IgG deficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Overview

IgG deficiency (Selective deficiency of immunoglobulin G) is a form of hypogammaglobulinemia where the proportional levels of the IgG isotype are reduced relative to other immunoglobulin isotypes. IgG deficiency is often found in children as transient hypogammaglobulinemia of infancy (THI), which may occur with or without additional decreases in IgA or IgM.

IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4. It is possible to have either a global IgG deficiency, or a deficiency of one or more specific subclasses of IgG.[1][2] The main clinically relevant form of IgG deficiency is IgG2. IgG3 deficiency is not usually encountered without other concomitant immunoglobulin deficiencies, and IgG4 deficiency is very common but usually asymptomatic.[3]

IgG1 is present in the bloodstream at a percentage of about 60-70%, IgG2-20-30%, IgG3 about 5-8 %, and IgG4 1-3 %. IgG subclass deficiencies affect only IgG subclasses (usually IgG2 or IgG3), with normal total IgG and IgM immunoglobulins and other components of the immune system being at normal levels. These deficiencies can affect only one subclass or involve an association of two subclasses, such as IgG2 and IgG4. IgG deficiencies are usually not diagnosed until the age of 10. Some of the IgG levels in the blood are undetectable and have a low percentage such as IgG4, which makes it hard to dertermine if a deficiency is actually present. IgG subclass deficiencies are sometimes correlated with bad responses to pneumoccal polyscaccharides, especially IgG2 and or IgG4 deficiency. Some of these deficiencies are also involved with pancreatitis and have been linked to IgG4 levels.

Historical Perspective

In 1952, Bruton reported a condition in an 8-year-old boy with recurrent episodes of bacterial infections and sepsis with the same serotypes of pneumococcus, while he had intact lymphoid tissue and B-cells but had decreased IgG levels and he had no antibodies against this pathogen.[4]

In the 1960s, by the discovery of the IgG subclasses, further aspects of IgG deficiency and recurrent infection, were uncovered. and thrown new light on the understanding of IgG deficiencies subclasses, as isolated deficiencies (eg, selective IgG deficiency) or in association with deficiencies of other immunoglobulin types. Moreover, how even if the total IgG concentration is normal, deficiencies of one or more individual IgG subclasses, may be observed.[5]

Classification

IgG deficiency may be classified according to individual IgG subclasses deficiency into four subtypes:

  • IgG1 deficiency : since IgG1 normally comprises almost two-thirds of the total serum IgG Most patients with IgG1 deficiency have generalized hypogammaglobulinemia.Thus, most patients with significant IgG1 deficiency are classified as common variable immunodeficiency (CVID), a diagnosis that also requires decreased levels of IgA and/or IgM. Only patients with selective IgG1 deficiency and normal levels of total IgG should be diagnosed with IgG1 deficiency. Selective IgG1 deficiency with normal total IgG is uncommon.[6]
  • IgG2 deficiency : is more prevalent among children than adults and is one of the most frequently identified disorders in children with recurrent infections.It has been described both as an isolated finding and in combination with IgG4 and/or IgA deficiency.[7][8]
  • IgG3 deficiency : is more common in adults than children. It may occur alone or in combination with other subclass deficiencies, especially IgG1.[9]
  • IgG4 deficiency : is considered to be common in the general population, meanwhile the majority of patients are asymptomatic. It may occur alone, or in combination with IgG2 deficiency, and with IgA-IgG2 deficiencies[10][11]

Pathophysiology

Immunodeficiency diseases are described according to involvement one or more of the 4 major components of the immune system. These components are 1) B cells; 2) T cells, 3) phagocytes; and 4) complement

B-cell or humoral immunity is mediated by the immunoglobulins. There are five types or classes of immunoglobulin: IgG, IgA, IgM, IgD, and IgE. The IgG class of antibodies is composed of four different subtypes of IgG molecules called the IgG subclasses. These are designated IgG1, IgG2, IgG3, and IgG4. The term "IgG subclass deficiency" refers to a significant decrease in the serum concentrations of one or more subclasses of IgG in a patient whose total IgG concentration is normal [12]

PATHOGENESIS

The primary mechanisms underlying IgG subclass deficiency are unclear. Gene deletions, transcription errors, cytokine dysregulation, immunosuppressive therapy, and allotypic variations are some mechanisms that have been described:

  • Gene deletions: Heterozygous gene deletions cause the reduction in the serum concentration of the corresponding subclass. Deletions have been detected for genes C-gamma-1, C-gamma-2, and C-gamma-4 . Homozygous deletions of large portions of the immunoglobulin heavy chain gene, causes the absence of multiple immunoglobulin classes, and are also described. Such patients may have no detectable IgG1, IgG2, IgG4, IgA1, or IgE .[13]
  • Transcription errors: Changes of germline transcription and limitation fragment length polymorphisms 5' of the S-gamma-4 loci within the gamma-chain constant region gene complex have been described among patients with IgG4 deficiency compared with controls.[14]
  • Effect of allotype: Some IgG subclass deficiencies may be affected by allotype. The absence of the G2m(n) allotype and homozygosity for the G3m(g) and G3m(b) allotypes has been discoverd among Caucasian patients.[15]

Causes

  • There are no established causes for IgG deficiency, and mechanisms underlying IgG subclass deficiency are unclear. Genetic, transcription errors, allotypic variations,and immunosuppressive therapy are some mechanisms that have been proposed.

Differentiating IgG deficiency from other Diseases

IgG deficiency must be differentiated from other diseases that cause recurrent episodic infections, especially recurrent sinopulmonary infections include otitis media, rhinosinusitis, and pneumonia. Besides serious infections such as osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections, are conditions propose the possibility for immunodeficiency:

  • Malignancy: can cause the reduction in the immunoglobulin production.[16]
  • Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
  • Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.[17]
  • Other causes of primary humoral immunodeficiencies.
  • Smoking: may cause IgG2 subclass deficiency.[18]
  • Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

Epidemiology and Demographics

The prevalence of IgG deficiency is not clear. Some studies estimated that the prevalence of IgG deficiency may be 1 case per 10,000 persons.Among patient populations with more frequent or severe infections, IgG subclass deficiency is a common finding. In two large series from France, IgG subclass deficiency was reported in 20 percent of 483 patients with abnormally recurrent, prolonged, or severe infection; IgG3 was the most common deficiency.[19][20]

In a report of 1175 adults with symptoms suggestive of an antibody deficiency, decreased IgG1, IgG2, IgG3, and IgG4 levels were reported in 28, 17, 13, and 9 percent, respectively.[21]

Age

  • IgG deficiency can affect both children and adults. The most common subclass deficiency in early childhood is IgG2 deficiency; in adults, IgG1 and IgG3 deficiencies predominate. In children, IgG1 deficiency accounts for higher cases of the total IgG deficiency in comparison to adults. even though children reach the adult levels of IgG1 and IgG3, but the development of IgG2 and IgG4 is slower. In some children, maturation of IgG subclasses may be delayed until the adolescence.[22]

Gender

  • The gender prevalance of IgG deficiency differs in children and adults. In children, IgG deficiency is more common in boys by a ratio of 3:1. In contrast, there is a predominance of females after age 16. This shift in gender distribution may be owing to hormonal influences upon the immune system.[23]

Race

  • There is no racial predilection for IgG deficiency.

Risk Factors

Common risk factors in the development of IgG deficiency:

  • Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.
  • Intense exercise or excessive physical stress
  • Smoking
  • Aging

Natural History, Complications and Prognosis

  • The majority of patients with IgG deficiency remain asymptomatic.[24] In addition, there are patients with complete deficiencies of multiple combinations of IgG1, IgG2, IgG4, IgE, or IgA deficiency who remain healthy and free of infections.[25]
  • Early clinical features include recurrent sinopulmonary infections. More serious infections that can occur include osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections
  • If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
  • Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
  • Prognosis is generally influenced by the age of the patient as well as the degree of deficiency.
  • Evidence suggests that the majority of children younger than six to eight years of age with clinically significant IgG subclass deficiency and diminished specific antibody responses will normalize both antibody responsiveness and IgG subclass level(s).[26]
This appears to be particularly true for young children with IgG2 and IgA deficiency and impaired responses to polysaccharide antigens. In contrast, if the condition persists beyond the age of six years, it is likely to be permanent.
  • Adults with clinically significant IgG subclass deficiency and diminished specific antibody responses will rarely achieve normalization of a deficient IgG subclass level

Diagnosis

Diagnostic Criteria

IgG subclass deficiency is a laboratory finding that does not necessarily equate to a clinical disorder. The diagnosis of a clinically significant IgG subclass deficiency requires evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge.

