level is indeterminate.

Absent or low (< 1%) CD19+ B cells confirm the diagnosis of XLA in male patients. Numbers of CD4+ and CD8+ T cells are often increased or sometimes normal, but they are rarely low. Low T-cell percentages suggest a diagnosis of SCID or another T-cell disorder. In an infant or child, the presence of low absolute T-cell numbers suggests a form of SCID, not XLA. An inverted CD4/CD8 T-cell ratio occurs in some types of SCID and in human immunodeficiency virus (HIV) infection.

Confirmation of XLA involves molecular diagnostic studies to measure the amount of Btk protein levels in platelets or monocytes and sequence analysis of the Btk gene. If sequencing does not detect a Btk mutation in a patient with absent Btk protein deletion/duplication analysis should be performed to detect mutations occurring outside the coding regions such as mutations in the promoter region. Such a mutation has been described which resulted in defective binding of the transcription factor PU.1, leading to defective transcription of Btk. However, a small subset of patients with XLA have normal protein expression. Additionally, detection of a mutation in Btk gene does not always result in phenotypic XLA.

A definitive diagnosis for XLA can be assumed in any male subject with less than 2% CD19+ cells and 1 of the following: (1) a mutation in Btk, (2) absent Btk mRNA on Northern blot analysis, (3) absent Btk protein in monocytes or platelets; and (4) maternal male cousin, uncles, or nephews with less than 2% CD19+ cells. Patients meeting these criteria account for approximately 85% of cases of agammaglobulinemia. About 5-10% have mutations in genes associated with the autosomal recessive forms. In the remaining 5% of cases, an ill-defined defect is likely because normal levels of Btk protein are seen.

Imaging Studies

Plain radiographic studies may contribute to the diagnosis of XLA but are not an essential part of the workup. Plain radiography of the head may reveal the absence of tonsillar and adenoid tissues. Chest radiographs may be used to diagnose more extensive infection or a chronic infection that is not clinically apparent.

Imaging studies are primarily used to assess chronic sinopulmonary disease.

CT scanning of the sinuses and the lungs is more effective than plain radiography in documenting disease progression in these locations. One study found bronchiectasis in 58% patients with agammaglobulinemia.[46] Their presence appears to increase the likelihood of pneumonia and decreasing lung function.

Some physicians advocate using brain MRI in patients with agammaglobulinemia or hypogammaglobulinemia who develop unexplained neurological symptoms and signs of meningeal inflammation despite extensive investigation of cerebral spinal fluid (CSF), including polymerase chain reaction (PCR) analyses.

Delayed bone age is evident in patients with growth hormone deficiency.

Other Tests

The slowly progressive nature of chronic lung disease makes pulmonary function tests (PFTs) essential in XLA. These tests include spirometry, diffusion capacity tests, and lung volume tests. They are recommended annually. Children younger than 5 years may not be able to reliably undergo these tests but some centers perform infant PFTs and/or impulse oscillometry.

PFT findings are evaluated upon diagnosis because the literature suggests that decreased parameters upon diagnosis of hypogammaglobulinemia correlate with chronic and progressive pulmonary disease such as bronchiectasis.[47]

Both restrictive and obstructive patterns of chronic lung disease may occur in antibody deficiency diseases.

Procedures

Bronchoscopy is an important adjunct for diagnosing pulmonary infections because it obviates most contamination with mouth flora and because it can be used to procure sputum from infants and others who are unable to voluntarily cough it out.

Examination of the GI tract using endoscopy and colonoscopy is necessary to assess the extent of inflammatory bowel disease. The biopsy results, videotapes, and photographs obtained from these procedures can be used to delineate the disease.

Histologic Findings

Inflammatory responses are the most common findings in tissue biopsy samples obtained to evaluate infection.

Inflammation is usually nonspecific and is not helpful in distinguishing specific infectious agents.

The presence of pleocytosis in the spinal fluid is a special circumstance in which inflammation is associated with specific infection by an enterovirus.

Lymphoid tissues lack germinal centers, and plasma cells are absent in bone marrow and the lamina propria of the gut.

