ai 25-739 pid in clinical-office

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ALLERGY AND IMMUNOLOGY 00954543 / 98 $8.00 + .OO

PRIMARY IMMUNODEFICIENCYDISORDERSRobert J. Mamlok, MD

Immunodeficiency is a common thought among both patients andphysicians when confronted with what is perceived as an excessive num-ber, duration, or severity of infections. Because of this, the starting pointfor evaluating patients for suspected immunodeficiency is based on whatconstitutes too many infections. It generally is agreed that children withnormal immune systems may have an average of 6 to 8 respiratory tractinfections per year for the first decade of life. Even after a pattern of ab-normal infection is established, questions of secondary immunodeficiencyshould first be raised. The relatively uncommon primary immunodefi-ciency diseases are statistically dwarfed by secondary causes of recurrentinfection, such as malnutrition, respiratory allergy, chronic cardiovascular,pulmonary, and renal disease, and environmental factors. On the otherhand, a dizzying spiral of progress in our understanding of the geneticsand immunology of primary immunodeficiency disease has resulted inimproved diagnostic and therapeutic tools. Twenty-five newly recognizedimmunologic disease genes have been cloned in the last 5 ~ear s .2~t hasbecome arguably more important than ever for us to recognize the clinicaland laboratory features of these relatively uncommon, but increasinglytreatable, disorders.

CLASSIFICATIONThe immune system has been classically divided into four separatearms: The B-cell system responsible for antibody formation, the T-cell sys-

From the Division of Pediatric Allergy and Immunology, Texas Tech University Health Sci-ences Center, Lubbock, Texas

PRIMARY CAREVOLUME 25 NUMBER 4 DECEMBER 1998 739


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740 MAMLOKtem responsible for immune cellular regulation, the phagocytic (poly-morphonuclear and mononuclear) system and the complement (opsonic)system. The World Health Organization (WHO) expert committee recentlyhas classified the primary immunodeficiencies to reflect the interactionsof these four components and the different variants that have been rec-o g n i ~ e d ? ~ , ~ ~his includes immune deficiency diseases with a primary de-fect in humoral immunity, immunodeficiency defects in cellular immunity,partial combined immunodeficiency diseases, and disorders of comple-ment and phagocytic cells (Table 1).

GENERAL FEATURESSeveral excellent, recent reviews of the primary immunodeficiency

disorders are a ~ a i l a b l e . ~ , ~ ~ , ~his article concentrates on some of the rep-resentative and common features of primary immunodeficiency that maypresent to the primary care physician. These clinical presentations areplaced in the context of our recent advances in the understanding of theirmolecular genetics.

IncidenceThe incidence of congenital immunodeficiencies varies from the rela-tively common, selective IgA deficiency (1:400) to the rare, severe, com-bined immunodeficiency (1:100,000 to 1:500,000). Chronic granulomatousdisease has been estimated to occur at a 1:200,000 incidence, and commonvariable immunodeficiency occurs 1 75,000. These disorders present witha male to female ratio of 5:l in infants and children and with no discerniblesex difference in adults. This is because of the respective frequency of X-linked primary immunodeficiency disorders in childhood, and the rela-tively frequent occurrence of late-onset, common-variable immunodefi-ciency in females. The primary immunodeficiency disorders are seen morecommonly in infants and children than in adults. It has been estimatedthat 40% of cases are diagnosed in the first year of life, another 40% byage 5 years, another 15% by age 16 and only 5% in ad ~l thood .~

Physical ExaminationThe physical stigmata of the primary immunodeficiency diseases canbe divided into consequences of recurrent infection (such as persistentsinusitis and bronchiectasis) and associated congenital defects. The skin

may show monilial infection (T-cell deficiency), eczema (Wiskott-Aldrichsyndrome, hyper IgE syndrome), petechia (Wiskott-Aldrich syndrome),partial albinism (Chkdiak-Higashi syndrome, immunodeficiency withpartial albinism), rash secondary to graft-verses-host disease (GVHD) (T-cell disease or Omenns syndrome), or telangiectasia (ataxia telangiecta-sia). There may be abnormal features, such as the facial dysmorphology


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742 MAMLOKof DiGeorges syndrome or coarse facies of hyper IgE syndrome. Childrenwith leukocyte adhesion defects can present with severe gingivostomatitisand dental erosion as a consequence of abnormal leukocyte function.Short stature is associated specifically with X-linked hypogamma-globulinemia with growth hormone deficiency and generally with recur-rent infection. Many of the immune deficiency states are associated withneurologic disorders, including seizures associated with hypocalcemia inthe newborn (DiGeorges syndrome), cerebellar degeneration (ataxia andtelangiectasia), echovirus encephalitis (humoral syndromes associatedwith absence of B cells), intracranial hemorrhage (Wiskott-Aldrich syn-drome), and lymphomas involving the brain (Wiskott-Aldrich syndromeand ataxia teIangie~tasia).3~aucity of peripheral lymphatic tissue is char-acteristic of X-linked agammaglobulinemia, although lymphadenopathyis a common feature of Omenns syndrome and common variable immunedeficiency.

