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AgammaglobulinemiaBackground

Agammaglobulinemia, or hypogammaglobulinemia, is the most common of the primaryimmunodeficiencies, 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 wasfirst described by Bruton in 1952, the molecular defect in X-linked agammaglobulinemia (XLA) hasbeen elucidated. In Bruton's honor, the gene responsible has been named Btk,which stands forBruton tyrosine kinase. Several historical reviews have been written.[1, 2]

An estimated 90% of patients with early-onset agammaglobulinemia and absence of B cells haveabnormalities in the Btkgene (ie, Bruton agammaglobulinemia or XLA). XLA is further discussed indetail in the articleBruton Agammaglobulinemia.Late-onset disease is usually referred to ascommonvariable immunodeficiency(CVID), also described separately. However, reports are increasing ofadults who are diagnosed with XLA. An approach in evaluating an adult with hypogammaglobulinemiahas been published[3] and possible molecular-genetic mechanisms speculated.[4]

The remaining type is early onset nonBruton agammaglobulinemia, with low or absent serumimmunoglobulin (Ig). Most cases are agammaglobulinemia with autosomal recessive/dominant

heritage and represent a very heterogeneous group, including immunoglobulin (Ig) deficiency withincreased immunoglobulin M (hyper-IgM syndrome), which is also discussed separately (seeX-linkedImmunodeficiency With Hyper IgM). In addition, some infants have an initially low Ig level thateventually increases to normal levels. This is known astransient hypogammaglobulinemia ofinfancyand is discussed in detail in a separate article.

Defective antibody production and low circulating numbers of B cells were described in some femaleinfants and in males in whom no Btkabnormalities were detected. These observations imply theinvolvement of other genes. This article describes the cases of agammaglobulinemia caused bydefects 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 describedbecause 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] subclassdeficiencies), refer to the articleB-Cell Disorders.

Pathophysiology

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

Early stages of B-cell differentiation can be identified by the status of theimmunoglobulin genes and by the cell surface markers CD34, CD19, and surface immunoglobulin (sIg). From: ConleyME. Genes required for B cell development. J Clin Invest. 2003;112: 1636-8. Reproduced with permission of AmericanSociety 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 lateproB cells in which rearrangement of the heavy chain genes occurs. This rearrangement processrequires the recombination activating genes RAG1and 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 proB-cell to the pre

B-cell stage involves the rearrangement and joining of the various segments of the heavy chaingenes. The completion of rearrangement of the light and heavy chains and the presence of surfaceIgM results in the immature B cell, which then leaves the bone marrow.
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Increasing expression of IgD in the transitional cells finally results in the mature B cell with IgM andIgD both expressed on their cell surface. The mature B cells circulate between secondary lymphoidorgans and migrate into lymphoid follicles of the spleen and lymph nodes in response to further stimuliand various chemokines. T cells stimulate B cells to undergo further proliferation and Ig classswitching, leading to the expression of the various isotypes IgG, IgA, or immunoglobulin E (IgE).

Mutations on Btkcomponents of the preB-cell and B-cell receptor (lambd5, Ig-, and Ig-), or thescaffolding protein BLNK account for approximately 90% of defects in early B-celldevelopment.[5] Mutations in Btkresult inBruton agammaglobulinemia.The defect of heavy-chain

gene on chromosome 14 is the most frequent abnormality in patients with agammaglobulinemia anddecreased B cells but no defect in Btk.

Ig- and Ig- are encoded by themb-1and B29genes, 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 alsobeen described.

Other mutations in the components of the preB-cell and B-cell antigen receptor complex (eg, defectsin the B-cell linker protein [BLNK]) account for 5-7% of patients with defects in early B-celldevelopment. 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, acontributor to the activation of Btkthat affects other intracellular signaling events.

These findings indicate that a defect in any of the steps in B-cell development may be clinicallyimportant. 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, sucha patient clearly does not have Bruton agammaglobulinemia or mutations in the Btkgene unless shehas XO karyotype. The elucidation of her specific gene defects may shed additional information on B-cell development.

