Agammaglobulinemia

Background
Agammaglobulinemia, or hypogammaglobulinemia, is the most common of the primary immunodeficiencies, accounting for approximately 50% of cases. Three major types can be described: X-linked, early onset, and late onset. After more than 50 years since the clinical entity was first described by Bruton in 1952, the molecular defect in X-linked agammaglobulinemia (XLA) has been elucidated. In Bruton's honor, the gene responsible has been named Btk, which stands for Bruton tyrosine kinase. Several historical reviews have been written.[1, 2] An estimated 90% of patients with early-onset agammaglobulinemia and absence of B cells have abnormalities in the Btk gene (ie, Bruton agammaglobulinemia or XLA). XLA is further discussed in detail in the article Bruton Agammaglobulinemia. Late-onset disease is usually referred to as common variable immunodeficiency(CVID), also described separately. However, reports are increasing of adults who are diagnosed with XLA. An approach in evaluating an adult with hypogammaglobulinemia has been published[3] and possible molecular-genetic mechanisms speculated.[4] The remaining type is early onset nonBruton agammaglobulinemia, with low or absent serum immunoglobulin (Ig). Most cases are agammaglobulinemia with autosomal recessive/dominant heritage and represent a very heterogeneous group, including immunoglobulin (Ig) deficiency with increased immunoglobulin M (hyper-IgM syndrome), which is also discussed separately (see X-linked Immunodeficiency With Hyper IgM). In addition, some infants have an initially low Ig level that eventually increases to normal levels. This is known as transient hypogammaglobulinemia of infancy and is discussed in detail in a separate article. Defective antibody production and low circulating numbers of B cells were described in some female infants and in males in whom no Btk abnormalities were detected. These observations imply the involvement of other genes. This article describes the cases of agammaglobulinemia caused by defects other than Btk.However, because the clinical manifestations and treatments are similar, information from Btk -deficient patients is included because of the lack of sufficient numbers of such patients. Finally, some conditions secondary to acquired immunodeficiency are also described because they need to be recognized in addition to the primary diseases. For other B-cell defects, such as specific Ig deficiencies (eg, immunoglobulin A [IgA] or immunoglobulin G [IgG] subclass deficiencies), refer to the article B-Cell Disorders.

Pathophysiology
Although defects may occur in many steps in B-cell development and maturation resulting in the lack of Ig production, the most common and well-described defect is the one at the stage of proB-cell to preB-cell maturation (see the image below).

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.

In the fetal bone marrow, the first committed cell in B-cell development is the early pro-B cell, identified by its ability to proliferate in the presence of interleukin-7 (IL-7). These cells develop into late proB cells in which rearrangement of the heavy chain genes occurs. This rearrangement process requires the recombination activating genes RAG1 and RAG2, which are controlled by IL-7 and perhaps other factors. When the heavy chain is produced, it is transported to the cell surface by the Ig- (CD79a) and Ig- (CD82) heterodimers or by the surrogate light chain. Progression from this late pro B-cell to the pre B-cell stage involves the rearrangement and joining of the various segments of the heavy chain genes. The completion of rearrangement of the light and heavy chains and the presence of surface IgM results in the immature B cell, which then leaves the bone marrow.