Laboratory InvestigationMost immunodeficiency disorders can be ruled out at little cost to thepatient if the proper choice of screening tests is made. A great deal ofimmunologic-related data can be obtained from a complete blood countand differential (Fig. 1 . Neutropenia, lymphopenia, and abnormalities inwhite blood cell morphology can be found directly. Anemia may be sup-porting evidence of chronic illness, or may be secondary to hemolysisfrom autoimmune dysregulation or parvovirus infection. Normocyticthrombocytopenia is characteristic of bone marrow failure and autoim-mune disease, and microcytic thrombocytopenia is highly suggestive ofthe Wiskott-Aldrich syndrome. If an infants neutrophil count is persis-tently high in the absence of malignancy and active infection, a leu-

LYMHOCYTES PLATELETS NGuTRopMLs

Decreased Increased Miaocytic Normocytic Decreasedhcreased

SCIDSdue 1menn T Tone Bone 1A D .Wiscott marrowoADA Syndrome Aldrich marrowor or Syndrome failure failureIL-2R SCIDwithdeficiency GVHD

Figure 1. Characteristic changes in the complete blood cell count in selected primary im-munodeficiency disorders.


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PRIMARY IMMUNOD EFICIENCY DISORDERS 743kocyte adhesion deficiency should be suspected. If the absolute lympho-cyte count is elevated or normal, it is less likely that the patient has asevere T-cell defect. If the pattern of infection suggests predominant hu-moral or cellular immune system involvement, specific studies should bedirected as described in the following sections.Humoral Immune System Evaluation

The evaluation of humoral immunity should begin with quantifica-tion of serum immunoglobulins (Fig. 2). At term birth, IgG is present atmaternal levels because of placental transport of IgG from the mother. IgGlevels decline and normally reach a nadir at 3 to 6 months. The adultconcentration of IgM (1.4 + / - 0.6 mg/mL) is reached at 1year, IgG (12.6+ / - 2.6 mg/mL) at 5 to 6 years, and of IgA (2.6 + / - 1 mg/mL) atQuantification of serum IgA levels is a particularly cost-effectivestudy in that IgA levels are low in almost all permanent types of agam-maglobulinemia and in selective IgA deficiency. Measurement of serumIgE levels would be appropriate in patients with suspected atopy, Wiskott-Aldrich syndrome, or suspected hyper IgE syndrome. The WHO also rec-ommends screening for isohemagglutinins as an initial screening study ofhumoral immunity. Isohemagglutinins are IgM antibodies that cross-reactwith polysaccharide blood group A or B antigens found in all normalindividuals, with the exception of those with type AB red cells. By the ageof 3 years, 98% of normal persons with type A, B or 0 blood have titers

of isohemagglutinins at least 1:16.2O These studies usually are adequate torule out a deficiency of humoral immunity; however, when patients arepotential candidates for replacement intravenous immunoglobulin (IVIG)therapy, or if there remains a dissociation between normal screening stud-ies and the patients clinical course, studies of functional antibody re-sponses are more definitive tests of humoral immunity. Antibody re-sponses are measured by obtaining serum samples before and 3 to 4 weeksafter immunization with such representative protein antigens as diphthe-ria and tetanus toxoids and such polysaccharide antigens aspneumococcus.In addition, B cells can be identified and enumerated by the presence ofunique surface proteins (such as CD19 and CD20), which are identifiedby immunofluorescent-tagged monoclonal antibodies and quantified byflow cytometry. IgG subclass testing should not be used for routine screen-ing of patients with suspected immunodeficiency, but may help in defin-ing syndromes of poor antibody formation and borderline low serum IgGlevels.Cellular Immune System Evaluation

The presence of a thymic shadow on a chest radiograph is comforting,but nonspecific, reassurance when questions of T-cell deficiency are raisedin a newborn. The laboratory evaluation of cellular immunity should be-gin with quantification of an absolute lymphocyte count (Fig.3). This isobtained by multiplying the total white blood cell count by the percentageof lymphocytes. Lymphocyte counts persistently below 1500 per cubic


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744 MAMLOKDocumented increasednumber, eventy or durationof infebons?

+Measure serumimmunoglobulinsand sohemagglutinins

- rule out respiratoryallergy- rule out chronic cardiovasular,respiratoryor renal disease- rule out maternalrisk factors orHIV 1Infection

Normal Decreasedor absentPrimary humoral defectnot probable.Reassess for secondaryimmunodeficiency. Re-evaluate in6 months ifcontinued pattern ofinfection L W S t h a n t w O More than woAyears of age years of age1 1Measure functionalantibody Measurefunctoxlalantiwyresponses to diphtherh and etauus responsesto diph ihe tetanustoxoids andpneumococcal antigem

NormalB cell disease s not probable DeficientReimmllnizewithrespectivevaccines. Ifstill deficient, candidatefor IVIG replacementtherapy.Figure 2. Laboratory evaluation of suspected primary defects in humoral immunity.

