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.
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.
The remaining type is early onset non–Bruton 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 pro–B-cell to pre–B-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 pro–B 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-α (CD79a) and Ig-β (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 pre – B-cell and B-cell receptor (lambd α 5, Ig-α, and Ig-β), or the scaffolding protein BLNK account for approximately 90% of defects in early B-cell development.[1] Mutations in Btk result in Bruton agammaglobulinemia. The defect of µ 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-α and Ig-β are encoded by the mb-1 and B29 genes, respectively. A case involving a female patient with a mutation in the Ig-λ 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 pre–B-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 pro–B cells but no pre–B 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 B-cell development.
The exact defects have not yet been determined in other patients in whom agammaglobulinemia has been associated with a mosaic of ring chromosome 18[3] or hypogammaglobulinemia in a male with ring chromosome 21.[4] Patients with B-cell deficiency associated with intrauterine growth retardation have been described,[5] and patients with agammaglobulinemia with spondyloepiphyseal dysplasia and retinal dystrophy have also been described.[6] The syndrome of X-linked hypogammaglobulinemia with growth hormone deficiency has also been reported.[7] This has been mapped to the same region that encompasses the Btk gene 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.[8] 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.[9] Of these, 49 were reported as XLA.
In Brazil, of 166 cases of primary immunodeficiencies diagnosed over 15 years, 60.8% (101) were primary humoral deficiencies; of these, XLA was the least frequent (9), compared with IgA deficiency (60) and transient hypogammaglobulinemia (14).[10]
In South Africa, antibody deficiencies predominate, accounting for 56% (52 of 93) of diagnoses,[11] compared with Australia, where antibody deficiencies comprised 71% of 500 cases enrolled in a national registry.[12]
In Hong Kong, humoral defects were identified in 50 of 117 patients diagnosed with primary immunodeficiency.[13]
Mortality/Morbidity
Patients with agammaglobulinemia are at risk of frequent and recurrent infections. Severe bacterial infections resulting in pneumonias or meningitis and subsequent bacteremia 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-Btk mutations tend to be younger at the time of diagnosis, and they are more likely to have severe complications.
Conley ME, Famer DM, Dobbs AK, et al. A minimally hypomorphic mutation in Btk resulting in reduced B cell numbers but no clinical disease. Clin Exp Immunol. 2008;152:39-44.
Ferrari S, Lougaris V, Caraffi S, et al. Mutations of the Igbeta gene cause agammaglobulinemia in man. J Exp Med. Sep 3 2007;204(9):2047-51. [Medline].
Litzman J, Brysova V, Gaillyova R, et al. Agammaglobulinaemia in a girl with a mosaic of ring 18 chromosome. J Paediatr Child Health. Feb 1998;34(1):92-4. [Medline].
Ohga S, Nakao F, Narazaki O, et al. Hypogammaglobulinaemia in a patient with ring chromosome 21. Arch Dis Child. Sep 1997;77(3):252-4. [Medline].
Revy P, Busslinger M, Tashiro K, et al. A syndrome involving intrauterine growth retardation, microcephaly, cerebellar hypoplasia, B lymphocyte deficiency, and progressive pancytopenia. Pediatrics. Mar 2000;105(3):E39. [Medline].
Roifman CM. Antibody deficiency, growth retardation, spondyloepiphyseal dysplasia and retinal dystrophy: a novel syndrome. Clin Genet. Feb 1999;55(2):103-9. [Medline].
Stewart DM, Tian LL, Notaranelo LD, Nelson DL. X-linked hypogammaglobulinemia and isolated growth hormone deficiency: an update. Immunol Rev. 2008;40:262-70. [Medline].
al-Attas RA, Rahi AH. Primary antibody deficiency in Arabs: first report from eastern Saudi Arabia. J Clin Immunol. Sep 1998;18(5):368-71. [Medline].
Mila J, Matamoros N, Pons de Ves J, et al. [The Spanish Registry of Primary Immunodeficiencies. REDIP-1998]. Sangre (Barc). Apr 1999;44(2):163-7. [Medline].
Leal RC, Bertelli EC, Soler ZA. Recurrent pneumonia caused by genetic immunodeficiency: a prophylactic and rehabililtative approach. Braz J Infect Dis. 2007;11:307-10. [Medline].
Eley BS, Hughes J, Cooper M, Pienaar S, Beatty DW. Primary immunodeficiency diseases at Red Cross War Memorial Children's Hospital. S Afr Med J. Dec 1997;87(12):1684-8. [Medline].