Increasing expression of IgD in the transitional cells finally results in the mature B cell with IgM and IgD both expressed on their cell surface. 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 IgG, IgA, or immunoglobulin E (IgE). Mutations on Btk components of the preB-cell and B-cell receptor (lambd5, Ig-, and Ig-), or the scaffolding protein BLNK account for approximately 90% of defects in early B-cell development.[5] Mutations in Btk result in Bruton agammaglobulinemia. The defect of heavy-chain gene on chromosome 14 is the most frequent abnormality in patients with agammaglobulinemia and decreased B cells but no defect in Btk. Ig- and Ig- are encoded by the mb-1 and B29 genes, respectively. A case involving a female patient with a mutation in the Ig-5/14/1 gene that resulted in a defect in the surrogate light chain has also been described. Other mutations in the components of the preB-cell and B-cell antigen receptor complex (eg, defects in the B-cell linker protein [BLNK]) account for 5-7% of patients with defects in early B-cell development. These patients have normal numbers of proB cells but no preB or mature B cells. Their clinical features are similar to those of patients with XLA. Activation of 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. 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. However, when a female patient presents with absence of serum Ig and peripheral blood B cells, such a patient clearly does not have Bruton agammaglobulinemia or mutations in the Btk gene unless she has XO karyotype. The elucidation of her specific gene defects may shed additional information on Bcell development. Such a patient was recently described and subsequent whole exome sequencing found a premature stop codon in exon 6 of PIK3R1.[6] She had in absence of p85 but normal expression of the p50 and p55 regulatory subunits of P13K. Bone marrow aspirates showed less than 0.01% CD19+ B cells with normal percentages of TdT+VpreB+CD19- B cell precursors. The exact defects have not yet been determined in other patients in whom agammaglobulinemia has been associated with a mosaic of ring chromosome 18[7] or hypogammaglobulinemia in a male with ring chromosome 21.[8] Patients with B-cell deficiency associated with intrauterine growth retardation have been described,[9] and patients with agammaglobulinemia with spondyloepiphyseal dysplasia and retinal dystrophy have also been described.[10] The syndrome of X-linked hypogammaglobulinemia with growth hormone deficiency has also been reported.[11] This has been mapped to the same region that encompasses the Btkgene and may involve a gene that controls growth hormone production, implying a small contiguous gene deletion that includes both the gene for XLA and another closely linked gene involved in growth hormone production. The structural gene for growth hormone is located on the long arm of chromosome 17. In addition to the genetic defects described above, other pathophysiology mechanisms may result in hypogammaglobulinemia or agammaglobulinemia, such as viral infections, malignancy, or drug effects. These are described in more detail in Causes.

Epidemiology
Frequency
United States Agammaglobulinemia occurs in approximately 1 in 250,000 males in the United States. International In a study of serum Ig levels in 2000 consecutive patients in Saudi Arabia, agammaglobulinemia was diagnosed at a rate of 250 cases per 100,000 individuals.[12] These patients accounted for 16% of the primary humoral immunodeficiency groups (with selective IgA at 45%, CVID at 29%, and selective IgG at 10%).

Spain's Registry for Primary Immunodeficiency Diseases reported 1079 cases registered between January 1980 and December 1995.[13] Of these, 49 were reported as XLA. In Caucasians, between 60 and 70% of primary immunodeficiencies are antibody-deficiencies. In Brazil, of 101 cases of humoral deficiencies, XLA was the least frequent (9), compared with IgA deficiency (60) and transient hypogammaglobulinemia (14).[14] In South Africa, antibody deficiencies predominate, accounting for 56% (52 of 93) of diagnoses,[15] compared with Australia, where antibody deficiencies comprised 71% of 500 cases enrolled in a national registry.[16] In Asians, specifically in Hong Kong, humoral defects were identified in 50 of 117 patients diagnosed with primary immunodeficiency.[17] A similar percentage was seen in China.[18]

Mortality/Morbidity
Patients with agammaglobulinemia are at risk of frequent and recurrent infections. Severe bacterial infections resulting in pneumonias or meningitis and subsequentbacteremia could be fatal; however, the major causes of morbidity are chronic upper pulmonary disease (eg, sinusitis) or lower pulmonary disease (eg,bronchiectasis). In patients with agammaglobulinemia, one study indicated that, although the incidence of bacterial infections resulting in hospitalization decreased from 0.40-0.06 per patient per year during intravenous Ig replacement, chronic sinusitis and bronchiectasis continue to occur. Central nervous enteroviral infections can be especially disabling, resulting in a long-term CNS debilitating state. Autoimmune and allergic manifestations are another source of morbidity in these patients.

Sex
Agammaglobulinemia can be either X-linked (XLA) or autosomal recessive. XLA is more often recognized as Bruton agammaglobulinemia.

Age
Because of passive, transplacental acquisition of maternal IgG, newborns have normal levels of serum IgG and do not have problems until the IgG is catabolized. Because newborns cannot produce their own Ig, increased susceptibility to infections develops in infants older than 6 months. Patients with non-Btkmutations tend to be younger at the time of diagnosis, and they are more likely to have severe complications.