Such a patient was recently described and subsequent whole exome sequencing found a prematurestop 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+ Bcells with normal percentages of TdT+VpreB+CD19- B cell precursors.

The exact defects have not yet been determined in other patients in whom agammaglobulinemia hasbeen associated with a mosaic of ring chromosome 18[7] or hypogammaglobulinemia in a male withring chromosome 21.[8] Patients with B-cell deficiency associated with intrauterine growth retardationhave been described,[9] and patients with agammaglobulinemia with spondyloepiphyseal dysplasia andretinal dystrophy have also been described.[10] The syndrome of X-linked hypogammaglobulinemiawith growth hormone deficiency has also been reported.[11] This has been mapped to the same regionthat 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 closelylinked gene involved in growth hormone production. The structural gene for growth hormone islocated on the long arm of chromosome 17.

In addition to the genetic defects described above, other pathophysiology mechanisms may result inhypogammaglobulinemia or agammaglobulinemia, such as viral infections, malignancy, or drugeffects. 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.

InternationalIn a study of serum Ig levels in 2000 consecutive patients in Saudi Arabia, agammaglobulinemia wasdiagnosed 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 selectiveIgG at 10%).
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Spain's Registry for Primary Immunodeficiency Diseases reported 1079 cases registered betweenJanuary 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 IgAdeficiency (60) and transient hypogammaglobulinemia (14).[14]

In South Africa, antibody deficiencies predominate, accounting for 56% (52 of 93) ofdiagnoses,[15] compared with Australia, where antibody deficiencies comprised 71% of 500 casesenrolled in a national registry.[16]

In Asians, specifically in Hong Kong, humoral defects were identified in 50 of 117 patients diagnosedwith 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 bacterialinfections resulting inpneumoniasor meningitis and subsequentbacteremiacould be fatal; however,the major causes of morbidity are chronic upper pulmonary disease (eg,sinusitis)or lower pulmonarydisease (eg,bronchiectasis).

In patients with agammaglobulinemia, one study indicated that, although the incidence of bacterialinfections resulting in hospitalization decreased from 0.40-0.06 per patient per year duringintravenous Ig replacement, chronic sinusitis and bronchiectasis continue to occur.

Central nervous enteroviral infections can be especially disabling, resulting in a long-term CNSdebilitating 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 oftenrecognized as Bruton agammaglobulinemia.

Age

Because of passive, transplacental acquisition of maternal IgG, newborns have normal levels ofserum IgG and do not have problems until the IgG is catabolized. Because newborns cannot producetheir own Ig, increased susceptibility to infections develops in infants older than 6 months. Patientswith 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 Brutonagammaglobulinemia because the patient is unable to produce functional humoral immunity. Patientsmay 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-Btkmutations tend todevelop symptoms earlier and are more likely to have severe symptoms.

Encapsulated bacteria with Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcusaureus,and pseudomonal species (in that order) cause most infections. Other bacteria, suchas Salmonellaand Giardiaspecies, may also cause problems. Chronic bacteremia and skin infectionsby Helicobacterand related species such as Flexispiraand Campylobacterin patients with X-linkedagammaglobulinemia (XLA) are now appreciated.[19]

Almost three fourths of patients with agammaglobulinemia have infections occurring in the upperrespiratory 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,andsepticarthritisoccur less frequently. Lower-grade pathogens, such asPneumocystis
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cariniipneumonia, have also been reported. Additionally, sites of infection may be unusual with theencapsulated pyogenic bacteria, such as H influenzaelymphadenopathy or pneumococcal meningitis.