 

Treatment

Medical Care

Until gene therapy becomes developed,[48] the mainstay therapy for Bruton agammaglobulinemia, formally termed X-linked agammaglobulinemia (XLA), and other primary antibody deficiencies is to replace immunoglobulin (Ig). Aggressive treatment with antibiotics for bacterial infections may prevent long-term complications. Live viral vaccines (eg, measles, mumps, rubella [MMR]) are contraindicated in these patients and their families because they may cause vaccine-related infections. On the other hand, it has been demonstrated that the dendritic and T-cell responses are normal toward influenza in patients with XLA after administration of inactivated trivalent influenza vaccine.[49]

IVIG administration has supplanted IMIG injections in most instances.[50] SCIG administration is also possible and offers the advantage of providing IgG levels that are relatively constant compared with the peaks and troughs observed with monthly intravenous therapy.

Numerous studies have shown that IVIG and SCIG given in equal doses provide equal infection prevention in patients with primary antibody deficiency syndromes.[51] A major advantage is that SCIG can be administered at home. However, subcutaneous administration causes frequent local discomfort in various sites in the abdomen, thighs, upper arms, and/or lateral hips. In addition, whether home health care is appropriate for each patient must be evaluated. Not only is compliance an issue, but the lack of close medical observation is also a concern because these patients no longer need to come to the hospital for monthly infusions.

IVIG results in improved clinical status with a decrease in serious infections, such as pneumonia, meningitis, and GI infection. IVIG doses are usually 400-600 mg/kg/mo or more. The administration interval is usually every 3-4 weeks, based on the average IgG half-life of 21-28 days. The dose and interval are chosen based on the clinical response. Maintaining a trough serum IgG level of approximately 500-800 mg/dL is necessary.

Clinical situations in which higher IVIG doses are given include, but are not limited to, chronic pulmonary infection and chronic enteroviral infection. Therefore, patients with bronchiectasis may need higher doses (eg, 600 mg/kg). Because of the blood-brain barrier, patients with viral meningitis may require 1000 mg/kg.

For SCIG administration, 14 days of 200 mg/kg body weight resulted in serum IgG levels of more than 7 g/L and was tolerated well in adult patients with XLA and CVID.[52, 53]

Antibiotics are frequently required to manage the infectious complications of antibody deficiencies. Obtain appropriate cultures to identify causative microorganisms and to establish sensitivities; these results allow for optimal antibiotic therapy. In patients with chronic upper or lower respiratory tract infections and subsequent structural changes, strategic long-term broad-spectrum antibiotics may be needed, in addition to chest physiotherapy and sinus surgery.

Because most infections are sinopulmonary and involve encapsulated bacterial agents, first-line oral antibiotics include amoxicillin, amoxicillin/clavulanate, and cefuroxime axetil. Intravenous ceftriaxone may be required for chronic pulmonary infection, acute severe pneumonia, or sepsis.

As with other patient populations, the risk for penicillin-resistance among S pneumoniae is an increasing concern; ceftriaxone, cefotaxime, and vancomycin are used to treat penicillin-resistant organisms.

Less frequent, but significant, infectious agents include Mycoplasma and Ureaplasma species; these organisms are best treated with clarithromycin, which is generally better tolerated than erythromycin in terms of adverse GI effects. Clarithromycin is more effective than azithromycin.

Antibiotic therapy for antibody deficiencies is in the high end of the dose range for immunocompetent individuals, and the duration is the same or longer. Some clinicians advocate rotating the use of antibiotics in select patients with bronchiectasis and frequent exacerbations.

Opportunistic organisms are uncommon in XLA, but the risk of infection is increased, particularly in the presence of chronic debilitating pulmonary disease or (more rarely) chronic colitis. Pneumocystis carinii and B cepacia can be etiologic agents in these settings. Trimethoprim-sulfamethoxazole is the first-line drug for both.

Recently released antibiotics such as linezolid for penicillin-resistant pneumococci are presumably effective, although results in primary immunodeficiency diseases are not yet published.

Many infections require interventions in addition to antibiotics. Recurrent or chronic pulmonary infections require annual PFTs. Children older than 5 years should be able to undergo these tests.