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 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. Other bacterial infections, such as pyoderma, sepsis, meningitis, osteomyelitis, and septic arthritis occur less frequently. Lower-grade pathogens, such asPneumocystis

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.[20, 21] 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. [22] 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. [23] 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.[24] In addition, rare CNS disorders such as progressive multifocal leukoencephalopathy may present in patients with hypogammaglobulinemia.[25] 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.[26] 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. A case of juvenile onset psoriatic arthritis has been described in a patient with agammaglobulinemia. Reactive arthritis with Campylobacter coli infections are more common. Enthesitis-related arthritis has also been described in a boy with XLA.[27] The constellation of symptoms in a family of brothers with leukoencephalopathy, arthritis, colitis, and hypogammaglobulinemia prompted some to label this the LACH syndrome.[28] 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. 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.[29] Similarly, total IgG levels were below the reference range for age in 14 of 20 patients admitted to a pediatric ICU. [30] 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.[31] The concomitant occurrence of hypogammaglobulinemia and thymoma is known as Good syndrome.[32] 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 proB-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). 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.[33] Secondary hypogammaglobulinemia was found most often due to chemotherapy, or from complex cardiac anomalies, malignancy, or autoimmune disorders. Genetic factors are described in the following examples: 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 proB-cell to preB-cell transition.[34] She had minor facial anomalies and congenital agammaglobulinemia and absent B cells in peripheral blood. Patients with mutations in the 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- 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 light chain had recurrent otitis media at age 2 months. At age 3 years, he had H influenzae meningitis with arthritis. 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. 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. [35] In a detailed study performed in China of 21 children with congenital agammaglobulinemia, mutations of in Btk was identified in 18 patients.[36] A compound heterozygote mutation in the IGHM gene was found in one patient. No molecular etiology was found in the other two. 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), epilepsy medications (eg, phenytoin, carbamazepine), 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. [37] IgG levels should be determined in patients with drug rash with eosinophilia and systemic symptoms (DRESS).[38] 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.[39] Hypogammaglobulinemia is also frequently seen in steroidsensitive 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 lifethreatening, 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.[40] The most common autoimmune disorder associated with hypogammaglobulinemia is systemic lupus erythematosus.[41, 42] As noted above, antibody deficiency must be distinguished from an underlying condition versus drug-induced or renal losses. 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. [43] 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/L).[44] Finally, cow's milk allergy may also result in hypogammaglobulinemia, possibly due to immunoglobulin leakage through inflamed GI mucosa.[45] Avoidance of the allergen resulted in normalization of immunoglobulin levels.

Differential Diagnoses
Bronchitis, Acute and Chronic Bruton Agammaglobulinemia Common Variable Immunodeficiency Cystic Fibrosis Transient Hypogammaglobulinemia of Infancy

Laboratory Studies
In patients with agammaglobulinemia, or hypogammaglobulinemia, all circulating immunoglobulin (Ig) levels (IgG, IgA, IgM, IgE) are low. The physician must compare the patient's specific levels with ageappropriate controls. Serum IgG levels lower than 100 mg/dL should arouse concern. In some patients with X-linked agammaglobulinemia (XLA), IgG levels may be as high as 200-300 mg/dL. This does not necessarily exclude a diagnosis of XLA. Patients are also unable to make specific antibody responses. They usually revealed decreased antibody levels against common childhood vaccine antigens such as diphtheria, pertussis, varicella, hepatitis B, and H influenzae. In young infants (< 6 mo), because the serum IgG level is unreliable secondary to the presence of a maternal antibody, the physician cannot rely on Ig level determinations. Patients' families also have anxiety about a diagnosis of possible immunodeficiency. Determining diphtheria and tetanus antibody titers prior to vaccine administration and after administration in 3-4 week intervals to assess responses. If specific diphtheria and tetanus levels rise, this indicates that the infant is able to produce antigen-specific antibody, rendering agammaglobulinemia (or any other B-cell deficiency) unlikely. In one study of premature infants with hypogammaglobulinemia normalization of IgG occurred at a mean age of 7.2 months.[46] The concomitant occurrence of low IgM, impaired antibody response and low B-cell counts was predictive of persistence of hypogammaglobulinemia beyond 5 years of age and chronic lung disease.[47] Functional IgM production can be measured by checking isohemagglutinin titers. Note that preB cells can produce IgM in detectable quantities, including IgM autoantibodies particularly directed against hematopoietic cells (typical antirhesus [anti-Rh] in autoimmune hemolytic anemia, antineutrophil antibodies). Because B-cell maturation is arrested, patients lack mature B lymphocytes in their peripheral blood or tissue. Performing flow cytometry to analyze B- and T-cell marker expression is necessary. This can be assessed by staining for B-lymphocytespecific surface cell markers by flow cytometry. Most laboratories should be able to perform this test because similar technology examines the Tlymphocyte markers of CD4 and CD8 used in assessing HIV infection. However, laboratory personnel must be informed that B-lymphocytespecific monoclonal antibodies (CD19 and/or CD20) should be used for analysis. Reduced numbers of peripheral blood B lymphocytes suggest the diagnosis, no matter what the age of the patient. Mutational analysis must be performed to confirm the specific type of agammaglobulinemia. In addition, plasma cells and B lymphocytes in lymphoid follicles and in germinal centers of lymph nodes may be lacking. Because intestinal biopsy may be obtained to evaluate patients with chronic diarrhea, examination for hypoplastic Peyer patches in the lamina propria of intestinal mucosa may be helpful in diagnosing agammaglobulinemia. Patients with growth hormone deficiency have a deficient growth hormone response to insulin, arginine, or levodopa (L-dopa). Plasma somatomedin levels are also reduced. Continued examination for infection by various pathogens to explain various clinical symptoms (ie, respiratory, GI, arthritic, neurologic complaints) is needed. Persistence of pathogens in