Although patients with agammaglobulinemia are usually able to handle viral infections, they aresusceptible to certain viruses that replicate in the GI tract and then spread to the CNS. This indicatesthe 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 poliovirusvaccine.[20, 21]Although prolonged secretions of a virus have been described (up to 637 days aftervaccination), 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 ormeningoencephalitis. In 13 patients with primary hypogammaglobulinemia, Rudge et al (1996)described 3 clinical pictures: (1) progressive myelopathy in 1 patient, (2) myelopathy progressing toan encephalopathy in 4 patients, and (3) pure encephalopathy in 8 patients.[22] Enteroviral infectionwas 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 andsuggested 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 thesepatients. The use of an antiviral agent Pleconaril with intravenous immunoglobulin (IVIG) in thesepatients has been described.[24]

In addition, rare CNS disorders such as progressive multifocal leukoencephalopathy may present inpatients with hypogammaglobulinemia.[25]

Virus-induced autoimmune diseases such as a dermatomyositislike syndromes and chronic arthritismay also occur. These diseases suggest an element of dysregulated antibody production in theirpathogenesis. 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 autoimmunedisorders such as lupus or rheumatoid arthritis.[26]

Mycoplasmaor Ureaplasmaorganisms may play a role in other cases of chronic arthritis. In a surveyof 358 patients with primary antibody deficiency, mycoplasmal infection was the most common causeof 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 coliinfections are more common. Enthesitis-related arthritis hasalso 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-losingenteropathy, malabsorption with disaccharidase deficiency, and amyloidosis.

Other patients in whom measurements of Ig may be helpful include those with renal dialysis andpatients in pediatric ICUs. In the former, IgG and IgG subclass deficiency were found in 8 out of 12children undergoing continuous ambulatory peritoneal dialysis.[29] Similarly, total IgG levels were belowthe reference range for age in 14 of 20 patients admitted to a pediatric ICU.[30] However, these studiesincluded 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-celllymphoma.


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Physical

Patients with agammaglobulinemia appear to be healthy between bouts of infections. Patients usuallydo not fail to thrive, although chronic diarrhea, if present, could cause some dehydration andmalabsorption. Any abnormal physical findings indicate presence of various infections for whichpatients have increased susceptibility. Concomitant short stature in a male suggests X-linkedhypogammaglobulinemia with growth hormone deficiency syndrome.

Most patients with agammaglobulinemia were recognized to have immunodeficiency during or shortlyafter their first hospitalization for infection. Most of the patients had a history of recurrent otitis orupper respiratory tract infection at the time of diagnosis, which when combined with the physicalfinding of markedly small or absent tonsils and cervical lymph nodes, should alert physicians to thediagnosis of agammaglobulinemia.

Some patients have cutaneous manifestations representing several unique syndromes. One of theseis known as WHIM syndrome, consisting of warts, hypogammaglobulinemia, infections, andmyelokathexis. The gene responsible for this syndrome has been identified as a chemokinereceptor 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 ofopportunistic infections.

Causes

Genetic factors have included mutations of Btkonly (accounting for 85-90% of patients with earlyonset agammaglobulinemia and absence of B cells). The remaining cases in males and females areclinically similar to XLA and represent mutations affecting the IGHM, CD79AA,and IGLL1genesinvolved in the composition of the pre-BCR or the BLNKgene involved in pre-BCR signaltransduction. Patients who do not have XLA may have other defects that result in an arrest of B-celldifferentiation at a proB-cell level (before the onset of Ig gene rearrangements) or defects in anadjacent gene to the Btkgene responsible for growth hormone production (XLA with growth hormonedeficiency).

Also, certain infections and drugs may result in low or absent Ig levels. In a survey of laboratoryvalues indicating hypogammaglobulinemia, patients with IgG levels less than half of the lower limit forage revealed 33% with a primary immune deficiency.[33] Secondary hypogammaglobulinemia wasfound most often due to chemotherapy, or from complex cardiac anomalies, malignancy, orautoimmune 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 minorfacial 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 withpneumonia, otitis, gastroenteritis, chronic enterovirus encephalitis, and septic shock

with Pseudomonas aeruginosainfection. 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 inthe first month of life. By age 1 year, she had chronic bronchitis.

One infant boy with mutation in the light chain had recurrentotitis mediaat age 2 months. At age 3years, he had H influenzaemeningitis with arthritis.