millimeter may signify a defect in the T-cell system. Lymphocyte countsin infants normally are very high in comparison with adult values. Inaddition, false elevation of peripheral lymphocyte counts may result fromengraftment of maternal lymphocytes in T-cell deficient newborns or may


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PRIMARY IMMUNODEFICIENCY DISORDERS 745Absolute Lymphocyte Count

DWreased Normal or IncreasedW I D ? ) (Omenn Svndmme7l(SCIDSwhGVHD?)DScreen for lymphocyte function(DelayedHypersensitivity Responses)PrimaryTcelldefectisnotprobable studyLymphoblastogenesis

Decreased or absent Normal

1 1Refer to tertiary cafe center RimaryTCelldefectis not probableFigure3. Laboratory evaluation of suspected primary defects in cellular immunity.

be secondary to proliferation of an uncontrolled T-cell clone as seen inOmenns syndrome. T-cell function may be screened for in vivo by mea-suring delayed hypersensitivity responses to skin test antigens. Intrader-ma1 testing material, with such common recall antigens as mumps, Tri-chophyton, purified protein derivative (PPD), Candida, tetanus anddiphtheria toxoid, and keyhole-limpet hemocyanin, is available widely.The maximum wheal resulting from intradermal injection of 0.1 mL ofappropriate dilutions of these antigens should be read 48 o 72 hours afterinjection. These studies have excellent positive predictive values of intactcellular immunity, but negative tests may not be informative in veryyoung children. More definitive in vitro studies of T-cell function involvethe measurement of uptake of radioactive thymidine into new D N A inresponse to substances that stimulate lymphoblastogenesis.This includessuch mitogens as concanavalinA (Con A ) and phytohemagglutinin (PHA)or recall antigens such as candida or PPD. Flow cytometry may be usedto characterize the presence of surface markers unique to different T-cellsubtypes.


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746 MAMLOK

TreatmentAlthough attempts at immunomodulation and gene replacementtherapy are ongoing and promising, the treatment of choice for severe

defects in humoral immunity is passive antibody replacement with IVIG,and the standard treatment for most severe T-cell defects is bone marrowtransplantation.Treatment for Immune Defects with PrimaryHumoral Defects

Patients with primary humoral immune defects may often requireprolonged and aggressive antimicrobial therapy to clear pyogenic bacteriafrom sino-pulmonary sites. Even with WIG replacement, these patientsmay have relative defects in mucosal immunity that require aggressivemanagement with postural drainage and prolonged oral and occasionalintravenous antibiotic coverage. Some authors have recommended rotat-ing oral antibiotic coverage to help minimize development of bacterialresistance in patients requiring repeat courses of oral antibiotics for si-nusitis or bronchiectatic disease. Prophylactic antibiotic coverage also hasbeen considered in patients with subtle antibody formation defects withhypogammaglobulinemia.Immunoglobulin replacement therapy is indicated for patients at riskfor recurrent pyogenic infections caused by an inability to make specificantibody. Their rapid degradation and relative lack of clinical efficacy limitintramuscular products. All of the currently licensed intravenous prod-ucts in the United States meet acceptable standards of safety and efficacy.The most common side effect of immunoglobulin replacement therapy isan anaphylactoid type reaction, which may include fever and chills. Thisis largely secondary to rate of infusion, can be controlled by reducinginfusion speeds, and can be minimized by pretreatment with acetamino-phen and antihistamines. There have been no reports of HIV transmissionwith IVIG. The Cohn fractionation process of serum proteins destroys HIVand a viricidal detergent treatment is now routine. Reports of Hepatitis Ctransmission with two IVIG products has resulted in the donor pool beinglimited to patients with no antibodies to Hepatitis B and HIV. Many IVIGhave been withheld from distribution because of the threat of transmissionof Jakob-Cruetzfeldt disease from an inadvertent donor.IVIG replacement therapy for primary immunodeficiency diseasecommonly begins at a dose of 400 mg/kg/m.21 Trough serum titers andclinical response are used to titrate the infusion dose. If extensive bron-chiectasis or disseminated echovirus infection is present, consideration ofhigh dose or intrathecal IVIG may need to be given. Patients with rela-tively low immunoglobulin levels but normal antibody responses usuallyare not candidates for IVIG replacement therapy.Treatment for Immune Defects with PredominantCellular Defect

The therapeutic options for cellular immune defects are dependenton rapid recognition of these potentially lethal disorders. Early risks in-


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748 MAMLOKX-Linked Agammaglobulinemia(XLA)