immunodeficient patients has been well-documented. For example, rhinovirus is the most common respiratory virus and can persist for up to 4 months.[48]

Imaging Studies
No radiological findings are specific for agammaglobulinemia, although it is suggested by an absence of adenoidal tissue (eg, adenoidal tissue in lateral head films to evaluate chronic sinusitis). Chest radiography findings of unexplained bronchiectasis should also lead to an evaluation of the patient's immune status. High resolution CT scanning of the chest is helpful to delineate the extent of lung damage. One study found bronchiectasis in 58% patients with agammaglobulinemia.[49] Their presence appears to increase the likelihood of pneumonia and decreasing lung function. Sinus CT examinations may be required as clinically needed.[49] Some physicians advocate using MRI of the brain in patients with agammaglobulinemia or hypogammaglobulinemia who develop unexplained neurological symptoms and signs of meningeal inflammation, despite extensive investigation of cerebrospinal fluid (CSF), including polymerase chain reaction (PCR) analyses. Delayed bone age is evident in patients with growth hormone deficiency.

Other Tests
Pulmonary function tests are evaluated at diagnosis because the literature suggests that decreased parameters at diagnosis of hypogammaglobulinemia correlate with chronic and progressive pulmonary disease.

Histologic Findings
Findings of hypoplastic or absent tonsils, adenoids, and lymph nodes in tissue usually rich in B lymphocytes suggest the diagnosis.

Medical Care
Because a patient with agammaglobulinemia is unable to produce specific antibodies, the primary medical treatment 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 vaccinerelated infections. On the otherhand, 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 (Liu et al, 2012). Intravenous Ig (IVIG) results in improved clinical status with a decrease in serious infections, such as pneumonia, meningitis, and GI infection. This also appears to be the case for hypogammaglobulinemia secondary to malignancy. Patients who received high-dose IVIG (400-500 mg/kg every 3-4 wk) and who maintained IgG levels higher than 500 mg/dL had fewer hospitalizations and infections. Although the goal is to maintain a trough serum IgG level of at least 500 mg/dL, in practice, patients are treated so that they have fewer infections. This may involve higher doses, more frequent infusions, or both. Patients with bronchiectasis need higher doses (eg, 600 mg/kg). Because of the blood-brain barrier, patients with viral meningitis require 1000 mg/kg. Intravenous access may be difficult to obtain in some patients. Although intramuscular injection of IgG immune serum globulin (ISG) can be performed (0.75 mL/kg), much lower levels result; thus, injections should be given more frequently. Subcutaneous IgG (SCIG) administration is now available with a different preparation.[50] Administration every 14 days of 200 mg/kg body weight resulted in serum IgG levels greater then 7 g/L and was tolerated well in adult patients with X-linked agammaglobulinemia (XLA) and common variable immunodeficiency (CVID).[51, 52] Its advantage is that SCIG can be administered in a patient's home without a visiting nurse. The disadvantages are the

lack of medical supervision at home and questions of compliance. These considerations need to be addressed on an individual patient basis. 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. [14] Specific antibiotic choices must cover the usual polysaccharide-encapsulated organisms. Higher doses and longer courses are commonly required. 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.

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.