One boy with a BLNKdefect presented with overwhelming sepsis during childhood. Withintravenous immunoglobulin (IVIG) treatment, he survived to adulthood without any growth ordevelopmental 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, Hinfluenzaearthritis, and herpes simplex stomatitis. Another girl had microcephaly, persistentdiarrhea, failure to thrive, and recurrent respiratory and gastrointestinal infections. This patient

eventually developed pancytopenia with progressive bone marrow failure.
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Finally, hypogammaglobulinemia (with almost absent B cells) has been described in several patientswith 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, mutationsof in Btkwas identified in 18 patients.[36]A compound heterozygote mutation in the IGHMgene wasfound 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 humanimmunodeficiency virus (HIV) usually causes hypergammaglobulinemia, hypogammaglobulinemiahas been reported in some pediatric cases.

Patients with X-linked lymphoproliferative syndrome (ie, Duncan disease, Purtilo syndrome) maydevelop overwhelming disease with infection by Epstein-Barr virus with subsequentagammaglobulinemia and a decrease in B cells. Therefore, any male with persistenthypogammaglobulinemia following mononucleosis should be closely monitored for X-linkedlymphoproliferative disease.

Drug-induced hypogammaglobulinemia has been described with immunosuppressive agents (eg,corticosteroids, rituximab),epilepsymedications (eg, phenytoin, carbamazepine), and antipsychotic

medications (eg, chlorpromazine). Recurrent infections and reduced serum Ig levels resolved whenthe 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 tocause hypogammaglobulinemia.[39] Hypogammaglobulinemia is also frequently seen in steroid-sensitive nephrotic syndrome. Therefore, in patients with autoimmune diseases such assystemiclupus erythematosuswho are being treated with prednisone and other immunosuppressivemedications, the hypogammaglobulinemia could be due to either medication use or could reflect theunderlying autoimmune process.

Some have speculated on the association between anticonvulsant hypersensitivity syndrome (a life-threatening, drug-induced, multiorgan system reaction) with herpesvirus reactivation andhypogammaglobulinemia.

Speculation that phenytoin-induced suppressor T-cell activity and subsequent antibody deficiency hasfound some support with in vitro experiments.

Malignancies such as leukemias, multiple myeloma, and neuroblastoma may also manifesthypogammaglobulinemia.

The association of hypogammaglobulinemia associated with thymoma is known as Goodsyndrome.[40] The most common autoimmune disorder associated with hypogammaglobulinemia issystemic lupus erythematosus.[41, 42]As noted above, antibody deficiency must be distinguished froman underlying condition versus drug-induced or renal losses.

Excessive protein loss from the GI tract may result in hypogammaglobulinemia; however, primaryantibody deficiency may also cause chronic diarrhea. Therefore, anyprotein-losingenteropathyshould be considered in patients presenting with hypogammaglobulinemia. In thesesituations, specific antibody responses are intact, and circulating B cells are normal. About 4% ofpatients with malabsorption syndrome have been found to have hypogammaglobulinemia.[43] On theother hand, GI protein loss may also occur from lymphatic obstruction in diseases such as intestinallymphangiectasia. Concomitant loss of lymphocytes into the intestinal tract may result in lymphopenia.

Similarly, patients with chylothorax also have hypogammaglobulinemia (IgG = 179 35 mg/dL) andlymphopenia (985 636 cells/L).[44]

Finally, cow's milk allergy may also result in hypogammaglobulinemia, possibly due toimmunoglobulin leakage through inflamed GI mucosa.[45]Avoidance of the allergen resulted innormalization of immunoglobulin levels.
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Differential Diagnoses Bronchitis, Acute and Chronic

Bruton Agammaglobulinemia

Common Variable Immunodeficiency

Cystic Fibrosis

Transient Hypogammaglobulinemia of InfancyLaboratory 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 age-appropriate controls.

Serum IgG levels lower than 100 mg/dL should arouse concern. In some patients with X-linkedagammaglobulinemia (XLA), IgG levels may be as high as 200-300 mg/dL. This does not necessarilyexclude a diagnosis of XLA.