The characteristic clinical features of this disease were well describedby Bruton in 1952.*He recognized a group of male infants that appearedto do well during the first months of life, but developed progressive, re-current sino-pulmonary infections. Advances in protein chemistry al-lowed him and others to link this relative infection-free period during thefirst months of life to active maternal transport of IgG across the placenta.Recent epidemiological studies have shown that most children developclinical problems during the first year of life, but as many as 21% firstpresented clinically as late as 3 to 5 years of age." Although recurrentsino-pulmonary infections are the most common infections in XLA, sep-ticemia, septic arthritis, and osteomyelitis may present in untreatedchildren. The sequel of untreated XLA includes chronic sinusitis and pro-gressive bronchiectasis. Once these entities have become well established,aggressive antimicrobial therapy often is needed as adjunctive care inspite of IVIG replacement. A chronic enteroviral infection of the centralnervous system, which can develop in the faceof gammaglobulin replace-ment, remains a poorly understood complication. Patients also may de-velop a dermatomyositis-like syndrome as a consequence of enteroviralinfection. This involves development of peripheral edema and a shufflinggait secondary to flexion contractures from the underlying fasciitis andmyositis. The disease gene for X-linked agammaglobulinemia was iden-tified in 1993 as encoding Bruton tyrosine kinase (Btk).33,34efective Btkresults in an inability to develop B cells from pre-B cells. Diagnosis is madeby extremely low or absent immunoglobulin and few or no B cells. Specificmutation detection or measurement of Btk kinase activity can confirm thegenetic cause in patients without an X-linked family history. Reductionsin hospitalizations and infection rates have been well documented in pa-tients receiving high dose (>400 mg/kg every 3 weeks) IVIG, and main-taining trough levels of IVIG above 500 mg/dL is a reasonable standardof care.16

Common Variable Immune Deficiency (CVID)CVID is a diagnosis of exclusion, as the genetic basis remains un-known. It is clinically indistinguishable from the other primary B-cell dis-orders and shares features of hypogammaglobulinemia, recurrent pyo-genic infection, and impaired antibody responses. In contrast to XLA, theonset usually is in the second or third decade of life. The clinical, immu-nologic, and genetic diversity of CVID suggests that this may represent acommon clinical framework for several genetically distinct disorders? Inaddition to the features of impaired humoral immunity, up to 50% ofCVID patients exhibit some alteration of T-cell function. This has includedlow CD4/CD8 ratios, low expression of T-cell activation molecules, ab-normal responses to T-cell mitogens, and reduced lymphokine produc-tion. Passive replacement therapy with high dose IVIG has been shown


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PRIMARY IMMUNODEFICIENCY DISORDERS 749to reduce the incidence of pyogenic infections and is a standard of carefor this group of illness.

Selective IgA DeficiencyAlthough this is the most common of the primary immunodeficiencydiseases (with an estimate of 1:400 of the population affected), it remainsone of the more poorly understood. Most immunologists believe that onlya small percentage of patients with selective IgA deficiency seek care forrecurrent upper respiratory tract infections or pulmonary or gastrointes-tinal disease. On the other hand, patients diagnosed with selective IgAdeficiency have been found to have increased risk of numerous infectious,autoimmune, and malignant disorder^.^ Recognition of IgA deficiency is

of potential clinical significance in the setting of transfusion reactions.Patients with selective IgA deficiency may mount IgE antibodies to traceamounts of IgA in blood products and experience risk of anaphylacticrea~tion.~

X-Linked Immunodeficiencywith Hyper IgMThe initial clinical presentation of this X-linked disorder is similar toXLA; however, the frequency of Pneumocystis carinii pneumonia, asso-

ciated lymphoproliferative diseases, and a rare parvoviral-induced formof hemolytic anemia suggested early on that aberrant T-cell control waspresent. As the name suggests, the immunologic hallmark is elevated se-rum IgM levels at the expense of low IgG, IgA and IgE levels. The geneticbasis for this failure of isotype switching is attributed to a gene encodinga T-cell receptor known as the CD40 ligand. Failure of interaction betweenCD40 on B cells and the CD40 ligand on T cells results in a defect in B-cell differentiation characterized by inability to undergo immunoglobulinisotype switching. Although the elucidation of the genetic basis of thisdisorder holds the promise of more specific genetic therapy, current treat-ment of X-linked hyper IgM syndrome is limited to the provision of pas-sive immunity with IVIG.*

IgG Subclass DeficiencyThis group of disorders includes patients with low levels of IgG sub-classes, with normal IgG and IgA levels, who have depressed antibodylevels. For children older than the age of two, this means that the IgGllevel should be less than 250 mg/dL, the IgG2 level less than 50 mg/dLand the IgG 3 level less than 25 mg/dL. The IgG4 level may be undetect-able in up to 10% of the normal population. It is difficult to distinguishpatients with IgGl deficiency from CVID, as it is commonly associatedwith other Ig subclass deficiencies. IgG2 deficiency is paired frequentlywith IgG4 and IgA deficiency*; however, it is still uncertain whether the


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750 MAMLOKabsent subclass is significant clinically, or whether this is a marker foimmune dy~regulation.~he presence of genetic deficiency of IgG2 ancIgG4 in healthy individuals suggests that subclass deficiency may in itselnot be of great clinical significance. The propensity to have recurrent in.fections correlates most closely with the inability to make specific anti-bodies rather than IgG subclass concentration.