  • The diagnosis of IgG deficiency is made when at least one of the following two diagnostic criteria are met:
  • low IgG subclass levels
  • poor antibody response to vaccine challenge

Symptoms

  • IgG deficiency is usually asymptomatic.
  • Symptoms of IgG deficiency may include the symptoms of recurrent sinopulmonary infections include otitis media, rhinosinusitis, and pneumonia and More serious infections that can occur include osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections:

Physical Examination

  • Physical examination of patients with longstanding immune defectsmay may be remarkable for:
  • low body mass index (BMI)
  • scarring (of tympanic membranes or skin)
  • signs of chronic lung disease (chronic cough, absent gag reflex, clubbing, crackles, or wheezing to suggest bronchiectasis)
  • ongoing infection (signs of chronic sinusitis, oral thrush, warts, or dermatophyte infections)

Laboratory Findings

  • IgG subclass deficiency is a laboratory finding that does not necessarily equate to a clinical disorder.

The normal ranges for IgG subclasses are broad and vary with the age of the population studied, presence or absence of disease, and the method of analysis (table 1) [2-9].

For children 4 to 10 years of age, levels below the following are considered abnormal:

●IgG1 level <250 mg/dL

●IgG2 level <50 mg/dL

●IgG3 level <15 mg/dL

●IgG4 level <1 mg/dL

For individuals older than 10 years of age, levels below the following are considered abnormal:

●IgG1 level <300 mg/dL

●IgG2 level <50 mg/dL

●IgG3 level <25 mg/dL

●IgG4 level <1 mg/dL

Vaccine Challange Response

IgG subclass deficiency is a laboratory finding that does not necessarily equate to a clinical disorder. The diagnosis of a clinically significant IgG subclass deficiency requires evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge.

Vaccine response is part of the evaluation of possible immunodeficiency. The clinical indications for assessing vaccine responsiveness include frequent and recurrent sinopulmonary or ear infections, chronic gastrointestinal infections, any severe or unusual infections, and abnormal need for antibiotics (table 1). Most patients have already had serum levels of immunoglobulin (Ig)G, IgA, and IgM measured, but if not, these can be obtained at the same time that vaccine response is assessed. The different warning signs of immunodeficiency are reviewed in more detail elsewhere:

Titers of IgG antibodies to tetanus and diphtheria in vaccinated children and adults are used to evaluate immune responsiveness to protein antigens. Results are reported as IgG in general, although the antibody responses generated by these vaccines are largely (but not exclusively) composed of IgG1 and IgG3 antibodies, which is sometimes important in evaluation of IgG subclass deficiency.

Interpretation of Hib titers — The capsular polysaccharide polyribosylribitol phosphate (PRP) is an important antigen in immunity to Haemophilus influenzae type B (Hib). Anti-PRP IgG titers ≥1 mcg/mL are considered protective [28]. Although the polysaccharide PRP is the primary antigen, the conjugate vaccines employ either diphtheria toxoid or the outer membrane protein complex of meningococcus as the immunogenic protein. Therefore, antibodies to the Hib capsular polysaccharide in patients who received the conjugated Hib vaccine reflect a protein response, and protective antibodies against the PRP polysaccharide do not exclude unresponsiveness to the pure pneumococcal polysaccharides. Children in the United States have been receiving conjugated vaccines for prophylaxis against Hib since the early 1990s.