Baumgart KW, Britton WJ, Kemp A, et al. The spectrum of primary immunodeficiency disorders in Australia. J Allergy Clin Immunol. Sep 1997;100(3):415-23. [Medline].
Lam DS, Lee TL, Chan KW, et al. Primary immunodeficiency in Hong Kong and the use of genetic analysis for diagnosis. Hong Kong Med J. Apr 2005;11(2):90-6. [Medline].
Freeman AF, Holland SM. Persistent bacterial infections and primary immune disorders. Curr Opin Microbiol. 2007;10:70-5. [Medline].
Mamishi S, Shahmahmoudi S, Tabatabaie H, et al. Novel BTK mutation presenting with vaccine-associated paralytic poliomyelitis. Eur J Pediatr. Nov 2008;167(11):1335-8. [Medline]. [Full Text].
Hidalgo S, Garcia Erro M, Cisierna D, Freire MC. Paralytic poliomyelitis caused by a vaccine-derived polio virus in an antibody-deficient Argentinean child. Pediatr Infect Dis J. 2003;22:570-2. [Medline].
Rudge P, Webster AD, Revesz T, et al. Encephalomyelitis in primary hypogammaglobulinaemia. Brain. Feb 1996;119 ( Pt 1):1-15. [Medline].
Katamura K, Hattori H, Kunishima T, et al. Non-progressive viral myelitis in X-linked agammaglobulinemia. Brain Dev. Mar 2002;24(2):109-11. [Medline].
Tasca G, Iorio R, Basile U, et al. Progressive multifocal leukoencephalopathy in a patient with Franklin disease and hypogammaglobulinemia. J Neurol Sci. Sep 15 2009;284(1-2):203-4. [Medline].
Bloom KA, Chung D, Cunningham-Rundles C. Osteoarticular infectious complications in patients with primary immunodeficiencies. Curr Opin Rheumatol. Jul 2008;20(4):480-5. [Medline]. [Full Text].
Bonkowsky JL, Bohnsack JF, Pennington MJ, et al. Leukoencephalopathy, arthritis, colitis, and hypogammaglobulinemia (LACH) in two brothers: a novel syndrome?. Am J Med Genet A. 2004;128:52-6. [Medline].
Akman S, Guven AG, Ince S, et al. IgG and IgG subclasses deficiency in children undergoing continuous ambulatory peritoneal dialysis and its provocative factors. Pediatr Int. Jun 2002;44(3):273-6. [Medline].
Rehman S, Bytnar D, Berkenbosch JW, et al. Hypogammaglobulinemia in pediatric ICU patients. J Intensive Care Med. Sep-Oct 2003;18(5):261-4. [Medline].
Gulino AV. WHIM syndrome: a genetic disorder of leukocyte trafficking. Curr Opin Allergy Clin Immunol. 2003;3:443-50. [Medline].
Lynn J, Knight AK, Kamoun M, Levinson AI. A 55-year-old man with hypogammaglobulinemia, lymphopenia, and unrelenting cutaneous warts. J Allergy Clin Immunol. Aug 2004;114(2):409-14. [Medline].
Agarwal S, Cunningham-Rundles C. Thymoma and immunodeficiency (Good syndrome): a report of 2 unusual cases and review of the literature. Ann Allergy Asthma Immunol. 2007;98:185-90. [Medline].
Onigbanjo MT, Orange JS, Perez EE, Sullivan KE. Hypogammaglobulinemia in a pediatric tertiary care setting. Clin Immunol. 2007;125:52-9. [Medline].
Sawada A, Takihara Y, Kim JY, et al. A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest. Dec 2003;112(11):1707-13. [Medline].
Okumura A, Tsuge I, Kamachi Y et al. Transient hypogammaglobulinemia after antileptic drug hypersensitivity. Pediatr Neurol. 2007;36:342-4. [Medline].
Boccara O, Valevrie-Allanore L, Crickx B et al. Association of hypogammaglobulinemia with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms). Eur J Dermatol. 2006;16:666-8. [Medline]. [Full Text].
Kawano T, Matsuse H, Obase Y, et al. Hypogammaglobulinemia in steroid-dependent asthmatics correlates with the daily dose of oral prednisolone. Int Arch Allergy Immunol. Jul 2002;128(3):240-3. [Medline].