Specific Antibody DeficiencyImmunologists have debated the potential clinical significance of la-cunar gaps in the arsenal of specific antibody formation. Patients with ahistory of recurrent pyogenic infection have been reported with normalserum immunoglobulin and IgG subclass concentrations, but defective

antibody production to polysaccharide antigens. Patients older than 5years of age who have an inability to respond to polysaccharide antigensmay be at risk for recurrent pyogenic infections and may require treatmentwith prophylactic antibiotics or IVIG.

Transient Hypogammaglobulinemiaof InfancyWhenever children present with hypogammaglobulinemia, consid-eration needs to be given to the potential for these children to be immu-

nologically competent, but statistically delayed in the rise in serum im-munoglobulin concentrations. These children have normal ability torespond to protein antigens, but have serum immunoglobulin concentra-tions two standard deviations below the normal range. Some of thesepatients may have an inability to respond to polysaccharide antibodieslater in life, but the vast majority remains immunologically normal. Theincidence and severity of infection in these infants largely dictates consid-eration of therapy with prophylactic antibiotics or IVIG.

IMMUNODEFICIENCY DISEASE WITH PRIMARYDEFECT IN CELLULAR IMMUNITYAbnormalities of T-cell immunity are characterized clinically by in-fection with many different organisms. This includes disseminated viral,fungal, and parasitic infections. Common presentations include severemucocutaneous candidiasis; overwhelming viremia; and progressive in-terstitial pneumonia with parainfluenza, cytomegalovirus, varicella, andPneumocystis ~a rini i. ~ ,~hese T-cell disorders may be caused by embry-ologic misadventures of the branchial arches, inborn errors of T-cell sig-naling, and receptor expression or specific T-cell toxicity from geneticforms of enzyme deficiency. These T-cell disorders may be similar clini-cally to pediatric acquired immunodeficiency syndrome (AIDS), but canbe distinguished by the absence of HIV-1 on culture or HIV DNA bypolymerase chain reaction. The following descriptions highlight the ge-


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PRIMARY IMMUNODEFICIENCY DISORDERS 751netic basis and clinically distinguishing features of some representativedisorders.

Thymic Hypoplasia (DiGeorges Syndrome)Embryologists define this disorder as a developmental field defectinvolving the third and fourth branchial arches. These structures areneeded for the normal development of the thymus, parathyroid glands,and the great vessels of the heart. Defective function of these organs ac-counts for the respective features of variable immunodeficiency, neonatalhypocalcemia secondary to hypoparathyroidism, and congenital cardiacdefects. Abnormal ear, maxilla, and mandible development accounts forthe characteristic facies of this disorder. Parathyroid and thymic deficiencyalso have been described in a disorder of peroxisomes known as Zellwegersyndrome. When the DiGeorges syndrome phenotype is paired with cleftpalate and learning disorders, the term velocardiofacial syndrome is used.Diagnosis in newborns should be suspected when hypocalcemia is pairedwith such relatively uncommon cardiac anomalies as an interrupted aorticarch type B, right-sided aortic arch or truncus arteriosus. Ninety percentof DiGeorges syndrome patients have associated chromosome disorders,with the majority involving chromosome 22. The immunologic findingsare variable, and spontaneous improvement in the immunologic defecthas been described. In its severest form, bone marrow transplantation maybe required.

Severe Combined Immunodeficiency (SCID)This term is used to describe a group of disorders that involve boththe B and T cells. Most of the B-cell abnormalities appear secondary tothe lack of T-cell help, which points again to the critical role of the T cellas the leader of the immune system. The consequence of absent T-cell

function is opportunistic infections and overwhelming septicemia, withsuch pathogens as Pneumocystis carinii, vaccinia, varicella and measles.These infants also are at risk for lethal GVHD if given transfusions withnonirradiated blood products. Lymphopenia is a common finding in X-linked SCID, but may be masked by the presence of maternal T cells,which have crossed the placenta and engraftment in the infant. Rarerforms of SCID may present with lymphocytosis secondary to proliferationof clones of dysfunctional T cells. The severity of these immunologic dis-orders has made them logical, early candidates for such advances in treat-ment as bone marrow transplantation and gene replacement therapy.Early diagnosis and availability of matched donors for bone marrowtransplantation remains the most important prognostic factor for thisgroup of severe disorders. SCID has become recognized as a heteroge-neous group of disorders of stem cell and thymic differentiation, surfacereceptor expression, cellular signaling and enzyme deficiency.


