Immune Deficiency Foundation Patient & Family Handbook

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Immune Deficiency FoundationPatient & FamilyHandbookFor Primary Immunodeficiency DiseasesChapter 6

Immune Deficiency FoundationPatient & FamilyHandbookFor Primary Immunodeficiency Diseases6th EditionThe development of this publication wassupported by Shire, now Takeda.110 West Road, Suite 300Towson, MD

Chapter 6IgG Subclass Deficiency and SpecificAntibody DeficiencyElizabeth Wisner, MD, Children’s Hospital New Orleans, New Orleans, Louisiana, USARicardo Sorensen, MD, Children’s Hospital New Orleans, New Orleans, Louisiana, USAIgG Subclass DeficiencyThe main immunoglobulin (Ig) in human blood is IgG. This is the second mostabundant circulating protein and contains long-term protective antibodiesagainst many infectious agents. IgG is a combination of four slightly differenttypes of immunoglobulin called IgG subclasses: IgG1, IgG2, IgG3 and IgG4.When one or more of these subclasses is persistently low and total IgGis normal, a subclass deficiency is present. IgG subclass deficiencies areclinically relevant only when the levels are absent or very low and whenthey are detected in people with recurrent upper and/or lower respiratoryinfections. In individuals without frequent or severe infections, low levelsof IgG subclasses may be a clinically irrelevant finding. In the absence ofinfections, mild or moderately decreased subclass concentrations shouldnot lead to unnecessary long-term use of immunoglobulin (Ig) replacementtherapy. A subclass deficiency needs to be considered and looked for onlyunder special circumstances discussed in this chapter.DefinitionMost of the antibodies (also known asimmunoglobulins) in the blood and the fluid thatsurround the tissues and cells of the body are ofthe IgG class. This class of antibodies is composedof four different subtypes designated IgG1, IgG2,IgG3, and IgG4. Each subclass is present in differentconcentrations in the blood and also varies with age.The IgG in the bloodstream is 60 to 70% IgG1, 20to 30% IgG2, 5 to 8% IgG3, and 1 to 3% IgG4. IgG1and IgG3 reach normal adult levels by 5 to 7 yearsof age; while IgG2 and IgG4 levels rise more slowly,reaching adult levels at about 10 years of age.Each subclass serves predominantly (but notexclusively) a slightly different function in protectingthe body against infection. For example, IgG1and IgG3 subclasses play a role in protectionagainst toxins from bacteria such as diphtheriaand tetanus and also viral infections. In contrast,IgG2 predominantly aids in protection against thepolysaccharide (complex sugar) capsule of certaindisease-producing bacteria such as Streptococcuspneumoniae and Haemophilus influenzae.Individuals with IgG Subclass Deficiency are definedas having recurrent infections, persistently lowlevels of one or more IgG subclasses, and normalconcentrations of total IgG, IgM, and IgA. IgG2 orIgG3 deficiencies are the most common IgGsubclass deficiencies. Since IgG1 comprises 60%of the total IgG level, having a deficiency of IgG1usually drops the total IgG level below the normalrange, resulting in hypogammaglobulinemia.Because IgG4 does not reach adult levels until theage of 10 years, a diagnosis of IgG4 deficiencyshould not be made in young children. In addition,it may also be undetectable in the serum of manynormal adult individuals, and therefore low IgG4alone is insufficient evidence of an antibodydeficiency disorder.All individuals with IgG subclass deficiency requireadditional diagnostic evaluation. This evaluationmust include the demonstration of a poor antibodyresponse to vaccine challenge and carefuldocumentation of recurrent infection. If these areboth present, then the individual can be diagnosedwith a clinically significant IgG subclass deficiencynecessitating specific treatment.IDF Patient & Family Handbook27