Patients are also unable to make specific antibody responses. They usually revealed decreasedantibody 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 amaternal antibody, the physician cannot rely on Ig level determinations. Patients' families also haveanxiety about a diagnosis of possible immunodeficiency. Determining diphtheria and tetanus antibodytiters prior to vaccine administration and after administration in 3-4 week intervals to assessresponses. If specific diphtheria and tetanus levels rise, this indicates that the infant is able to produceantigen-specific antibody, rendering agammaglobulinemia (or any other B-cell deficiency) unlikely.

In one study of premature infants with hypogammaglobulinemia normalization of IgG occurred at amean age of 7.2 months.[46] The concomitant occurrence of low IgM, impaired antibody response andlow B-cell counts was predictive of persistence of hypogammaglobulinemia beyond 5 years of ageand 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 autoantibodiesparticularly directed against hematopoietic cells (typical antirhesus [anti-Rh] in autoimmune hemolyticanemia, antineutrophil antibodies).

Because B-cell maturation is arrested, patients lack mature B lymphocytes in their peripheral blood ortissue. 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 T-lymphocyte markers of CD4 and CD8 used in assessing HIV infection. However, laboratory personnelmust be informed that B-lymphocytespecific monoclonal antibodies (CD19 and/or CD20) should beused for analysis.

Reduced numbers of peripheral blood B lymphocytes suggest the diagnosis, no matter what the ageof 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 lymphnodes may be lacking. Because intestinal biopsy may be obtained to evaluate patients with chronicdiarrhea, examination for hypoplastic Peyer patches in the lamina propria of intestinal mucosa may behelpful 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
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immunodeficient patients has been well-documented. For example, rhinovirus is the most commonrespiratory 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 absenceof 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'simmune status.

High resolution CT scanning of the chest is helpful to delineate the extent of lung damage. One studyfound 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 orhypogammaglobulinemia who develop unexplained neurological symptoms and signs of meningealinflammation, despite extensive investigation of cerebrospinal fluid (CSF), including polymerase chainreaction (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 decreasedparameters at diagnosis of hypogammaglobulinemia correlate with chronic and progressivepulmonary disease.

Histologic Findings

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

Medical CareBecause a patient with agammaglobulinemia is unable to produce specific antibodies, the primarymedical treatment is to replace immunoglobulin (Ig). Aggressive treatment with antibiotics for bacterialinfections 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 otherhand, it has been demonstrated that the dendritic and T cell responsesare normal toward influenza in patients with XLA after administration of inactivated trivalent influenzavaccine (Liu et al, 2012).

Intravenous Ig (IVIG) results in improved clinical status with a decrease in serious infections, such aspneumonia, meningitis, and GI infection. This also appears to be the case forhypogammaglobulinemia secondary to malignancy.

Patients who received high-dose IVIG (400-500 mg/kg every 3-4 wk) and who maintained IgG levelshigher than 500 mg/dL had fewer hospitalizations and infections. Although the goal is to maintain atrough serum IgG level of at least 500 mg/dL, in practice, patients are treated so that they have fewerinfections. This may involve higher doses, more frequent infusions, or both. Patients withbronchiectasis need higher doses (eg, 600 mg/kg). Because of the blood-brain barrier, patients withviral meningitis require 1000 mg/kg.

Intravenous access may be difficult to obtain in some patients. Although intramuscular injection of IgGimmune 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 availablewith a different preparation.[50]Administration every 14 days of 200 mg/kg body weight resulted inserum IgG levels greater then 7 g/L and was tolerated well in adult patients with X-linkedagammaglobulinemia (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


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lack of medical supervision at home and questions of compliance. These considerations need to beaddressed 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 andsinus surgery.

An intriguing report from Brazil showed clinical improvement in patients with XLA without IVIGreplacement therapy but receiving aggressive respiratory physiotherapy.[14]

Specific antibiotic choices must cover the usual polysaccharide-encapsulated organisms. Higherdoses 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 intranasalcorticosteroid 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 maybe invaluable in obtaining cultures for microbiological studies. In addition, further surgical interventionmay be required to promote sinus drainage. Similarly, obtaining other samples for culture, such aslymph node samples in patients presenting with adenopathy or bronchoalveolar lavage fluid samplesin patients with pneumonia who are unable to provide sputum specimen, will allow for a greaterselection of appropriate antibiotics for treatment.