Kitamura A, Takiguchi Y, Tochigi N, et al. Durable hypogammaglobulinemia associated with thymoma (Good syndrome). Intern Med. 2009;48(19):1749-52. [Medline].
Yong PF, Aslam L, Karim MY, Khamashta MA. Management of hypogammaglobulinaemia occurring in patients with systemic lupus erythematosus. Rheumatology (Oxford). Sep 2008;47(9):1400-5. [Medline].
Carneiro-Sampaio M, Liphaus BL, Jesus AA, Silva CA, Oliveira JB, Kiss MH. Understanding systemic lupus erythematosus physiopathology in the light of primary immunodeficiencies. J Clin Immunol. May 2008;28 Suppl 1:S34-41. [Medline].
Orange JS, Geha RS, Bonilla FA. Acute chylothorax in children: selective retention of memory T cells and natural killer cells. J Pediatr. 2003;143:243-9. [Medline].
Bezrodnik L, Raccio AC, Canil LM, Rey MA, Carabajal PC, FOssati CA, et al. Hypogammaglobulinemia secondary to cow-milk allergy in children under 2 years of age. Immunology. 2007;122:140-6. [Medline].
Bondioni MP, Duse M, Plebani A et al. Pulmonary and sinusal changes in 45 patients with primary immunodeficiencies: computed tompgraphy evaluation. J Comput Assist Tompgr. 2007;31:620-8. [Medline].
Rusconi F, Panisi C, Dellepiane RM, et al. Pulmonary and sinus diseases in primary humoral immunodeficiencies with chronic productive cough. Arch Dis Child. Dec 2003;88(12):1101-5. [Medline].
Chinen J, Shearer WT. Subcutaneous immunoglobulins: alternative for the hypogammaglobulinemic patient?. J Allergy Clin Immunol. 2004;114:934-5. [Medline].
Ochs, HD, Gupta S, Kiseeling P et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol. 2006;26:265-73. [Medline].
Gustafson R, Gardulf A, Hansen S et al. Rapid subcutaneous immunoglobulin administration every second week results in high and stable serum immunoglobulin G levels in patients with primary antibody deficiencies. Clin Exp Immunol. 2008;152:274-9. [Medline].
Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook 2008-2009. 16th edition. Cleveland, OH: Lexi-Comp Inc; 2008.
Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. Nov 2008;28(4):765-78, viii. [Medline].
Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. Aug 15 2005;62(16 Suppl 3):S5-11. [Medline].
Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacother. 2005;25(11 Pt 2):78S-84S.
Howard V, Myers LA, Williams DA, et al. Stem cell transplants for patients with X-linked agammaglobulinemia. Clin Immunol. May 2003;107(2):98-102. [Medline].
Quinti I, Pierdominici M, Marziali M, et al. European surveillance of immunoglobulin safety--results of initial survey of 1243 patients with primary immunodeficiencies in 16 countries. Clin Immunol. Sep 2002;104(3):231-6. [Medline].
Buckley RH. Pulmonary complications of primary immunodeficiencies. Paediatr Respir Rev. 2004;5 (Suppl A):S225-33. [Medline].
Patiroglu T, Akyildiz B, Patiroglu TE, Gulmez IY. Recurrent pulmonary alveolar proteinosis secondary to agammaglobulinemia. Pediatr Pulmonol. Jul 2008;43(7):710-3. [Medline].
Berlucchi M, Soresina A, Redaelli De Zinis LO, et al. Sensorineural hearing loss in primary antibody deficiency disorders. J Pediatr. Aug 2008;153(2):293-6. [Medline].
Brosens LA, Tytgat KM, Morsink FH et al. Multiple colorectal neoplasms in X-linked agammaglobulinemia. Clin Gastroenterol Hepatol. 2008;6:115-9. [Medline].
Ziegner UH,, Kobayashi RH, Cunningham-Rundles C, et al. Progressive neurodegeneration in patients with primary immunodeficiency disease on IVIG treatment. Clin Immunol. 2002;102:19-24. [Medline].
Papapetropoulos S, Friedman J, Blackstone C et al. A progressive, fatal dystonia-Parkinsonism syndrome in a patient with primary immunodeficiency receiving chronic IBIG therapy. Mov Disord. 2007;22:1664-6. [Medline].
Dalal I, Reid B, Nisbet-Brown E, Roifman CM. The outcome of patients with hypogammaglobulinemia in infancy and early childhood. J Pediatr. Jul 1998;133(1):144-6. [Medline].