Clinical PresentationsMost individuals with IgG Subclass Deficiencyare completely asymptomatic. They may present,however, to a healthcare provider with recurrent earand/or sinus infections; bronchitis and pneumoniamay also have occurred. These infections arecommonly caused by encapsulated bacteria suchas Streptococcus pneumoniae and Haemophilusinfluenzae, infections common in other people withantibody deficiencies. These types of infectionsare seen most commonly among those withIgG2 deficiency with or without IgG4 deficiency.Infections occurring in those with selective IgGsubclass deficiency may not be as severe asinfections in individuals with more significantantibody deficiencies, such as agammaglobulinemiaor Common Variable Immune Deficiency (CVID).Individuals with IgG subclass deficiencies may haveother types of invasive infections such as episodes ofbacterial meningitis or infections of the bloodstream(sepsis), but these are extraordinarily rare. Frequentviral infections have been associated with IgG3subclass deficiencies.As in people with Selective IgA Deficiency, allergicdiseases and autoimmune diseases are morecommon in those with IgG subclass deficiency.DiagnosisMeasurement of IgG subclass levels is not universallyrecommended as part of the evaluation of antibodymediated immunity in individuals with recurrentor severe infections. Assessing IgG subclassesadds cost and may not add clinical value whentotal immunoglobulins and specific antibodies aremeasured. Most clinical immunologist do not obtainor measure IgG subclasses.When IgG subclasses are measured, all four shouldbe measured at the same time. An abnormal levelshould be confirmed at least one month after thefirst measurement. It is important to consider thatIgG subclasses vary over time and among differentlaboratories. In addition, normal range values areusually defined as those values found in 95% ofnormal individuals of that person’s age. This meansthat 2.5% of normal individuals will be considereddeficient, and 2.5% of normal individuals will havevalues above that range. (See Laboratory TestsChapter.)28Measurement of IgG subclasses can berecommended in the presence of known associatedabnormalities, particularly if recurrent infectionsare also present. These circumstances includeindividuals with: Selective IgA Deficiency with recurrent infectionsto determine if there is an associated IgG2 andIgG4 subclass deficiency Wiskott-Aldrich Syndrome or AtaxiaTelangiectasia at the onset of recurrent infections Specific Antibody Deficiency with normaltotal immunoglobulinsInheritanceNo clear-cut pattern of inheritance has beenobserved in the IgG subclass deficiencies. Bothmales and females may be affected. Occasionally,two individuals with IgG subclass deficiency maybe found in the same family. In some families, IgGsubclass deficiencies have been found in some familymembers while other family members may haveSelective IgA Deficiency or CVID. A partial genedeletion has been found in a few individuals with IgGsubclass deficiency. Rarely individuals with completeabsence of IgG2 due to deletion of the gene codingfor its production have been described.TreatmentThe mainstay of treatment includes appropriate useof antibiotics to treat and to prevent infections. Thetype and severity of infection usually determines thetype of antibiotic used and the length of treatment.Additional immunization with pneumococcalvaccines may also be used to enhance immunity. It isimportant to encourage patients to continue normalactivities of daily living, such as school or work.A trial (6 months) of immunoglobulin replacementtherapy may be considered in patients withrecurrent infections affecting quality of life, whohave failed antibiotic therapy. (See ImmunoglobulinReplacement Therapy Chapter.) At minimum, mostinsurers before they will approve Ig therapy willrequire documentation demonstrating failure of suchconservative treatment in addition to persistentlylow IgG subclass levels and deficient antibodyresponses to vaccines. Children diagnosed withIgG subclass deficiency should be reevaluated withincreasing age, as many appear to outgrow their IgGsubclass deficiencies.Chapter 6: IgG Subclass Deficiency and Specific Antibody Deficiency