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752 MAMLOKSurface Receptor Defects

IL-2 receptor defect (X-LINKEDSCID). This is the most commonform of SCID. In 1993, common X-linked SCID was found to be causedby defects in the gamma chain of the IL-2 receptor Defects in thefunction of this protein result in lymphocyte progenitors being unable toreceive differentiation signals that are necessary for normal T and B cellfunction, and in severe lymphopenia. X-linked SCID is seen only in males,although healthy female carriers can be detected by nonrandom X inac-tivation in their lymph0cytes.2~ he best treatment is HLA-matched bonemarrow transplantation. Methods of prenatal diagnosis and experimentaltrials of in utero bone marrow transplantation have been de~cribed.~The bare lymphocyte syndrome. The bare lymphocyte syndrome isrecognized as a combination of disorders characterized by deficient ex-pression of MHC class I (HLA-A, -B, and -C) antigens, class I1 (HLA-DR,-DQ, and -DP) MHC antigens, or both. It results in faulty communicationbetween T cells and other cells. In contrast to other forms of SCID, T-cellfunction, as measured by in vitro response to PHA and ConA; numbersof circulatingB and T cells may be normal. It is clinically indistinguishablefrom the other forms of SCID.Ceituiar Signaling Defects

Additional forms of SCID with normal gamma chain expression havebeen recently described. This includes a clinically indistinguishable formof SCID with normal IL-2 receptor genes. These patients are defective inan intracellular kinase, Jak3, which serves as an activation signal betweenthe lymphokines IL-2 and IL-4.17,27

lmmunodeficiency with Enzyme DeficiencyAdenosine deaminase (ADA) deficiency. ADA was the first form ofSCID in which a genetic basis was described. The genetic deficiency ofthis enzyme results in an accumulation of purine metabolites, such as

deoxyadenosine, which are exquisitely toxic to T cells. Most patients withADA deficiency present with a pathognostic pattern of radiographic find-ings. This includes cupping and flaring of the ribs and squaring of thescapula tip. Diagnosis depends on the measurement of low, red-blood cellADA enzyme levels and high levels of purine metabolites, such as deoxy-adenosine. In addition to the preferred treatment of HLA-matched. bonemarrow transplantation, attempts at enzyme replacement with ADA cou-pled to polyethylene glycol have proven beneficial.I2 Intrauterine treat-ment with autologous cord blood in which the normal gene for ADA wastransduced has been attempted.15Purine nucleoside phosphorylase (PNP) deficiency. PNP deficiencyis a rare disorder of purine metabolism with considerable clinical hetero-geneity. In its severe form, it is clinically indistinguishable from otherforms of SCID. Milder forms have been reported later in childhood withdiverse neurologic findings such as developmental delay, hypotonia, and


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PRIMARY IMMUNODEFICIENCY DISORDERS 753pas ti city.'^ This disorder differs from ADA by the low uric acid levels,absence of associated skeletal anomalies, and presence of Hassals cor-puscles in thymic tissue.

Other Forms of Predominant Cellular Immune DefectsOmenns syndrome. The unique clinical features of this form of SCIDinclude the presence of lymphadenopathy, desquamating erythroderma,eosinophilia, high IgE levels, hepatosplenomegaly and relatively normallymphocyte counts and serum IgG, IgM, and IgA levels. The pathologiccutaneous findings in Omenns syndrome are similar to those of acuteGVHD disease, but usually no maternal engraftment of lymphocytes ispresent. Omenns syndrome involves cytotoxic autologous T cells attack-ing target organs such as the skin. The pathogenesis and genetic basis ofthis rare disorder remain unknown. Bone marrow transplantation hasbeen successful with several patients.Cellular immunodeficiency with immunoglobulins (Nezelof syn-drome). This form of combined immunodeficiency is associated com-monly with hemolytic anemia, thrombocytopenia, and lymphoreticularmalignancies. It is distinguished from X-linked SCID caused by 11-2 re-ceptor deficiency by the presence of lymphatic tissue, (though histologi-cally abnormal), hepatosplenomegaly, and normal serum immunoglobu-lins.PARTIAL COMBINED IMMUNODEFICIENCY DISEASESWiskott-Aldrich syndrome

This is an X-linked disorder characterized by an altered cell surfaceglycoprotein structure (CD43 or sialophorin) common to lymphocytes andplatelets. Its classic clinical features include a microcytic thrombocytope-nia that distinguishes this disorder from idiopathic thrombocytopenicpurpura and other forms of normocytic thrombocytopenia. The immu-nologic findings are variable but usually include impaired humoral re-sponses to polysaccharide antigens and elevated serum IgA and IgE lev-els. Atopic dermatitis and recurrent pyogenic infections of the upperrespiratory tract are common but variable associated clinicalSince the gene for sialophorin is located on chromosome 16, it was ap-parent that a genetic deficiency of sialophorin could not account for allthe features of this X-linked disorder. More recently, the gene for WiskottAldrich syndrome has been identified and codes a large molecular weightsignal transduction protein expressed on lymphocytes, megakaryocytes,spleen, and thymus. Techniques for both gene carrier detection and inutero diagnosis have been described.8Ataxia Telangiectasis

Ataxia telangiectasia is an autosomal recessive disorder clinicallycharacterized by progressive oculocutaneous telangiectasia, which be-


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756 MAMLOKbones and gastrointestinal tract caused by a relatively narrow spectrumof catalase-positive organisms such as Staphylococcus aureus, Aspergillusspecies, Chromobacterium violaceum and Pseudomonas cepacia. The mo-lecular basis for several forms of this disorder have been described inrelation to genetic defects in the oxidase system that is used by leukocytesto kill bacteria. This includes the common X-linked form, with a lack ofcytochrome b-558 on the cell membrane, and an autosomal recessive formwith a normal membrane cytochrome b-558, but a defective cytosol com-ponent of the oxidase system. Neutrophil oxidative function can bescreened with the nitroblue tetrazoleum (NBT) slide test. This colorimetricassay involves formazan being converted to nitro blue tetrazolium in thepresence of a normal oxidative burst. Prophylaxis with trimethoprim-sulfamethoxazole and recombinant human interferon gamma have be-come standards of care for this disorder.