Treatment

Medical Therapy

  • The mainstay of therapy for IgG deficiency includes the following:
  • ●Immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines
  • All patients with IgG subclass deficiency and poor responses to polysaccharide vaccines should receive a conjugated pneumococcal vaccine in order to boost immunity to this common respiratory pathogen. ●Aggressive management of other conditions predisposing to recurrent sinopulmonary infections (eg, asthma, allergic rhinitis)
  • Aggressive management of any conditions predisposing to recurrent sinopulmonary infections (especially allergic rhinitis and asthma) is critical to improving the clinical outcome of patients with IgG subclass deficiency. Atopic disorders occurred in 55 to 58 percent of the children with SAD with or without IgG2-IgA deficiency in one report ●Increased vigilance and appropriate antibiotic therapy for infections
  • Prompt recognition and treatment of sinopulmonary bacterial infections is a significant component of management of these patients, since infections are less likely to clear spontaneously in patients with antibody defects. ●Prophylactic antibiotics
  • Patients with recurrent sinopulmonary infections, despite the previously described measures, usually require prophylactic antibiotics. Evidence in support of this approach is largely derived from benefits observed in retrospective studies of children with this and similar antibody deficiencies. ●Intravenous or subcutaneous immune globulin replacement
  • Judicious use of immune globulin therapy is appropriate if the use of prophylactic antibiotics does not result in fewer infections and/or in patients with persistent and symptomatic chronic rhinosinusitis. This therapy should be reserved for patients with clearly impaired responses to protein and/or polysaccharide antigens [93-95]. Most of the patients requiring this intervention have impaired antibody responses to bacterial polysaccharide antigens with IgG2 +/-IgG4 deficiency, although there are reported cases of benefit in IgG3 deficiency as well [71]. Intravenous immune globulin therapy, at a standard dose range of 400 to 600 mg/kg, can be infused every three to four weeks [96]. Immune globulin can also be replaced subcutaneously at weekly intervals. (See "Immune globulin therapy in primary immunodeficiency".) Patients with selective IgG4 or IgG3 deficiency usually have normal antibody responses, although differing degrees of impaired specific antibody responses in patients with IgG3 deficiency have been noted [73,97,98]. The role of immune globulin in these patients is not as clear. However, several studies have reported clinical improvement in patients with IgG3 deficiency as a result of this intervention [73,97,99,100]. In the largest study, which included 33 patients with IgG3 deficiency, patients with more than four antibiotic-requiring RTIs per year were treated with immune globulin, and the number of infections before and during treatment was compared [100]. Reduction in the number of RTIs was seen in 29 of 33 patients with IgG3 deficiency: 23 experienced a ≥50 percent reduction, and 6 had a reduction of <50 percent. Immune globulin therapy should be administered for one to two years initially, at which point the patient's status should be re-evaluated to determine if the number and/or severity of infections have been reduced. Not all patients with IgG subclass deficiencies benefit from immune globulin replacement, and the therapy should be discontinued if not effective in that individual [100].

Prevention

  • There are no primary preventive measures available for IgG deficiency.
  • Secondary prevention strategies following IgG deficiency include avoidance measures, vaccination, prophylactic antibiotics, immune globulin therapy,and when infections do occur, broader spectrum and more prolonged antibiotics are often required.
  • Avoidance: to reduce exposure to others with potentially contagious illnesses: proper handwashing and use of alcohol-based disinfectants should be provided to patients and their families Co-sleeping among family members should be minimized, and immunization of family members and close contacts
  • Careful attention should be paid to patient's oral hygiene and dental health.
  • Vaccination Immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines Advisory Committee on Immunization Practices (ACIP)[27]
  • recommended that conjugated Hib vaccine be administered in patients with IgG2 subclass deficiency and those with specific antibody deficiency (SAD) [28][29]
  • ANTIMICROBIAL THERAPY Treating acute infections Prophylactic antimicrobial therapy Patients with recurrent sinopulmonary infections, despite the previously described measures, usually require prophylactic antibiotics