ExpectationsThe natural history of individuals with a clinicallysignificant IgG subclass deficiency is not completelyunderstood, but the outlook is generally good. Manychildren appear to outgrow their deficiency as theyget older. For those with a persistent deficiency andimpaired antibody responses, the use of prophylacticantibiotics and, in certain circumstances, the use of Igreplacement therapy may prevent serious infectionsand complications, such as impaired lung function,hearing loss, or injury to other organ systems.Recent studies have shown that many children witha subclass deficiency in early childhood (youngerthan 5 years of age) develop normal subclass levelsand the ability to make antibodies to polysaccharidevaccines as they get older. IgG subclass deficiencies,however, may persist in some children and adults. Insome instances, a selective IgG subclass deficiencymay evolve into a more serious antibody deficiency,such as Common Variable Immune Deficiency (CVID).(See Common Variable Immune Deficiency.) At thistime, it is not possible to determine which individualswill have the transient type of subclass deficiencyand which individuals may later evolve into a moresignificant immunodeficiency. For these reasons,regular reevaluation of immunoglobulin levels andfunction, as well as IgG subclass levels, is necessary.Specific Antibody DeficiencyAmong the five classes of immunoglobulins: IgG, IgA, IgM, IgD, andIgE, IgG has the predominant role in protection against infection. Somepeople have normal levels of immunoglobulins and all subclasses of IgG,but they do not produce sufficient specific IgG antibodies that protectthem from some viruses and bacteria. People who produce normalimmunoglobulin levels but who lack the ability to produce protectiveIgG antibodies against the types of organisms that cause upper andlower respiratory infections are said to have Specific Antibody Deficiency(SAD). SAD is sometimes termed partial antibody deficiency or impairedpolysaccharide responsiveness.DefinitionEach individual IgG molecule is uniquely designedto protect against a specific pathogen. We call thesemolecules specific antibodies, and they are usuallyformed in response to natural exposure to bacteriaand viruses, or through exposure to vaccines.Some of these antibodies can be measured in thelaboratory, and these levels (or titers) are used tohelp diagnose problems with immunity.Children less than 2 years of age often do not havea robust response to infections with bacteria such asStreptococcus pneumoniae, Moraxella catarrhalis,or Haemophilus influenzae. This is primarily dueto an inability to make antibodies against thepolysaccharide (sugar) coat that covers thesebacteria. Children in this age group typically acquireprotection against these microbes through the use ofcertain vaccines in which a protein is added to elicitan immunologic response (conjugate vaccines). Mostchildren begin to naturally make stronger immuneresponses to these bacteria around 2 years of age,and they can then fight off these infections moreeffectively. Children and adults who fail to developthe immune response to the polysaccharide coatingon bacteria (and therefore lack protection to thesemicrobes) but who otherwise have normal antibodylevels are diagnosed with having SAD.Specific IgG antibodies are important in fightingoff infections; however, other components of ourimmune system also work to eradicate bacteria andviruses. T cells, complement proteins, IgM and IgAantibodies (to name a few) are parts of our immunesystem that work together during a completeimmune response. If these other components workwell, some individuals with low specific antibodylevels may rarely get sick. Antibodies of certain IgGIDF Patient & Family Handbook29

subclasses interact readily with the complementsystem, while others interact poorly, if at all, with thecomplement proteins. Thus, an inability to produceantibodies of a specific subclass or mild deficienciesof other arms of the immune system may render theindividual susceptible to certain kinds of infectionsbut not others. These factors must be taken intoaccount before an individual’s immune system isconsidered to be abnormal, either by virtue of havinga low IgG subclass level or an inability to make aspecific type of antibody.Clinical PresentationRecurrent ear infections, sinusitis, bronchitis, andpneumonia are the most frequently observedillnesses in people with SAD. Some individuals willshow an increased frequency of infection beginningin the first years of life. In others, the onset ofinfections may occur later. In general, the infectionsin individuals with SAD are not as severe as thosewho have combined deficiencies of IgG, IgA, andIgM, like X-linked Agammaglobulinemia (XLA) orCVID. Some, however, may present with a singlesevere pneumonia or other infection at the timeof diagnosis.DiagnosisProblems with specific antibody production may besuspected in children and adults who have a historyof recurrent infections of the ears, sinuses, bronchi,and/or lungs. The recommended evaluation usuallyincludes measurement of total immunoglobulins, andantibody levels to specific bacteria such as tetanus,diphtheria, and/or Streptococcus pneumoniae. Whentotal immunoglobulins are low, a more profoundimmunodeficiency may be present. If isolated lowantibody levels to Streptococcus pneumoniae arefound during the initial evaluation, a Pneumococcalvaccine (Pneumovax) is administered and follow-uplevels are measured. Individuals older than 1 yearof age may be immunized with the pneumococcalpolysaccharide vaccine (Pneumovax 23 or Pnuimmune 23). These vaccines have the ability toinduce protective levels to 23 strains (serotypes)of Streptococcus pneumoniae. Antibody levels aremeasured again four to six weeks later to determineif adequate protective antibody levels wereproduced. It is felt that normal individuals respondto a majority of the serotypes in these vaccines andretain those protective levels for years after receivingthem. Antibody responses may not last as long inyoung children. For therapy, it is also possible tore-immunize with Prevnar 13, a conjugate type of30pneumococcal vaccine, which, for most, may bemore immunogenic than Pneumovax. This vaccine,however, cannot be used to diagnose SAD.A classification for mild, moderate, and severe formsof SAD exists which factors in the individual’s ageand number of normal post-immunization serotypesto define immunologic severity. Responses in whichchildren respond to less than 50% of serotypes andadults respond to 70% have a moderate form ofSAD with an increased risk of upper/lower respiratorytract infections that may warrant treatment. In theexperience of many clinical immunologists, however,a normal vaccine response for an individual consistsof producing protective titers of antibodies to atleast 50% of the serotypes present in the vaccine.Furthermore, there are individuals who may fall intoa response zone between 50 to 70% that havesignificant infections that may warrant a trial ofreplacement Ig therapy.An additional subset of people are defined ashaving a memory phenotype meaning they respondnormally initially and subsequently lose protectivelevels within 6 months.When interpreting pneumococcal levels, it isimportant to recognize the variability in testingmethodology and subsequent results that may occuramong different labs. This highlights the importanceof utilizing a detailed clinical history in additionto laboratory findings to guide the immunologicevaluation when considering a diagnosis of SAD.InheritanceNo clear-cut pattern of inheritance has beenobserved with SAD.TreatmentIndividuals with SAD frequently have recurrent orchronic infections of the ears, sinuses, bronchi andlungs. Treatment of these infections usually requiresantibiotics. One goal of treatment is to preventpermanent damage to the ears and lungs that mightresult in hearing loss or chronic lung disease withscarring. Another goal is to maintain individuals withSAD as symptom-free as possible so that they maypursue the activities of daily living such as schoolor work. Sometimes antibiotics may be used forprevention (prophylaxis) of infections.As in IgG subclass deficiency, the use of Igreplacement therapy for SAD is not as clear-cutas it is for those with XLA or CVID. For individualsChapter 6: IgG Subclass Deficiency and Specific Antibody Deficiency

