ISSUES AND INFORMATION ON CURRENT TOPICS

Volume 2 Issue 1 August 2000

Immune Deficiency Foundation, the national nonprofit organization devoted to research and education forthe primary immune deficiency diseases, publishes other materials for physicians and healthcare professionals (eg.Physicians Primer and Guide for Nurses) and for patients (eg.Patient and Family Handbook, Our Immune System, andNewsletter). For Information about our programs, patient groups and publications, call 1-800-296-4433.

Immune Deficiency Foundation - 40 West Chesapeake Avenue, Suite 308, Towson, MD 21204 (800) 296-4433 (410) 321-6647 Fax: (410) 321-9165 www.primaryimmune.org

Howard M. Lederman, M.D., Ph.D.Associate Professor of PediatricsJohns Hopkins University School of MedicineBaltimore, Maryland

The primary immunodeficiency diseases were originallyviewed as rare disorders, characterized by severe clini-cal expression early in life. However, it has becomeclear that these diseases are not as uncommon as origi-nally suspected, that their clinical expression can some-times be relatively mild, and that they are seen nearly asoften in adolescents and adults as they are in infantsand children (Table 1). In fact, immunodeficiency maypresent so subtly that the diagnosis will be made only if

the physician is alert to that possibility.Early diagnosis of immunodeficiency is important

so that appropriate therapy can be instituted beforethere has been end-organ damage. Furthermore,because some primary immunodeficiency diseases areinheritable, early diagnosis is essential for makinggenetic information available to the families of affectedindividuals.

This article will review the most common clinicalsigns and symptoms of primary immunodeficiency dis-eases, and discuss the most useful screening laboratorytests.

Clinical ManifestationsPatients with primary immunodeficiency diseases

most often are recognized because of their increasedsusceptibility to infection, but these patients may alsopresent with a variety of other clinical manifestations(Table 2). In fact, non-infectious manifestations, suchas autoimmune disease, may be the first or the pre-dominant clinical symptoms of the underlying immun-odeficiency. Other immunodeficiency diseases may bediagnosed because of their known association with syn-drome complexes.

Immune DeficiencyFoundation40 West Chesapeake AvenueSuite 308Towson, MD 21204

Editor:Howard Lederman, MD, PhD

Medical Advisory CommitteeJerry Winkelstein, MDChairmanJohns Hopkins University School of MedicineBaltimore, MD

Douglas J. Barrett, MDUniversity of Florida, Gainesville, FL

R. Michael Blaese, MDKimeragen , Newton, PA

Rebecca H. Buckley, MDDuke University School of MedicineDurham, NC

Mary Ellen Conley, MDSt. Jude Children's Research HospitalMemphis, TN

Max Cooper, MDUniversity of Alabama School of Medicine Birmingham, AL

Charlotte Cunningham-Rundles, MD, PhDMt. Sinai Medical Center New York, NY

Erwin W. Gelfand, MDNational Jewish Center For Immune and Respiratory MedicineDenver, CO

Robert Good, MD, PhDUniversity of South Florida All Children's HospitalSt. Petersburg, FL

Richard Hong, MDUniversity of Vermont School of MedicineBurlington, VT

Richard B. Johnston, Jr., MDNational Jewish Medical & Research CenterDenver, CO

Alexander R. Lawton, III, MDVanderbilt University School of MedicineD3237 Medical Center North, Nashville, TN 37232

Stephen Miles, MDAll Seasons Allergy, Asthma & Immunology CenterWoodlands, TX

Hans D. Ochs, MDUniversity of Washington School of MedicineSeattle, WA

Fred Rosen, MDThe Center for Blood ResearchBoston, MA

Andrew Saxon, MDUCLA School of MedicineLos Angeles, CA

William T. Shearer, MDTexas Children's HospitalHouston, TX

E. Richard Stiehm, MDUCLA School of MedicineLos Angeles, CA

John L. Sullivan, MDUniversity of Massachusetts Medical CenterWorcester, MA

Diane W. Wara, MDUCSF Medical CenterSan Francisco, CA

The Clinical Presentation of PrimaryImmunodeficiency Diseases

Table 1: Primary Immunodeficiency

Is Not Rare May Present at Any Age Does Not Always Present with Severe Infections

Table 2: Clinical Features ofImmunodeficiency

Increased susceptibility to infectionChronic/recurrent infections without other explanation

Infection with organism of low virulence

Infection of unusual severity

Autoimmune or inflammatory disease

Syndrome complex

Infectious ManifestationsAn increased susceptibility to infection is

the hallmark of the primary immunodeficiencydiseases. In most patients, the striking clinicalfeature is the chronic or recurring nature of the

infections rather than the fact that individualinfections are unusually severe. It is difficult toassign a precise frequency of infections thatdefines increased susceptibility. As a guideline,immunodeficiency should be suspected when apatient has more than one pneumonia perdecade, chronic sinusitis, chronic bronchitiswithout a history of smoking, increasing num-bers of ear infections after early childhood,chronic diarrhea or recurrent bacteremia. Insome instances the patient not only has recur-rent infections, but one or more of these iseither unusually severe (e.g., sepsis), leads to anunexpected complication (e.g., empyema or fis-tula formation), or is caused by an organism ofrelatively low virulence (e.g., aspergillus).