Bronchodilators, inhaled corticosteroids, and leukotriene modifiers are integral in the therapy of many patients. In patients with chronic upper or lower respiratory tract infections and subsequent structural changes, strategic long-term broad-spectrum antibiotics may be needed, in addition to chest physiotherapy and sinus surgery. An intriguing report from Brazil showed clinical improvement in patients with XLA without IVIG replacement therapy but receiving aggressive respiratory physiotherapy.[54]

Sinusitis is typically chronic in older patients and requires therapy with nasal steroids, saline sprays, and surgical intervention in some cases. Some patients develop chronic sinusitis despite regular IVIG replacement therapy every 3 weeks. These patients are challenging to treat because antibiotics, N -acetylcysteine, and topical intranasal corticosteroid therapies fail to clear pathogens and do not decrease sinus inflammation.

Chronic eczema is treated with moisturizing creams and topical steroids, as in immunocompetent patients. Uncontrolled atopic dermatitis is associated with a greater risk for superinfection than that of topical steroid use.

Nutritional intervention or supplementation and the use of multivitamin and mineral preparations are usually unnecessary in XLA, although some patients with autoimmune colitis occasionally require such therapy. Determining the etiology of the diarrhea (often infectious) is more important.

Liver function tests are recommended annually because autoimmune hepatitis and hepatitis C may progress subclinically.

Surgical Care

Because of the possible development of chronic sinusitis, endoscopic procedures with irrigation may be invaluable in obtaining cultures for microbiological studies. In addition, further surgical intervention may be required to promote sinus drainage. Similarly, obtaining other samples for culture, such as lymph node samples in patients presenting with adenopathy or bronchoalveolar lavage fluid samples in patients with pneumonia who are unable to provide sputum specimen, will allow for a greater selection of appropriate antibiotics for treatment.

Patients with chronic sinusitis who may benefit from surgical drainage procedures usually require a consultation with an otolaryngologist, as do children with recurrent otitis media who may improve with the placement of tympanostomy tubes.

Surgical interventions for pulmonary infections include diagnostic and therapeutic thoracentesis, lung biopsy, and care for lung abscesses and bronchopleural fistulas.

Consultations

A pulmonologist, allergist/immunologist, infectious disease specialist, gastroenterologist, rheumatologist and/or hematologist may be consulted to manage specific complications.

Pulmonologists are particularly valuable in evaluating radiological findings, assisting with bronchodilator therapy, and interpreting detailed PFT results. Bronchoscopy with washings for culture of both aerobic and anaerobic organisms, fungal, mycobacterial, and viral pathogens may be needed in cases of pneumonia or bronchitis.

Allergy/immunology specialists are trained in the diagnosis and management of primary immunodeficiency disorders and are particularly valuable in diagnosing XLA and guiding IVIG therapy.

Infectious disease specialists are often consulted to determine the infectious etiologies, and they can recommend first-line antibiotics.

Gastroenterologists are essential in the diagnosis and management of inflammatory bowel disease.

Hematologists and clinical immunologists must collaborate to treat autoimmune cytopenias because immunosuppressive therapies for these hematologic disorders further compromise immune function in patients with XLA.

Despite aggressive antibiotic therapy, surgical intervention may be required for chronic sinusitis or for chronic lung disease with abscess, pleural effusion, or other conditions.

Diet

Most children and adults with XLA should maintain a normal and nutritious diet.

Patients with inflammatory bowel disease may require a low-fat diet and vitamin supplementation.

Nutritional supplementation with products such as PediaSure, Ensure, or Vivonex is necessary for some patients with persistent malabsorption and malnutrition.

Activity

Encourage patients with XLA to exercise actively, attend school, and maintain employment. Discourage patients from smoking, exposing themselves to smoke, and using illegal drugs. Instruct them to avoid unnecessary exposure to infectious agents. However, patients may generally benefit from outdoor activities. Considering the relatively good prognosis of XLA, the physician should encourage patients with this immunodeficiency disease to have a positive mental attitude.