Consultations
Because of the frequent infections and subsequent administrations of antibiotics, treatment requires close partnership with pediatric infectious-disease experts. Autoimmune disorders are treated similarly to diseases in patients with intact humoral immunity; patients may require the expertise of a pediatric rheumatologist. Despite aggressive antibiotic therapy, surgical intervention may be required for chronic sinusitis or for chronic lung disease with abscess, pleural effusion, or other conditions. Concomitant consultation with a pediatric pulmonologist and/or otolaryngologist may be needed.

Medication Summary
Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies
The overall consensus among clinical immunologists is that a dose of intravenous immunoglobulin (IVIG) of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels greater than 500 mg/dL is desirable. However, if lower respiratory infections continue to be a problem, increasing the trough level up to 1000 mg/dL is an option.[53] Patients with X-linked agammaglobulinemia (XLA) with meningoencephalitis require much higher doses (1 g/kg) and perhaps intrathecal therapy. Measurement 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 immunoglobulin (Ig)G may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required. For replacement therapy for patients with primary immune deficiency, all brands of IVIG are probably equivalent, although differences in viral inactivation processes are observed (eg, solvent detergent vs pasteurization and liquid vs lyophilized). The choice of brands may depend on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences. Recording all side effects that occur during the infusion is crucial. Monitoring liver and renal function test results periodically, approximately 3-4 times yearly, is also recommended. The US Food and Drug Administration (FDA) recommends that, for patients at risk for renal failure (eg, those with preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia; those older than

65 y; those who use nephrotoxic drugs), recommended doses should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable. The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatment is high, especially in patients with infections and those who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose halved (ie, 200-300 mg/kg), with the remaining dose given the next day to achieve a full dose. Treatment should not be discontinued. After achieving normal serum IgG levels, adverse reactions are uncommon unless patients have active infections. With the new generation of IVIG products, adverse effects are much reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions. Anticomplementary activity of 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 Fc receptors and trigger the release of inflammatory mediators is another 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), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose, maximum 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe side effects, analgesics and antihistamines may be repeated. Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose/kg/min. 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 BUN and creatinine levels before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued. IgE antibodies to IgA have been reported to cause severe transfusion reactions in IgA-deficient patients. True anaphylaxis has been reported in patients with selective IgA deficiency and common variable immunodeficiency (CVID) who developed IgE antibodies to IgA after treatment with Ig. In actual experience, however, this is very rare. In addition, this is not a problem for patients with XLA (Bruton disease) or severe combined immunodeficiency (SCID). Caution should be exercised in patients who are IgA deficient (< 7 mg/dL) and need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised. Subcutaneous immunoglobulin (SCIG) administration is also possible. 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 7 studies on SCIG, the incidence of infection was found to be inversely related to the trough serum IgG level.[54] Therefore, maintaining higher IgG levels may be beneficial but no given level was found to be adequate for all patients. SCIG therapy has been widely used in Europe for a number of years and has been introduced to the United States in 2006 with a FDA-approved product. A cost comparison analysis was made in France between SCIG and IVIG. SCIG was found to be 25% less expensive. Table 1. Immune Globulin, Intravenous[55, 56, 57, 58] (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 IgA Form and Final Content Concentrations (mcg/mL)

Carimune NF

Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration

6.4- 6% solution: 10% Lyophilized 6.8 sucrose, < 20 mg NaCl/g powder 3%, protein 6%, 9%, 12%

Trace

(ZLB Behring)

Flebogamma

(Grifols USA)

Cohn-Oncley fractionation, PEG precipitation, ionexchange chromatography, pasteurization

5.1- Sucrose free, contains 6 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 Cohn-Oncley fraction II/III; ultrafiltration; pasteurization

4.6- 0.25M glycine 5.1

Ready-for-use liquid 10%

37

Gammar-P IV

6.4- 5% solution: 5% sucrose, Lyophilized 7.2 3% albumin, 0.5% NaCl powder 5%

< 20

(ZLB Behring)

Gamunex

Cohn-Oncley

4-

Contains no sugar,

Liquid 10%

46

(Talecris Biotherapeutics)

4.5 fractionation, caprylatechromatography purification, cloth and depth filtration, low pH incubation

contains glycine

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 Cohn-Oncley fraction II/III; ultrafiltration; pasteurization

4.8- Contains sorbitol (40 5.1 mg/mL); do not administer if fructose intolerant

Ready-for-use solution 5%

< 10

Iveegam EN

6.4- 5% solution: 5% 7.2 glucose, 0.3% NaCl

Lyophilized powder 5%

< 10

(Baxter Bioscience)