Kidon MI, Handzel ZT, Schwartz R, et al. Symptomatic hypogammaglobulinemia in infancy and childhood - clinical outcome and in vitro immune responses. BMC Fam Pract. Oct 21 2004;5:23. [Medline].
Desar IM, Weemaes CM, van Deuren M et al. Reversible hypogammaglubulinaemia. Neth J Med. 2007;65:381-5. [Medline].
Abe S, Suzuki T, Hori T, Baba A, Shiraishi H. Hypogammaglobulinemia during antipsychotic therapy. Psychiatry Clin Neurosci. Feb 1998;52(1):115-7. [Medline].
Aghamohammadi A, Moin M, Farhoudi A, et al. Efficacy of intravenous immunoglobulin on the prevention of pneumonia in patients with agammaglobulinemia. FEMS Immunol Med Microbiol. Mar 8 2004;40(2):113-8. [Medline].
Asmar BI, Andresen J, Brown WJ. Ureaplasma urealyticum arthritis and bacteremia in agammaglobulinemia. Pediatr Infect Dis J. Jan 1998;17(1):73-6. [Medline].
Black C, Zavod MB, Gosselin BJ. Haemophilus influenzae lymphadenopathy in a patient with agammaglobulinemia: clinical-histologic-microbiologic correlation and review of the literature. Arch PatholLab Med. 2005;129:100-3. [Medline].
Buehring I, Friedrich B, Schaaf J, et al. Chronic sinusitis refractory to standard management in patients with humoral immunodeficiencies. Clin Exp Immunol. Sep 1997;109(3):468-72. [Medline].
Conley ME. Early defects in B cell development. Curr Opin Allergy Clin Immunol. 2002;2:517-22. [Medline].
Conley ME, Broides A, Hernandez-Trujillo V, et al. Genetic analysis of patients with defects in early B-cell development. Immunol Rev. 2005;203:216-34. [Medline].
Conley ME, Dobbs AK, Farmer DM, et al. Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol. 2009;27:199-227. [Medline].
Dittrich AM, Schulze I, Magdorf K, et al. X-linked agammaglobulinaemia and Pneumocystis carinii pneumonia--an unusual coincidence?. Eur J Pediatr. Jun 2003;162(6):432-3. [Medline].
Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. Aug 7 2001;135(3):165-74. [Medline].
Feydy A, Sibilia J, De Kerviler E, et al. Chest high resolution CT in adults with primary humoral immunodeficiency. Br J Radiol. Dec 1996;69(828):1108-16. [Medline].
Fijolek J, Wiatr E, Demkow U, Orlowsk TM. Immunological disturbances in Good's syndrome. Clin Invest Med. Aug 1 2009;32(4):E301-6. [Medline].
Halsey NA, Pinto J, Espinosa-Rosales F et al. Search for poliovirus carriers among people with primary immune deficiency diseases in the United States, Mexico, Brazil and the United Kingdom. Bull World Heatlh Organ. 2004;82:3-8. [Medline].
Kainulainen L, Nikoskelainen J, Vuorinen T, et al. Viruses and bacteria in bronchial samples from patients with primary hypogammaglobulinemia. Am J Respir Crit Care Med. Apr 1999;159(4 Pt 1):1199-204. [Medline].
Kano Y, Inaoka M, Shiohara T. Association between anticonvulsant hypersensitivity syndrome and human herpes 6 reactivation and hypogammaglobulinemia. Arch Dermatol. 2004;140:183-8. [Medline].
Kawai T, Malech HL. WHIM syndrome: congenital immune deficiency disease. Curr Opin Hematol. Jan 2009;16(1):20-6. [Medline]. [Full Text].
Kutukculer N, Gulez N. The outcome of patients with unclassified hypogammaglobulinemia in early childhood. Pediatr Allergy Immunol. Nov 2009;20(7):693-8. [Medline].
Morales P, Hernandez D, Vicente R, et al. Lung transplantation in patients with x-linked agammaglobulinemia. Transplant Proc. Aug 2003;35(5):1942-3. [Medline].
Mueller BU, Pizzo PA. Cancer in children with primary or secondary immunodeficiencies. J Pediatr. Jan 1995;126(1):1-10. [Medline].
Ozdoba C, Ramelli G, Schroth G. MRI in a patient with congenital agammaglobulinaemia. Neuroradiology. Aug 1998;40(8):516-8. [Medline].