 

Medication

Medication Summary

The overall consensus among clinical immunologists regarding replacement therapy with IVIG in patients with primary immune deficiencies is that an IVIG dose of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels greater than 500 mg/dL is desirable. The number and severity of infectious complications is inversely correlated with the dose of IVIG administered. A recent consensus statement suggests that maintaining trough IgG levels greater than 800 mg/dL prevents serious bacterial illness and enteroviral meningoencephalitis.[55] However, if infections continue to be a problem, increasing the trough level up to 1000 mg/dL is an option.[56]

Measure of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable. It may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, every 2-3 wk) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IVIG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required.

SCIG administration is also possible.[57] The recommended dose is 100-200 mg/kg SC every week. The initial weekly SC dose can be calculated by multiplying the previous IVIG dose by 1.37 and then dividing that dose into weekly doses, based on the patient's previous IVIG treatment interval. For example, if IVIG dosage is 200 mg/kg every 3 weeks, multiply 200 mg/kg by 1.37 and then divide by 3 to get a calculated dose of 91 mg/kg SC every week. The calculated SCIG dose provides systemic exposure similar to that of the previous IVIG dose. SCIG dose should be initiated 1 week after the last IVIG dose. For SCIG administration, do not exceed 15 mL (3200 mg) per injection site, and the administration rate is not to exceed 20 mL/h per injection site. In a review of seven studies on SCIG, the incidence of infection was found to be inversely related to the trough serum IgG level.[58] Therefore, maintaining higher IgG levels may be beneficial but no given level was found to be adequate for all patients.

Recently, a cost comparison analysis was made in France between SCIG and IVIG.[59] It appeared that SCIG appeared to be 25% less expensive.

Preinfusion (trough) serum IgG levels are measured every 3 months until a steady state is achieved and then every 6 months if the patient is stable. These measurements may be helpful in adjusting the dose of IVIG or SCIG to achieve adequate serum levels. For persons in whom the catabolism of infused IgG is high, more frequent (eg, every 2-3 wk) IV infusions of smaller doses may maintain the serum level within the reference range. The rate of elimination of IgG may be higher during a period of active infection. Therefore, serum IgG levels may need to be measured more frequently, doses may need to be increased, or shorter intervals may be required.

For replacement therapy in patients with primary immune deficiency, all brands of IVIG are probably equivalent, although viral inactivation processes (eg, solvent detergent vs pasteurization and liquid vs lyophilized) differ. The choice of brand may depend on the hospital or home care formulary and on local availability and cost. In addition, whether home SCIG administration is appropriate must be determined. In patients who have IV access problems or who develop adverse effects with IVIG administration (eg, headache, myalgias), SCIG is an alternative. Questions regarding compliance need to be answered. The requirement of weekly infusions and local reactions at the site of infusions are disadvantages.

In addition, contraindications include patients with thrombocytopenia or other bleeding disorders and patients who are receiving anticoagulant therapy. SCIG was shown to be equal in efficacy to the same dose administered IV. The dose, manufacturer, and lot number should be recorded for each infusion to facilitate review for adverse events or other consequences. Recording of all adverse effects that occur during the infusion is crucial.

Periodic liver and renal function testing, approximately 3-4 times yearly, is also recommended. The US Food and Drug Administration (FDA) advises that, in patients at risk for renal failure, the recommended doses should not be exceeded and that infusion rates and concentrations should be at the practicable minimum levels. Examples of patients at risk for renal failure include patients older than 65 years; patients who use nephrotoxic drugs; and patients with preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia.

The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatments is high, especially in patients with infections and in those in whom immune complexes form. In patients with active infection, infusion rates may need to be slower, and the dose may need to be halved (ie, to 200-300 mg/kg). The remaining half should be administered the next day to achieve a full dose. Treatment should not be discontinued. After normal serum IgG levels are achieved, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions include dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency and patients with active infections have more severe reactions.