Polygam S/D

Gammagard S/D

Cohn-Oncley cold 6.4- 5% solution: 0.3% 7.2 albumin, 2.25% glycine, ethanol fractionation, 2% glucose followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated

Lyophilized powder 5%, 10%

< 1.6 (5% solution)

(Baxter Bioscience for the American Red Cross)

Octagam

(Octapharma USA)

Cohn-Oncley fraction 5.1- 10% maltose 6 II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization

Liquid 5%

200

9/24/10: Withdrawn from market because of unexplained reports

of thromboembolic events

Panglobulin

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

(Swiss Red Cross for the American Red Cross)

Privigen

(CSL Behring)

pH 4 incubation; octanoic acid fractionation, depth filtration, and virus filtration

4.6- 10% solution; 5 Preservative-free, sucrose-free, and maltose-free

Ready-to-use solution 10%

< 25

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 2. Immune Globulin, Subcutaneous (Open Table in a new window) Brand(Manufacturer) Manufacturing Process pH Additives Parenteral Form and Final Concentrations Liquid 16% (160 mg/mL) IgA Content mcg/mL < 50 mcg/mL

Vivaglobin

Cold ethanol fractionation, pasteurization

6.47.2

2.25% glycine, 0.3% NaCl

(ZLB Behring)

Antibodies
Class Summary
Prevention of respiratory syncytial virus (RSV) in immunodeficient patients is possible with passive immunization humanized mouse monoclonal IgG.

Palivizumab (Synagis)

A humanized mouse monoclonal IgG preparation specifically directed toward RSV.

Immune Globulin, Subcutaneous

Class Summary
Subcutaneous administration of immune globulin provides an alternative method of administration to intravenous in select patients.

Immune globulin, subcutaneous (Vivaglobin)

IgG antibodies that neutralize a wide variety of bacterial and viral agents. Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade. Peak serum IgG levels are lower and trough IgG levels are higher than those achieved with IVIG. SC administration results in stable steady-state IgG levels when administered weekly. Available as a 160-mg/mL SC injectable.

Further Outpatient Care

Avoid live viral vaccines for patients with agammaglobulinemia and any siblings or other children in the household because the attenuated virus is excreted and poses a threat to immunodeficient patients. If the patient has been exposed to a live viral vaccine, or if the live poliovirus has been given, obtain a stool culture to determine if the patient has the attenuated virus. Although most laboratories can determine the presence of an enterovirus, poliovirus identification requires sending the viral specimen to a state referral laboratory. Administer intravenous immunoglobulin (IVIG) and maintain serum immunoglobulin (Ig)G levels higher than 500 mg/dL. Frequent monitoring of the patient's pulmonary status is important because the main long-term complication continues to be chronic lung disease. Regular measurements of pulmonary lung function should be obtained and high-resolution CT scanning of the lungs should be performed. If end-stage lung disease develops, lung transplantation has been performed in patients with agammaglobulinemia using intensive IVIG administration (every 48 h during the first 10 d after transplant). Extensive diagnostic tests including cerebrospinal fluid (CSF) analyses with polymerase chain reaction (PCR) for viral genomes, neuroimaging, and electrophysiologic studies need to be pursued to evaluate for infectious or autoimmune complications. Successful cure has been reported using stem cells from either cord blood or bone marrow from human leukocyte antigen (HLA)-matched siblings.[59]

Inpatient & Outpatient Medications

Administer IVIG to every patient with agammaglobulinemia. In rare circumstances (eg, temporary lack of venous access), intramuscular IgG can be given. Subcutaneous administration of IVIG is an option depending on individual preferences. A survey revealed that 90% of 1243 (1119) patients with primary immunodeficiencies in 16 countries receive IVIG in an inpatient setting, whereas 7% (87) are treated with subcutaneous Ig (SCIG), mainly at home.[60] However, this survey was performed before the SCIG preparation was available. Because these patients risk developing unusual infections, attempt to identify any pathogens in either the respiratory or gastrointestinal tracts. More modern techniques using PCR helped diagnose Mycoplasma pneumoniae osteomyelitis in a patient with hypogammaglobulinemia with repeatedly sterile pus cultures. For patients to have refractory Campylobacter jejuni infection longer than 2 years is not unusual, despite therapy with various antibiotics and IVIG preparations. In patients with respiratory symptoms, analyzing bronchial samples obtained during bronchoscopy using traditional culture as well as PCR may help determine the various viruses and bacteria present.