References

  1. ↑ Barton JC, Bertoli LF, Acton RT (June 2003). "HLA-A and -B alleles and haplotypes in 240 index patients with common variable immunodeficiency and selective IgG subclass deficiency in central Alabama". BMC Med. Genet. 4: 3. doi:10.1186/1471-2350-4-3. PMC 166147. PMID 12803653.
  2. ↑ Dhooge IJ, van Kempen MJ, Sanders LA, Rijkers GT (June 2002). "Deficient IgA and IgG2 anti-pneumococcal antibody levels and response to vaccination in otitis prone children". Int. J. Pediatr. Otorhinolaryngol. 64 (2): 133–41. doi:10.1016/S0165-5876(02)00068-X. PMID 12049826.
  3. ↑ Driessen, G; van der Burg, M (June 2011). "Educational paper: primary antibody deficiencies". European journal of pediatrics. 170 (6): 693–702. doi:10.1007/s00431-011-1474-x. PMID 21544519.
  4. ↑ Melamed, Isaac R.; Heffron, Melinda; McGee, Sean; Ulltate Sanz, Laura; Testori, Alessandro (2015). "A new subset of common variable immune deficiency characterized by reduced C1 esterase inhibitor levels". Annals of Allergy, Asthma & Immunology. 115 (1): 83–84. doi:10.1016/j.anai.2015.04.023. ISSN 1081-1206.
  5. ↑ Vidarsson, Gestur; Dekkers, Gillian; Rispens, Theo (2014). "IgG Subclasses and Allotypes: From Structure to Effector Functions". Frontiers in Immunology. 5. doi:10.3389/fimmu.2014.00520. ISSN 1664-3224.
  6. ↑ C. Lacombe, P. Aucouturier & J. L. Preud'homme (1997). "Selective IgG1 deficiency". Clinical immunology and immunopathology. 84 (2): 194–201. PMID 9245552. Unknown parameter |month= ignored (help)
  7. ↑ T. Soderstrom, R. Soderstrom, A. Avanzini, P. Brandtzaeg, G. Karlsson & L. A. Hanson (1987). "Immunoglobulin G subclass deficiencies". International archives of allergy and applied immunology. 82 (3–4): 476–480. PMID 3570516.
  8. ↑ V. A. Oxelius, A. B. Laurell, B. Lindquist, H. Golebiowska, U. Axelsson, J. Bjorkander & L. A. Hanson (1981). "IgG subclasses in selective IgA deficiency: importance of IgG2-IgA deficiency". The New England journal of medicine. 304 (24): 1476–1477. doi:10.1056/NEJM198106113042408. PMID 7231479. Unknown parameter |month= ignored (help)
  9. ↑ V. A. Oxelius (1993). "Serum IgG and IgG subclass contents in different Gm phenotypes". Scandinavian journal of immunology. 37 (2): 149–153. PMID 8434227. Unknown parameter |month= ignored (help)
  10. ↑ V. A. Oxelius (1974). "Chronic infections in a family with hereditary deficiency of IgG2 and IgG4". Clinical and experimental immunology. 17 (1): 19–27. PMID 4143113. Unknown parameter |month= ignored (help)
  11. ↑ V. A. Oxelius, A. B. Laurell, B. Lindquist, H. Golebiowska, U. Axelsson, J. Bjorkander & L. A. Hanson (1981). "IgG subclasses in selective IgA deficiency: importance of IgG2-IgA deficiency". The New England journal of medicine. 304 (24): 1476–1477. doi:10.1056/NEJM198106113042408. PMID 7231479. Unknown parameter |month= ignored (help)
  12. ↑ Herrod HG. Clinical significance of IgG subclasses. Curr Opin Pediatr 1993; 5:696
  13. ↑ H. Rabbani, N. Kondo, C. I. Smith & L. Hammarstrom (1995). "The influence of gene deletions and duplications within the IGHC locus on serum immunoglobulin subclass levels". Clinical immunology and immunopathology. 76 (3 Pt 2): S214–S218. PMID 7554471. Unknown parameter |month= ignored (help)
  14. ↑ A. Bottaro, M. DeMarchi, G. G. DeLange, C. Boccazzi, L. Fubini, C. Borra, N. Cappello & A. O. Carbonara (1989). "Human IGHC locus restriction fragment length polymorphisms in IgG4 deficiency: evidence for a structural IGHC defect". European journal of immunology. 19 (11): 2159–2162. doi:10.1002/eji.1830191128. PMID 2574682. Unknown parameter |month= ignored (help)
  15. ↑ V. A. Oxelius (1993). "Serum IgG and IgG subclass contents in different Gm phenotypes". Scandinavian journal of immunology. 37 (2): 149–153. PMID 8434227. Unknown parameter |month= ignored (help)
  16. ↑ T. Zenone, P. J. Souquet, C. Cunningham-Rundles & J. P. Bernard (1996). "Hodgkin's disease associated with IgA and IgG subclass deficiency". Journal of internal medicine. 240 (2): 99–102. PMID 8810936. Unknown parameter |month= ignored (help)