Plebani A, Soresina A, Rondelli R, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. Sep 2002;104(3):221-30. [Medline].
Quartier P, Debre M, De Blic J, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr. May 1999;134(5):589-96. [Medline].
Raynaud M, Ronce N, Ayrault AD, et al. X-linked mental retardation with isolated growth hormone deficiency is mapped to Xq22-Xq27.2 in one family. Am J Med Genet. Mar 19 1998;76(3):255-61. [Medline].
Skull S, Kemp A. Treatment of hypogammaglobulinaemia with intravenous immunoglobulin, 1973-93. Arch Dis Child. Jun 1996;74(6):527-30. [Medline].
Teramoto T, Kaneko H, Funato M, et al. Progressive multifocal leukoencephalopathy in a patient with X-linked agammaglobulinemia. Scand J Infect Dis. 2003;35(11-12):909-10. [Medline].
Tokuda K, Nishi J, Miyanohara H, et al. Relapsing cellulitis associated with Campylobacter coli bacteremia in an agammaglobulinemic patient. Pediatr Infect Dis J. Jun 2004;23(6):577-9. [Medline].
Wang LJ, Yang YH, Lin YT, Chiang BL. Immunological and clinical features of pediatric patients with primary hypogammaglobulinemia in Taiwan. Asian Pac J Allergy Immunol. 2004;22:25-31. [Medline].
| Brand(Manufacturer) | Manufacturing Process | pH | Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].) | Parenteral Form and Final Concentrations | IgA Content (mcg/mL) |
| Carimune NF (ZLB Behring) | Kistler-Nitschmann fractionation; pH 4 incubation, nanofiltration | 6.4-6.8 | 6% solution: 10% sucrose, < 20 mg NaCl/g protein | Lyophilized powder 3%, 6%, 9%, 12% | Trace |
| Flebogamma (Grifols USA) | Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization | 5.1-6 | Sucrose free, contains 5% D-sorbitol | Liquid 5% | < 50 |
| Gammagard Liquid 10% (Baxter Bioscience) | Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation | 4.6-5.1 | 0.25M glycine | Ready-for-use liquid 10% | 37 |
| Gammar-P IV (ZLB Behring) | Cohn-Oncley fraction II/III; ultrafiltration; pasteurization | 6.4-7.2 | 5% solution: 5% sucrose, 3% albumin, 0.5% NaCl | Lyophilized powder 5% | < 20 |
| Gamunex (Talecris Biotherapeutics) | Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation | 4-4.5 | Contains no sugar, contains glycine | Liquid 10% | 46 |
| Gammaplex (Bio Products) | Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation | 4.8-5.1 | Contains sorbitol (40 mg/mL); do not administer if fructose intolerant | Ready-for-use solution 5% | < 10 |
| Iveegam EN (Baxter Bioscience) | Cohn-Oncley fraction II/III; ultrafiltration; pasteurization | 6.4-7.2 | 5% solution: 5% glucose, 0.3% NaCl | Lyophilized powder 5% | < 10 |
| Polygam S/D Gammagard S/D (Baxter Bioscience for the American Red Cross) | Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated | 6.4-7.2 | 5% solution: 0.3% albumin, 2.25% glycine, 2% glucose | Lyophilized powder 5%, 10% | < 1.6 (5% solution) |
| Octagam (Octapharma USA) 9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events | Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization | 5.1-6 | 10% maltose | Liquid 5% | 200 |
| Panglobulin (Swiss Red Cross for the American Red Cross) | Kistler-Nitschmann fractionation; pH 4 incubation, trace pepsin, nanofiltration | 6.6 | Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl | Lyophilized powder 3%, 6%, 9%, 12% | 720 |
| Privigen (CSL Behring) | pH 4 incubation; octanoic acid fractionation, depth filtration, and virus filtration | 4.6-5 | 10% solution; Preservative-free, sucrose-free, and maltose-free | Ready-to-use solution 10% | < 25 |
| Brand(Manufacturer) | Manufacturing Process | pH | Additives | Parenteral Form and Final Concentrations | IgA Content mcg/mL |
| Vivaglobin (ZLB Behring) | Cold ethanol fractionation, pasteurization | 6.4-7.2 | 2.25% glycine, 0.3% NaCl | Liquid 16% (160 mg/mL) | < 50 mcg/mL |
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