DISORDERS OF COMPLEMENTThese are the rarest of the primary immunodeficiency disorders, ac-counting for 2% to 3% of these diseases. Deficiencies of essentially all ofthe components of the complement cascade have been described and ex-tensively reviewed.3'j Some unique clinical features include the suscepti-bility to recurrent Neisserial infections that characterizes patients withdeficiencies of the terminal complement components (C5-C9) of comple-

ment and the increased risk of developing rheumatic disorders in relationto deficiency of C2, C4, and C3. Deficiency of C2 is the most commoncomplement component deficiency. C3 deficient patients have a more se-vere phenotype because of involvement of both the classical and alternatecomplement pathways. A normal CH50 test is an effective screening toolto rule out complement deficiencies. One clinically unique form of com-plement dysregulation is hereditary angioneurotic edema.

Hereditary Angioedema (C1 Esterase InhibitorDeficiency, HAE)

This autosomal dominant disorder is characterized by recurrent, po-tentially life-threatening episodes of angioedema. In contrast to IgE-me-diated mechanisms of mast cell and basophil histamine-induced angio-edema, urticaria is not a part of this clinical syndrome. These patients arecharacterized by the presence of a positive family history of angioedema,swelling episodes in relation to trauma and surgical stress, and associatedabdominal pain. The diagnosis is established by measurement of defectiveC1 esterase inhibitor function and supported by evidence of decreased C2and C4 levels during symptomatic periods. Acquired forms of C1 esteraseinhibitor dysfunction have been described primarily in the setting of B-cell lymphoproliferative diseases. In contrast to patients with HAE, thesepatients have normal C1 esterase inhibitor structure and decreased levelsof c1.


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PRIMARY IMMUNODEFICIENCY DISORDERS 757CONCLUSION

The primary immunodeficiency diseases remain a rare but increas-ingly definable and treatable group of disorders. Recognizing the diversityof their clinical presentations is essential for timely intervention and im-proved prognosis. Screening studies of host immunity should be consid-ered in the setting of recurrent infection. The age of onset, microbes en-countered, complete blood count, and target organs of infection often giveclues to appropriate use of diagnostic studies. Replacement IVIG and bonemarrow transplantation remain the respective treatments of choice for themost severe forms of humoral and cellular immune defects. Ongoing ad-vances in the genetic and immunologic understanding of these disordershold the promise of more specific, cost effective, and successful therapy.

References1. Blaese RM, Culver K W Gene therapy for primary immunodeficiency diseases. Immu-2. Bruton OC:Agammaglobulinemia. Pediatrics 9:722-728, 19522a. Buckley RH, Schiff SE, Schiff RI, et al: Human severe combined immunodeficiency(SCID) genetic, phenotypic and functional diversity in 108infants. J Pediatr 130:378,19973. Burks AW, Sampson HA, Buckley RH:Anaphylactic reations after gamma globulin ad-ministration in patients with hypogammaglobulinemia. N Engl J Med 314:560-564,19864. Burks W, Fischer T Primary immunodeficiency disorders. In Condemni J, Dykewicz M(eds):Allergy and Immunology MKSAP. Philadelphia, American College of Physicians,5. Conley ME, Stiehm ER Immunodeficiency disorders: General considerations. In StiehmER (ed): Immunologic Disorders in Infants and Children, ed 4. Philadelphia, WB Saun-ders, 1996, pp 201-2526. Cunningham-Rundles C: Clinical and immunological analysis of 103 patients with com-mon variable immunodeficiency.J Clin Immunol922,19897. Cunningham-Rundles C: Disorders of the IgA System. In Stiehm ER (ed): Immunologicdisorders in infants and children, ed 4. Philadelphia, WB Saunders, 19968. Derry JMJ, Ochs HD, Francke U Isolation of a novel gene mutated in Wiskott-Aldrich

syndrome. Cell 78:635414,19949. Flake AW, Almeida-Porada G, Puck JM, et al: Treatment of X-linked SCID by the in uterotransplantation of CD34 enriched bone marrow. N Engl J Med 3551806,1996