The activation of complement due to IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with crystallizable fragment (Fc) receptors and that trigger the release of inflammatory mediators is a cause. Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg every 6-8 h), acetaminophen (15 mg/kg/dose; not to exceed 1000 mg/dose or 2.6 g/24 h if age < 12 y), diphenhydramine (1 mg/kg/dose; not to exceed 50 mg/dose), and/or hydrocortisone (6 mg/kg/dose; not to exceed 100 mg/dose) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, therapy with analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products with sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis suggest osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg/kg/min based on the amount of sucrose. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at increased risk, monitoring the BUN and creatinine levels before starting the treatment and prior to each infusion is necessary. If the patient's renal function deteriorates, the treatment should be discontinued.

IgE antibodies to IgA have rarely been reported to cause severe transfusion reactions in patients with IgA deficiency. A few cases of true anaphylaxis have been reported in patients with selective IgA deficiency and CVID who developed IgE antibodies to IgA after treatment with Ig. However, this is rare in actual experience. In addition, this is not a problem in patients with XLA or in patients with SCID. Caution should be exercised in patients with IgA deficiency (< 7 mg/dL) who need IVIG. (IgA levels can be low in patients with selective IgA deficiency, in patients with CVID, and in some patients with IgG-subclass deficiencies.) IVIG preparations with low concentrations of contaminating IgA are advised in these situations (see the Table below).

Although IVIG has improved the patient's ability to handle infections, aggressive treatment for acute bacterial infections with specific antibiotics continues to be necessary. No difference in efficacy among the brands of IVIG is recognized. One review indicated that IVIG at a mean dose of 0.42 g/kg in 162 treatment years resulted in an infection rate similar to the general pediatric population. All 18 children in that study had normal growth patterns. Thus far, the possibility of other infectious agents, notably hepatitis C virus (HCV), has not been a problem in the newer preparations of IVIG, with the additional viral inactivations steps incorporated into the manufacturing processes.

Table 1. Immune Globulin, Intravenous (Open Table in a new window)

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

Contents of table are adapted from the following sources:

  1. Manufacturers' literature.

  2. Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005; 25(11 Pt 2):78S-84S.

  3. Shah S. Pharmacy consideration for the use of IGIV therapy. Am J Health-Syst Pharm. 2005; 62(Suppl 3):S5-11.

Table 2. Immune Globulin, Subcutaneous (Open Table in a new window)

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

Antibiotics

Class Summary

Antibiotics are most commonly used to treat sinopulmonary infections caused by polysaccharide-encapsulated bacteria (S pneumoniae, H influenzae type b).

Amoxicillin, amoxicillin/clavulanate, and cefuroxime axetil are the drugs of choice for the common extracellular bacteria that cause sinopulmonary infections. Ceftriaxone is used in patients with more severe sinopulmonary infections, in patients who respond poorly to oral antibiotics, and in patients with significant bronchiectasis. Ceftriaxone is also used for penicillin-resistant pneumococcal infections. Clarithromycin covers mycoplasmal infections and many bacterial sinopulmonary infections. Vancomycin is chosen in patients who are allergic to cephalosporins and when the isolate is resistant to penicillin. Fluoroquinolones are valuable for respiratory pathogens, including staphylococci, and in patients with multiple antibiotic allergies.

Amoxicillin (Trimox, Amoxil, Biomox)

Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Amoxicillin/clavulanate (Augmentin)

Drug combination treats bacteria resistant to beta-lactam antibiotics. In children >3 mo, base dose on amoxicillin content. Because of different amoxicillin-clavulanic acid ratios in 250-mg tab (250:125) and in 250-mg chewable tab (250:62.5), do not use 250-mg tab until child weighs >40 kg

Cefuroxime axetil (Ceftin)

Second-generation cephalosporin that maintains gram-positive activity of first-generation cephalosporins; adds activity against Proteus mirabilis, H influenzae, Escherichia coli, Klebsiella pneumoniae, and M catarrhalis.

Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum activity; efficacy against resistant organisms. Arrests bacterial growth by binding to ≥ 1 penicillin-binding proteins.

Clarithromycin (Biaxin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Vancomycin (Lyphocin, Vancocin, Vancoled)

Potent antibiotic directed against gram-positive organisms and active against enterococcal species. Indicated for patients who cannot receive penicillins and cephalosporins, in patients in whom these failed, or in those with infections due to resistant staphylococci. To prevent toxicity, current recommendation is to assay vancomycin trough levels after third dose with sample drawn 0.5 h before next dose. Use CrCl to adjust dose in renal impairment.