  17. ↑ W. B. Klaustermeyer, M. E. Gianos, M. L. Kurohara, H. T. Dao & D. C. Heiner (1992). "IgG subclass deficiency associated with corticosteroids in obstructive lung disease". Chest. 102 (4): 1137–1142. PMID 1343817. Unknown parameter |month= ignored (help)
  18. ↑ I. Qvarfordt, G. C. Riise, B. A. Andersson & S. Larsson (2001). "IgG subclasses in smokers with chronic bronchitis and recurrent exacerbations". Thorax. 56 (6): 445–449. PMID 11359959. Unknown parameter |month= ignored (help)
  19. ↑ P. Aucouturier, C. Lacombe, C. Bremard, Y. Lebranchu, M. Seligmann, C. Griscelli & J. L. Preud'Homme (1989). "Serum IgG subclass levels in patients with primary immunodeficiency syndromes or abnormal susceptibility to infections". Clinical immunology and immunopathology. 51 (1): 22–37. PMID 2924438. Unknown parameter |month= ignored (help)
  20. ↑ P. Aucouturier, M. Mariault, C. Lacombe & J. L. Preud'homme (1992). "Frequency of selective IgG subclass deficiency: a reappraisal". Clinical immunology and immunopathology. 63 (3): 289–291. PMID 1623649. Unknown parameter |month= ignored (help)
  21. ↑ Meulenbroek AJ, Zeijlemaker WP. Human IgG subclasses: Useful diagnostic markers for immunocompetence, 2nd edition, CLB, Amsterdam, The Netherlands 2000
  22. ↑ F. C. 3rd Javier, C. M. Moore & R. U. Sorensen (2000). "Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital". Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 84 (1): 25–30. doi:10.1016/S1081-1206(10)62736-6. PMID 10674561. Unknown parameter |month= ignored (help)
  23. ↑ L. A. Hanson, R. Soderstrom, A. Avanzini, U. Bengtsson, J. Bjorkander & T. Soderstrom (1988). "Immunoglobulin subclass deficiency". The Pediatric infectious disease journal. 7 (5 Suppl): S17–S21. PMID 3041356. Unknown parameter |month= ignored (help)
  24. ↑ P. G. Shackelford, D. M. Granoff, J. V. Madassery, M. G. Scott & M. H. Nahm (1990). "Clinical and immunologic characteristics of healthy children with subnormal serum concentrations of IgG2". Pediatric research. 27 (1): 16–21. doi:10.1203/00006450-199001000-00004. PMID 2296465. Unknown parameter |month= ignored (help)
  25. ↑ M. P. Lefranc, L. Hammarstrom, C. I. Smith & G. Lefranc (1991). "Gene deletions in the human immunoglobulin heavy chain constant region locus: molecular and immunological analysis". Immunodeficiency reviews. 2 (4): 265–281. PMID 1905558.
  26. ↑ Wolpert, Joshua; Knutsen, Alan P. (1998). "Natural History of Selective Antibody Deficiency to Bacterial Polysaccharide Antigens in Children". Pediatric Asthma, Allergy & Immunology. 12 (3): 183–191. doi:10.1089/pai.1998.12.183. ISSN 0883-1874.
  27. ↑ R. U. Sorensen, L. E. Leiva, P. A. Giangrosso, B. Butler, F. C. 3rd Javier, D. M. Sacerdote, N. Bradford & C. Moore (1998). "Response to a heptavalent conjugate Streptococcus pneumoniae vaccine in children with recurrent infections who are unresponsive to the polysaccharide vaccine". The Pediatric infectious disease journal. 17 (8): 685–691. PMID 9726341. Unknown parameter |month= ignored (help)
  28. ↑ R. U. Sorensen, L. E. Leiva, P. A. Giangrosso, B. Butler, F. C. 3rd Javier, D. M. Sacerdote, N. Bradford & C. Moore (1998). "Response to a heptavalent conjugate Streptococcus pneumoniae vaccine in children with recurrent infections who are unresponsive to the polysaccharide vaccine". The Pediatric infectious disease journal. 17 (8): 685–691. PMID 9726341. Unknown parameter |month= ignored (help)
  29. ↑ Lorry G. Rubin, Myron J. Levin, Per Ljungman, E. Graham Davies, Robin Avery, Marcie Tomblyn, Athos Bousvaros, Shireesha Dhanireddy, Lillian Sung, Harry Keyserling & Insoo Kang (2014). "2013 IDSA clinical practice guideline for vaccination of the immunocompromised host". Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 58 (3): e44–100. doi:10.1093/cid/cit684. PMID 24311479. Unknown parameter |month= ignored (help)


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