nodeficiency Reviews 3:329, 1992

1997, pp 220-234

10. Fuleihan RL, Geha Rs: X-linked Hyper IgM. The Immunologist 5:133,199711. Heraszewsli RA, Webster ADB: Primary hypogammaglobulinemia: A survey of clinicalmanifestations and complications Q J Med 8631,199312. Hirschfield MS, ChaffeeS, Sorensen R U Enzyme replacement therapy with polyethyleneglycol-adenosine deaminase in adenosine deaminase deficiency. Pediatr Res 3:42-48,199313. Hirschfield MS, Mitchell BS Immunodeficiency diseases caused by adenosine deaminasedeficiency and purine nucleoside phosphorylase deficiency.In Scriver CR, Beaudet AL,Sly WS, Valle D (eds): The Metabolic Basis of Inherited Disease. New York, McGrawHill, 1995, pp 1725-176814. Hong, R: Disorder of the T-cell system. In Stiehm ER (ed): Immunologic disorders ininfants and children, ed 4. Philadelphia, WB Saunders, 1996, pp 33940815. Kohn DB, Weinberg KI, Nolta JA, et al: Engraftment of gene modified umbilical cordstem cells in neonates with adenosine deaminase deficiency. Nat Med 1:1017, 199516. Liese JG, Wintergerst U, et a1 High verse low dose immunoglobulin therapy in thetreatment of X-linked agammaglobulinemia. Am J Dis Child 146:335-339,1992


20/20

758 MAMLOK17. Macchi P, Villa A, Gilliani S, et a 1 Mutations of JAK 3 gene in patients with autosomalsevere combined immunodeficiency (SCID). Nature 37765,199518. Morel1 A, Melheim E, Schaad U, et a1 Susceptibility to infection in children with selectiveIgA and IgA-IgG subclass deficiency. Eur J Pediatr 145:199-203,198619. Noguchi M, Yi H, Rosenblatt HM, et a1 Interleukin 2-receptor gamma chain mutation

resulting in X-linked severe combined immunodeficiency in humans. Cell 73:147,199320. Ochs HD, WinkelsteinJ: Disorders of the 8-cell system. In Stiehm ER (ed): ImmunologicDisorders in Infants and Children, ed 4. Philadelphia, WB Saunders, 1996, pp 296-33821. Ochs HD, Fischer SH, et al: Comparison of high dose and low dose IVIG therapy inpatients with primary immunodeficiency diseases. Am J Med 76:78-82,198422. Puck JM, Deschenes SM, Porter JC, et a1 The interleukin 2 receptor gamma chain mapsto Xq13.1 and is mutated in X-linked severe combined immunodeficiency. Hum MolGenet 21099,199323. Puck JM, Nussbaum RL, Conley, ME: Carrier detection in X-linked severe combinedimmunodeficiency based on patterns of X chromosome inactivation. J Clin Inves 79:1395,198724. Puck, J M Primary Immunodeficiency Diseases. JAMA 278:1835,199725. Quie PG, Mills EL, Roberts RL, et a 1 Disorders of the polymorphonuclear phagocytesystem. In Stiehm ER (ed): Immunologic Disorders in Infants and Children, ed 4.Phila-delphia, WB Saunders, 1996, pp 443-46826. Rosen FS,Wedgewood RJ, Eibl M, et a1 Primary immunodeficiency diseases: Report ofa WHO scientific group. Clin Exp Immunol 1: 1,199527. Russell SM, Tayebi N, Nakajima H, et al: Mutation of Jak3 n a patient with SCID. Science270:797, 199528. Savitsky K, Bar-Shira A, Gilad S, et al: A single ataxia telangiectasia gene with a productsimilar to PI-3 kinase. Science 268:1749, 199529. Springer TA, Thompson WS, Miller LJ, Schmlstieg FC, Anderson DC: nherited defi-ciency of the Mac 1, LFA-I, p150/95 glycoprotein family and its molecular basis. J ExpMed 160:1901,198430. Stiehm ER Immunological Disorders in Infants and Children, ed 4. Philadelphia, WBSaunders, 199631. Stiehm ER, Fudenberg H H Serum levels of immune globulins in health and disease: Asurvey. Pediatrics 37715,196632. Sullivan KE, Mullen CA, Blaese RM, Winkelstein,JA. A multi-institutional survey of theWiskott-Aldrich syndrome. J Pediatr 125:876-885, 199433. Tsukada S, Saffran DC, et a1 Deficient expression of a B-cell cytoplasmic tyrosine kinasein human X-linked agammaglobulinemia. Cell 72279-290,199334. Vetrie D, Vorechovsky, et al: The gene involved in X-linked agammaglobulinemia is amember of the src family of protein-tyrosine kinases. Nature 361:226-233, 199335. Waldmann TA, Nelson DL: Inherited immunodeficiencies. In Frank MM, Austen KF,Claman HN, Unanue ER (eds): Samters Immunologic Diseases, ed 5., New York, LittleBrown, 199536. Winkelstein JA, Sullivan KE, Colton H R Genetically determined deficienciesof comple-ment. In Scriver CR, Beaudet AL, Sly WS, Valle DL (eds): Metabolic Basis of InheritedDisease. New York, =raw Hill, 1995, p 3912-394137. World Health Organization Scientific Group: Primary immunodeficiency diseases. ClinExp Immunol. 109:l-28,1997Address reprint requests to

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