Bronchodilators

Class Summary

Inhaler bronchodilator therapy is the mainstay of pulmonary care in most patients with XLA. A combination of a beta2-agonist (eg, albuterol, salmeterol) with a high-potency steroid (eg, budesonide, fluticasone) is conventional care.

Inhalers are used to relieve bronchoconstriction and decrease the inflammatory response in the respiratory tree. Both pulmonary and nasal inhalers may be needed. Inhaler use is hampered in young children and in others who cannot understand the technique of administration and in older individuals who are unable to achieve forceful inhalation. Adding a spacer is customary to improve coordination in children. If patients cannot reliably use a metered-dose inhaler, a nebulizer may be an option. Steroid inhalation is followed by rinsing the mouth to prevent thrush.

Albuterol (Proventil, Ventolin)

Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility. Is also available as a solution for nebulization. MDI delivers 90 mcg/actuation.

Salmeterol (Serevent Diskus)

Can relieve bronchospasms by relaxing the smooth muscles of the bronchioles. Effect may also facilitate expectoration. Each actuation delivers 50 mcg.

Formoterol (Foradil)

Can relieve bronchospasms by relaxing smooth muscles of bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis. Effect may also facilitate expectoration. Shown to improve symptoms and morning peak flows.

Incidence of side effects higher when administered at more frequent doses than recommended. Bronchodilating effect lasts >12 h. Use in addition to regular use of anticholinergic agents. Useful in cases in which bronchodilators are used frequently. Available as PO inhalant powder cap and administered via Aerolizer inhaler.

Corticosteroids, Inhaled

Class Summary

These agents are used to prevent and decrease inflammatory reaction within airway.

Beclomethasone (Qvar)

Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, decreasing airway hyperresponsiveness. Some patients may require higher doses of inhaled beclomethasone. Qvar available as 40 mcg or 80 mcg per actuation.

Fluticasone (Flovent HFA, Flovent Diskus)

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has weak HPA-axis inhibitory potency when applied topically. Some patients may require higher doses. Various inhalant devices deliver different dosages per actuation. Flovent HFA delivers 44 mcg, 110 mcg, and 220 mcg per actuation, whereas Flovent Diskus is specially designed with blister pack containing 50 mcg as a powder for inhalation.

Flunisolide (AeroBid, AeroSpan)

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has weak HPA-axis inhibitory potency when applied topically. Some patients may require higher doses. AeroBid (flunisolide CFC) delivers about 250 mcg/actuation. AeroSpan (flunisolide HFA) delivers about 80 mcg/actuation.

Budesonide inhaled (Pulmicort Turbuhaler, Pulmicort Respules)

Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, decreasing airway hyperresponsiveness. Available in various inhaled products. Pulmicort Turbuhaler delivers a powder that is inhaled (200 mcg/actuation). Pulmicort Flexhaler delivers a powder for inhalation as either 90 mcg or 180 mcg per dose. Pulmicort Respules is an inhalation susp administered via nebulization (available in 2 strengths: 0.25 mg/2 mL, 0.5 mg/2 mL).

 

Follow-up

Further Outpatient Care

New infections can usually be medically managed on an outpatient basis, and appropriate cultures, if indicated, can usually be obtained in the clinical setting. Extensive diagnostic tests including 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.

If indicated, blood samples should be obtained to detect viral RNA or DNA, and liver function tests should be performed to evaluate and to monitor hepatitis. Other infections require follow-up on an outpatient basis.

Frequent monitoring of the patient's pulmonary status is important because the main long-term complication continues to be chronic lung disease. Pulmonary lung function should be assessed regularly, and high-resolution CT scans of the lungs should be performed since bronchiectasis can develop (even in patients on chronic IVIG therapy). 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).

The medical provider is responsible for withholding live viral vaccines. The administration of the live-attenuated oral poliovirus vaccine can cause progressive and fatal meningoencephalitis, as can wild-type enteroviruses. Other live-attenuated vaccines are also contraindicated, although they have not caused such devastating infection.