Consultations

Because of the frequent infections and subsequent administrations of antibiotics, treatment requiresclose partnership with pediatric infectious-disease experts. Autoimmune disorders are treatedsimilarly to diseases in patients with intact humoral immunity; patients may require the expertise of apediatric rheumatologist. Despite aggressive antibiotic therapy, surgical intervention may be requiredfor 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 immunedeficiencies

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/dLis desirable. However, if lower respiratory infections continue to be a problem, increasing the troughlevel up to 1000 mg/dL is an option.[53]

Patients with X-linked agammaglobulinemia (XLA) with meningoencephalitis require much higherdoses (1 g/kg) and perhaps intrathecal therapy. Measurement of preinfusion (trough) serum IgGlevels 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 whohave a high catabolism of infused IgG, more frequent infusions (eg, every 2-3 wk) of smaller dosesmay maintain the serum level in the reference range. The rate of elimination of immunoglobulin (Ig)Gmay be higher during a period of active infection; measuring serum IgG levels and adjusting to higherdosages or shorter intervals may be required.

For replacement therapy for patients with primary immune deficiency, all brands of IVIG are probablyequivalent, although differences in viral inactivation processes are observed (eg, solvent detergent vspasteurization and liquid vs lyophilized). The choice of brands may depend on the hospital or homecare formulary and the local availability and cost. The dose, manufacturer, and lot number should berecorded 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 functiontest results periodically, approximately 3-4 times yearly, is also recommended. The US Food andDrug Administration (FDA) recommends that, for patients at risk for renal failure (eg, those withpreexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia; those older than


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65 y; those who use nephrotoxic drugs), recommended doses should not be exceeded and infusionrates 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 andthose 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 toachieve 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 includetachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache,pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatorycollapse, and loss of consciousness. Patients with more profound immunodeficiency or patients withactive infections have more severe reactions.

Anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes arethought to be related to the adverse reactions. The formation of oligomeric or polymeric IgGcomplexes that interact with Fc receptors and trigger the release of inflammatory mediators is anothercause. 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 (6mg/kg/dose, maximum 100 mg) 1 hour before the infusion may prevent adverse reactions. In somepatients 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 IVIGproducts using sucrose as a stabilizer may be associated with a greater risk for this renalcomplication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive ofosmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should notexceed 3 mg sucrose/kg/min. Risk factors for this adverse reaction include preexisting renalinsufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, andconcomitant use of nephrotoxic agents. For patients at increased risk, monitoring BUN and creatininelevels 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-deficientpatients. True anaphylaxis has been reported in patients with selective IgA deficiency and commonvariable immunodeficiency (CVID) who developed IgE antibodies to IgA after treatment with Ig. Inactual 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 inpatients who are IgA deficient (< 7 mg/dL) and need IVIG because of IgG subclass deficiencies. IVIGpreparations with very low concentrations of contaminating IgA are advised.

Subcutaneous immunoglobulin (SCIG) administration is also possible. The recommended dose is100-200 mg/kg SC every week. The initial weekly SC dose can be calculated by multiplying theprevious 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, multiply200 mg/kg by 1.37 and then divide by 3 to get a calculated dose of 91 mg/kg SC every week. Thecalculated SCIG dose provides systemic exposure similar to that of the previous IVIG dose. SCIGdose should be initiated 1 week after the last IVIG dose. For SCIG administration, do not exceed 15mL (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 thetrough serum IgG level.[54] Therefore, maintaining higher IgG levels may be beneficial but no givenlevel 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 theUnited States in 2006 with a FDA-approved product. A cost comparison analysis was made in Francebetween 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)


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Brand(Manufacturer) Manufacturing Process pH Additives (IVIG

products containing

sucrose are more often

associated with renal

dysfunction, acute renal

failure, and osmoticnephrosis, 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 4incubation,

nanofiltration

6.4-

6.8

6% solution: 10%

sucrose, < 20 mg NaCl/gprotein

Lyophilized

powder 3%,6%, 9%, 12%

Trace

Flebogamma

(Grifols USA)