Complications

Maintain IVIG and aggressively treat pneumonias with antibiotics to avoid chronic lung disease. Recurrent infections may eventually cause either obstructive disease alone or combined obstructive and restrictive lung disease. Aerosol treatments with bronchodilators and chest physiotherapy, such as postural drainage, may prevent further damage in these patients. Although most children with agammaglobulinemia or early onset hypogammaglobulinemia develop recurrent bacterial respiratory tract infections during infancy, 20% of cases are diagnosed in children aged 3-5 years, reflecting the widespread use of antibiotics. Unfortunately, permanent damage to the lungs with bronchiectasis may have already occurred.[61] This could be reflected in continued decline in pulmonary function testing.[62]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.[63] No good studies have examined the effectiveness of aerosol treatments in these patients, although one may speculate that mobilization of secretions should help. Similarly, no good studies have examined the usefulness of prophylactic antibiotics, either systemically or topically (ie, aerosolized). Unusual pulmonary disorders such as recurrent pulmonary alveolar proteinosis, which is not associated with any known infectious agent, have been seen in patients treated with IVIG.[64] Chronic sinusitis may also result from repeated infections and subsequent structural changes. Chronic ear infections may result in hearing loss. A study indicated that up to 38% of patients with primary antibody deficiency developed sensorineural hearing loss. [65] Finally, watch for mastoiditis. Patients with low or absent Ig levels have increased risk of malignancy, especially in the lymphoreticular and GI organs, which may be the result of altered immune surveillance, especially at the GI level, where multiple neoplasms have been described in X-linked agammaglobulinemia (XLA).[66] Gastric adenocarcinoma has been described in one 15-year old male with autosomal recessive agammaglobulinemia.[67] The risk for malignancy in certain patients with immunodeficiency is estimated to be 100-300 times higher than in the general population. Most are diagnosed when the patient is younger than 10 years, except for those whose immunodeficiencies developed later in life (eg, common variable immunodeficiency disease [CVID]). In one survey in Japan, approximately 2.7% of patients with primary immunodeficiency diseases developed malignant disorders. [68] The association of hypogammaglobulinemia with thymoma is well recognized and is known as Good syndrome. Reports of progressive neurodegeneration in patients with primary immunodeficiency on IVIG treatment are concerning.[69, 70] Extensive diagnostic tests including CSF analyses with PCR for viral genomes, neuroimaging, and electrophysiologic studies need to be pursued to evaluate for infectious or autoimmune complications. Autoimmune diseases (eg, inflammatory bowel disease, atrophic gastritis, pernicious anemia) are also observed in patients with agammaglobulinemia or hypogammaglobulinemia. Their occurrence suggests that the altered immune system, with its low resistance to infectious pathogens, may cause an inappropriate hyperfunction toward self-antigens that cause autoimmune disorders. Treatment may consist of increasing the dose of immunoglobulin replacement and/or steroids or rituximab.[71]

Prognosis
The outcome of patients with agammaglobulinemia or hypogammaglobulinemia depends on the underlying disease. For patients with agammaglobulinemia, overall prognosis is good when patients comply with their IVIG or SCIG therapy and attend to the possible complications of chronic infections in the upper and lower respiratory tracts.

In a 10-year prospective study of children younger than 4 years with hypogammaglobulinemia, Dalal et al identified 3 groups: (1) those who developed normal Ig levels with specific antibody production, (2) those who developed normal IgG levels but only transient antibody production, and (3) those with persistently low IgG levels.[72] In a similar study with 8-year follow-up, Kidon et al (2004) found that 75% of children with hypogammaglobulinemia normalized their serum Ig levels (and were therefore diagnosed with transient hypogammaglobulinemia of infancy). [73] Finally, Kutukculer and Gulez followed a group of 37 patients with hypogammaglobulinemia and found 49% spontaneously corrected their immunoglobulin abnormalities with IgG or IgM levels reaching normal levels at about 5 years of age and IgA levels by about 6 years of age. Cases of so-called "reversible hypogammaglobulinemia" have been reported in which adult patients on IVIG therapy resume immunoglobulin production.[74] In studies of patients before IVIG treatment was developed, 75% of patients older than 20 years had developed chronic lung disease, and 5-10% had cor pulmonale.

Patient Education
Patients can be expected to attend school and hold jobs.

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