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. 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.

Further Inpatient Care

Hospitalization has become unusual for patients with Bruton agammaglobulinemia, formally termed X-linked agammaglobulinemia (XLA), 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 XLA who are receiving IVIG replacement is usually to provide an adequate workup of a puzzling infection, to manage severe gastrointestinal 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.

Successful cure has been reported using stem cells from either cord blood or bone marrow from histocompatibility leukocyte antigen (HLA)–matched siblings.[60]

Inpatient & Outpatient Medications

Administer IVIG to every patient with agammaglobulinemia. In rare circumstances (eg, temporary lack of venous access), IMIG 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.[61] However, this survey was performed before the SCIG preparation was available in the US.

Because these patients risk developing unusual infections, attempt to identify any pathogens in either the respiratory or gastrointestinal tracts. More modern techniques using polymerase chain reaction (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.

See Medical Care and Medication.

Transfer

Most clinical immunologists believe that they should usually manage clinical illnesses related to XLA and other primary immunodeficiency diseases because these illnesses are rare and their complications are rarer still.

Generally, primary care physicians who treat patients with XLA and other primary immunodeficiency diseases must have a special interest in immunology and adequate experience in managing these complex problems.

Deterrence/Prevention

Prenatal diagnosis in families known to carry a mutated gene may allow better preparation for the infant's care by the family and the physician.

In families in which a male is diagnosed with XLA, females may wish to undergo evaluation to determine if they are carriers; if they are, genetic counseling regarding future pregnancies can be very beneficial.

Certainly, assessment of B and T cells with flow cytometry is important for an infant at risk before infections develop.

Gene therapy is not yet available for XLA. However, encouraging results using retroviral-mediated gene transfer have been recently reported in a murine model of XLA.

Because patients continue to have improved outcomes, stem cell transplantation is not considered appropriate because of its risk and need for aggressive immunosuppression.

Complications

Major complications are caused by frequent or recurrent infections that result in chronic pulmonary disease and/or chronic enteroviral infection of the CNS.

All of the complications (such as pneumonia, otitis media, and diarrhea) before immunoglobulin replacement therapy was started were reduced, except sinusitis and conjunctivitis. Although most children with XLA develop recurrent bacterial respiratory tract infections during infancy, 20% 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.[62] This could be reflected in continued decline in pulmonary function testing.[63] However, increasing the dose may blunt this decline.

The presence of bronchiectasis has also been found to correlate with continued risk for developing pneumonia despite immunoglobulin replacement therapy.[64] A recent report indicates that the development of chronic lung disease was significantly related to age at diagnosis and inappropriate treatment.[65] However, even with immunoglobulin replacement therapy, 38.4% of XLA patients continued to experienced pneumonia and respiratory problems.[66, 67]

Recurrent infections may eventually cause either obstructive disease or combined obstructive and restrictive lung disease. IVIG treatment, aerosol treatments with bronchodilators, and chest physiotherapy, such as postural drainage, may prevent further damage in these patients. 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).

Chronic sinusitis may also result from repeated infections and subsequent structural changes. Chronic ear infections may result in hearing loss.

Autoimmune diseases (eg, inflammatory bowel disease, atrophic gastritis, pernicious anemia) are also observed in patients. Other noninfectious complications that are particularly prevalent include autoimmune disorders such as arthritis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, and autoimmune neutropenia. One center reported that 26.7% of XLA patients have developed neutropenia.[68] There have been attempts to treat with granulocyte colony-stimulating factor (filgrastim).[69] Treatment may also consist of increasing the dose of immunoglobulin replacement and/or steroids or rituximab.[70] A dermatomyositis syndrome has been frequently reported in boys whose past treatments did not include IgG at the high doses currently administered. See section on History.

Reports that showed progressive neurodegeneration in patients with primary immunodeficiency on IVIG treatment are concerning.[71, 72] 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.

Sensorineural hearing loss may be increased in patients with antibody deficiency (both XLA and CVID) and suggest regular audiologic evaluation.[73]

Eczema and asthma are more frequent in these patients than in immunocompetent individuals.