Cohn-Oncley

fractionation, PEG

precipitation, ion-

exchange

chromatography,

pasteurization

5.1-

6

Sucrose free, contains

5% D-sorbitol

Liquid 5% < 50

Gammagard Liquid

10%

(Baxter Bioscience)

Cohn-Oncley cold

ethanol fractionation,

cation and anion

exchange

chromatography,

solvent detergent

treated, nanofiltration,

low pH incubation

4.6-

5.1

0.25M glycine Ready-for-use

liquid 10%

37

Gammar-P IV

(ZLB Behring)

Cohn-Oncley fraction

II/III; ultrafiltration;

pasteurization

6.4-

7.2

5% solution: 5% sucrose,

3% albumin, 0.5% NaCl

Lyophilized

powder 5%

< 20

Gamunex Cohn-Oncley 4- Contains no sugar, Liquid 10% 46


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(Talecris

Biotherapeutics)

fractionation,

caprylate-

chromatography

purification, cloth and

depth filtration, low pH

incubation

4.5 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

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)



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 becauseof unexplained reports



low pH incubation; S/D

treatment

pasteurization

5.1-

6

10% maltose Liquid 5% 200


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of thromboembolic

events

Panglobulin

(Swiss Red Cross for

the American Red

Cross)

Kistler-Nitschmann

fractionation; pH 4

incubation, trace

pepsin, nanofiltration

6.6 Per gram of IgG: 1.67 g

sucrose, < 20 mg NaCl

Lyophilized

powder 3%,

6%, 9%, 12%

720

Privigen

(CSL Behring)

pH 4 incubation;octanoic acid

fractionation, depth

filtration, and virus

filtration

4.6-5

10% solution;Preservative-free,

sucrose-free, and

maltose-free

Ready-to-usesolution 10%

< 25

Although IVIG has improved the patient's ability to handle infections, aggressive treatment for acutebacterial infections with specific antibiotics continues to be necessary. No difference in efficacyamong the brands of IVIG is recognized. One review indicated that IVIG at a mean dose of 0.42 g/kgin 162 treatment years resulted in an infection rate similar to the general pediatric population. All 18children 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 theadditional 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

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

Antibodies

Class Summary

Prevention of respiratory syncytial virus (RSV) in immunodeficient patients is possible with passiveimmunization humanized mouse monoclonal IgG.

Palivizumab (Synagis)
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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 circulatingmyelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines,including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells andaugments suppressor T cells; blocks complement cascade. Peak serum IgG levels are lower andtrough IgG levels are higher than those achieved with IVIG. SC administration results in stablesteady-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 inthe household because the attenuated virus is excreted and poses a threat to immunodeficientpatients. 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 laboratoriescan determine the presence of an enterovirus, poliovirus identification requires sending the viralspecimen to a state referral laboratory. Administer intravenous immunoglobulin (IVIG) and maintainserum immunoglobulin (Ig)G levels higher than 500 mg/dL.

Frequent monitoring of the patient's pulmonary status is important because the main long-termcomplication continues to be chronic lung disease. Regular measurements of pulmonary lung functionshould be obtained and high-resolution CT scanning of the lungs should be performed. If end-stagelung disease develops, lung transplantation has been performed in patients with agammaglobulinemiausing intensive IVIG administration (every 48 h during the first 10 d after transplant).

Extensive diagnostic tests including cerebrospinal fluid (CSF) analyses with polymerase chainreaction (PCR) for viral genomes, neuroimaging, and electrophysiologic studies need to be pursued toevaluate for infectious or autoimmune complications.

Successful cure has been reported using stem cells from either cord blood or bone marrow fromhuman leukocyte antigen (HLA)-matched siblings.[59]

Inpatient & Outpatient Medications

Administer IVIG to every patient with agammaglobulinemia. In rare circumstances (eg, temporary lackof venous access), intramuscular IgG can be given. Subcutaneous administration of IVIG is an optiondepending on individual preferences. A survey revealed that 90% of 1243 (1119) patients with primaryimmunodeficiencies 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 theSCIG preparation was available.