with SAD in whom infections and symptoms can becontrolled with antibiotics, Ig replacement therapy isusually not necessary. However, for those with moresevere clinical phenotypes whose infections cannotbe readily controlled with antibiotics or who havemore frequent and severe infections, Ig replacementtherapy may be considered.Since many young children appear to outgrowSAD as they get older, it is important to reevaluatethem to determine if the deficiency is still present.If Ig replacement therapy has been previouslyinitiated, reevaluation after a period of time isrecommended with discontinuation of Ig therapyfor 4 to 6 months before repeat immune testing,and re-immunization with pneumococcal vaccines (ifneeded) is performed. If the response to vaccinationis adequate, Ig replacement therapy may bediscontinued and the individual observed. It isreasonable to reevaluate antibody levels periodicallyto document retention of protective antibody levels.If the diagnosis of SAD is made in teenagers oradults, resolution of the deficiency is less likely.ExpectationsThe outlook for individuals with SAD is generallygood. Many children appear to outgrow theirdeficiency as they get older, usually by age 6. Forthose for whom the deficiency persists, the use ofprophylactic antibiotics and, in certain circumstances,the use of Ig therapy may prevent serious infectionsand the development of impaired lung function,hearing loss or injury to other organ systems.The natural history of individuals with SAD is notcompletely understood. SAD seems to occurmore often in children, probably due to a delay inthe natural maturation of the immune response.Children may outgrow SAD over time. Adults withsimilar symptoms and poor response to vaccinationare less likely to improve over time. Similar to IgGsubclass deficiencies, SAD may evolve into CVID.(See Common Variable Immune Deficiency Chapter.)At the present time, it is not possible to determinewhich individuals will have the transient type ofdeficiency and in which individuals the deficiencymay be permanent or the forerunner of a more wideranging immunodeficiency, such as CVID. For thesereasons, periodic reevaluation of immunoglobulinlevels and specific antibody levels is necessary.Adapted from: Chapter 5 IgG Subclass Deficiencyand Chapter 6 Specific Antibody Deficiency.IDF Patient & Family Handbook for PrimaryImmunodeficiency Diseases 5th Edition. 2013.IDF Patient & Family Handbook31

The development of this publicationwas supported by Shire, now Takeda.110 West Road, Suite 300Towson, MD

Chapter 6 IgG Subclass Deficiency and Specific Antibody Deficiency Elizabeth Wisner, MD, Children’s Hospital New Orleans, New Orleans, Louisiana, USA Ricardo Sorensen, MD, Children’s Hospital New Orleans, New Orleans, Louisiana, USA IgG Subclass Deficiency The main immunoglobulin (Ig) in human blood is IgG. This is the second most

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