Patients with low or absent immunoglobulin levels have increased risk of malignancy, especially in the lymphoreticular and GI organs, which may be the result of altered immune surveillance. However, the risk for XLA appears to be much less than the other immunodeficiency syndromes. There has been a report on multiple neoplasms in the GI tract[38] and gastric adenocarcinomas.[74]

Attempts to correlate clinical outcome with severity of various mutations have not been successful.[75] Early diagnosis and treatment continue to result in the best outcome.

Prognosis

IVIG treatment has increased the survival rates of patients with XLA. Interestingly, patients with XLA who receive early and adequate IgG replacement seem to do better than patients with other causes of hypogammaglobulinemia and CVID. Comparisons of XLA and CVID have shown that patients with XLA incur less severe chronic pulmonary disease, less devastating hepatitis C infection (acquired through intravenous immunoglobulin and other blood products), and little risk for malignancy.

The development of chronic lung disease is significantly related to age at diagnosis and inappropriate treatment.[65] However, even with immunoglobulin replacement therapy, 38.4% of patients may continue to experienced pneumonia.[67] Although patients continue to die from chronic pulmonary disease, some now survive into the fifth and sixth decades of life. The development of bronchiectasis despite immunoglobulin replacement therapy in XLA has been well documented.[64, 76]

Patients who begin IVIG replacement therapy when they are younger than 5 years have had prolonged survival and decreased morbidity and mortality rates.

Men with XLA have survived into the fifth decade of life despite suboptimal immunoglobulin replacement because IVIG did not become available until the mid 1980s. The oldest reported patients with XLA are in the sixth decade of life.[77]

Other causes of mortality include complications of colitis and liver disease.

Predominant serious viral infections are enteroviral and may involve the attenuated vaccine strains of poliovirus. Chronic enteroviral CNS infection is the major factor in severe outcomes. Patients with XLA adequately manage other viruses such as measles and varicella. Herpes simplex infections are more likely to be recurrent, and the common wart can be difficult to control.

A theoretical concern is that the frequency of malignancies may increase as the population of patients with XLA ages because the incidence of malignancies increases in older patients with other primary immunodeficiencies. Examples include X-linked hyper-IgM disease, CVID, and Wiskott-Aldrich syndrome, all of which involve antibody deficiencies. However, whether the risk of malignancy is due to the deficiency of antibody or due to other immune dysregulation that accompanies these disorders is not clearly known. Case reports of certain neoplasms, such as colorectal neoplasms,[38] suggest the need for colorectal screening in patients with XLA. GI adenocarcinomas are not unusual.[74]

Despite these health concerns, measurement of quality of life indicates that these patients perceive a higher quality than those with rheumatological disorders, although both groups were lower than healthy controls.[78]

Patient Education

Patients and families must understand the need to recognize and treat infections early.

Recognition of the disease can be difficult because of the subtle presentation of infections caused by the poor inflammatory response compared with that of an immunocompetent host. IVIG replacement may also lull patients into delaying medical care because of both their emotional reliance on IVIG and because of the slowly progressive manifestation of infection, compared with the acute overwhelming presentation in an individual with XLA who does not receive treatment.

Physicians can overcome the tedious nature of chronic pulmonary care and the difficulty in using inhalers by repeating patient education every 6 months, or even more often, as in patients with asthma. Persuading adolescents to maintain these therapies is particularly difficult because they may believe that the compliance activities may cause them to lose the acceptance of their peers.

The Immune Deficiency Foundation is an important resource for education and support for patients and families with any primary immunodeficiency disease. For consultation, the foundation can be reached at 1-877-666-0866. The foundation's mailing address is 25 W Chesapeake Ave, Suite 206, Towson, MD 21204. Some states have local chapters.

The Jeffrey Modell Foundation at 747 3rd Ave, New York, NY 10017, also provides educational support and raises funds for research. The foundation can be reached at 1-800-JEFF-855.

For additional information on related diseases and conditions, see the articles Agammaglobulinemia and B-Cell and T-Cell Combined Disorders.