Because these patients risk developing unusual infections, attempt to identify any pathogens in eitherthe respiratory or gastrointestinal tracts. More modern techniques using PCR helpeddiagnose Mycoplasma pneumoniaeosteomyelitis in a patient with hypogammaglobulinemia withrepeatedly sterile pus cultures.

For patients to have refractory Campylobacter jejuniinfection 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 bronchoscopyusing traditional culture as well as PCR may help determine the various viruses and bacteria present.

Complications
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Maintain IVIG and aggressively treat pneumonias with antibiotics to avoid chronic lung disease.Recurrent infections may eventually cause either obstructive disease alone or combined obstructiveand restrictive lung disease. Aerosol treatments with bronchodilators and chest physiotherapy, suchas 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 childrenaged 3-5 years, reflecting the widespread use of antibiotics. Unfortunately, permanent damage to thelungs with bronchiectasis may have already occurred.[61]

This could be reflected in continued decline in pulmonary function testing.[62]However, increasing thedose may blunt this decline. The presence of bronchiectasis has also been found to correlate withcontinued risk for developing pneumonia despite immunoglobulin replacement therapy.[63]

No good studies have examined the effectiveness of aerosol treatments in these patients, althoughone may speculate that mobilization of secretions should help. Similarly, no good studies haveexamined the usefulness of prophylactic antibiotics, either systemically or topically (ie, aerosolized).

Unusual pulmonary disorders such as recurrent pulmonary alveolar proteinosis, which is notassociated 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 withprimary 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 thelymphoreticular and GI organs, which may be the result of altered immune surveillance, especially atthe 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 recessiveagammaglobulinemia.[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 variableimmunodeficiency disease [CVID]). In one survey in Japan, approximately 2.7% of patients withprimary immunodeficiency diseases developed malignant disorders.[68]

The association of hypogammaglobulinemia with thymoma is well recognized and is known as Goodsyndrome.

Reports of progressive neurodegeneration in patients with primary immunodeficiency on IVIGtreatment are concerning.[69, 70] Extensive diagnostic tests including CSF analyses with PCR for viralgenomes, neuroimaging, and electrophysiologic studies need to be pursued to evaluate for infectiousor autoimmune complications. Autoimmune diseases (eg,inflammatory bowel disease,atrophicgastritis, pernicious anemia) are also observed in patients with agammaglobulinemia or

hypogammaglobulinemia. Their occurrence suggests that the altered immune system, with its lowresistance to infectious pathogens, may cause an inappropriate hyperfunction toward self-antigensthat cause autoimmune disorders.

Treatment may consist of increasing the dose of immunoglobulin replacement and/or steroids orrituximab.[71]

Prognosis

The outcome of patients with agammaglobulinemia or hypogammaglobulinemia depends on theunderlying disease.

For patients with agammaglobulinemia, overall prognosis is good when patients comply with theirIVIG or SCIG therapy and attend to the possible complications of chronic infections in the upper and

lower respiratory tracts.
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In a 10-year prospective study of children younger than 4 years with hypogammaglobulinemia, Dalalet 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 withpersistently low IgG levels.[72] In a similar study with 8-year follow-up, Kidon et al (2004) found that75% of children with hypogammaglobulinemia normalized their serum Ig levels (and were thereforediagnosed with transient hypogammaglobulinemia of infancy).[73] Finally, Kutukculer and Gulez

followed a group of 37 patients with hypogammaglobulinemia and found 49% spontaneouslycorrected their immunoglobulin abnormalities with IgG or IgM levels reaching normal levels at about 5years of age and IgA levels by about 6 years of age.

Cases of so-called "reversible hypogammaglobulinemia" have been reported in which adult patientson IVIG therapy resume immunoglobulin production.[74]

In studies of patients before IVIG treatment was developed, 75% of patients older than 20 years haddeveloped 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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