Not all immunodeficient patients are diag-nosed after recurrent infections. In some, thefirst infection may be unusual enough to raisethe question of immunodeficiency. For example,

a patient who presents with infection caused byPneumocystis carinii or another opportunisticpathogen is likely to be immunodeficient even ifit is his/her first recognized infection.

The type of pathogen and the location ofthe infection may give valuable insight into thenature of the immunologic defect. Individualswith defects in cell-mediated immunity charac-teristically have difficulty with viruses and fungi.Individuals with antibody deficiencies areunusually susceptible to encapsulated bacteriaand enteroviruses. Patients with complementdeficiencies most often present with bacteremia,septic arthritis and meningitis, caused byencapsulated bacteria. And finally, phagocyticdisorders are characterized by infections of theskin and reticuloendothelial system (lymphnodes, spleen and liver).

Autoimmune and InflammatoryManifestations

Immunodeficient patients can present withautoimmune or chronic inflammatory diseases.It is thought that the basic abnormality leadingto immunodeficiency may also lead to faultydiscrimination between self and non-self, andthus to autoimmune disease. The manifestationsof these disorders (Table 3) may be limited to asingle target cell or organ (e.g., autoimmunehemolytic anemia or thrombocytopenia,

autoimmune thyroiditis), or may involve anumber of different target organs (e.g., vasculi-tis, systemic lupus erythematosus, rheumatoidarthritis). The autoimmune and inflammatorydiseases are more commonly seen in particularprimary immunodeficiency diseases, mostnotably common variable immunodeficiency,selective IgA deficiency, chronic mucocutaneouscandidiasis, and deficiencies of early compo-nents of the classical complement pathway (C1-C4).

Occasionally a disorder that appears to beautoimmune in nature may, in fact, be due to aninfectious agent. For example, the dermato-myositis that is sometimes seen in patients withX-linked agammaglobulinemia is really a man-ifestation of chronic enterovirus infection andnot autoimmune disease.

Immunodeficiency SyndromesImmunodeficiency can also be seen as one

part of a constellation of signs and symptoms ina syndrome complex. In fact, the recognitionthat a patient has a syndrome in which immun-odeficiency occurs may allow a diagnosis ofimmunodeficiency to be made before there areany clinical manifestations of that deficiency(Table 4). Children with the DiGeorge Syndromeare usually identified initially because of theneonatal presentation of congenital heart dis-

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Table 3: Autoimmune or Inflammatory

Manifestations of PrimaryImmunodeficiency

Target Cells Hemolytic anemia Immune thrombocytopenia Thyroiditis

Target Tissues Vasculitis Systemic lupus erythematosus Rheumatoid arthritis

Associated Diseases Common variable immunodeficiency Selective IgA deficiency Chronic mucocutaneous candidiasis Complement pathway deficiencies

Table 4:Examples of Immunodeficiency Syndromes

Syndrome Clinical Presentation Immunologic Abnormality

DiGeorge syndrome Congenital heart disease Thymic hypoplasiaHypoparathryroidismAbnormal facies

Wiskott-Aldrich syndrome Thrombocytopenia Variable B- and T-Eczema lymphocyte dysfunction

Ataxia-Telangiectasia Ataxia Variable B- and T-Telangiectasia lymphocyte dysfunction

Ivemark syndrome Congenital heart disease AspleniaBilateral 3-lobed lungs

Polyendocrinopathy syndrome Endocrine organ dysfunction Chronic mucocutaneous candidiasis

ease and/or hypocalcemic tetany. This shouldlead to T-lymphocyte evaluation prior to theonset of opportunistic infections. Similarly, adiagnosis of Wiscott-Aldrich Syndrome canoften be made in young boys with eczema andthrombocytopenia even prior to the onset ofinfections.

LABORATORYEVALUATION

Although immune system dysfunction canbe suspected by the clinician after carefulreview of the history and physical exam, specificdiagnoses are rarely evident without the use ofthe laboratory. However, the types of infectionsand other symptoms should help to focus thelaboratory workup on specific parts of theimmune system (Table 5). Patients with anti-body deficiency typically have sinopulmonaryinfections as a prominent presenting feature.Deficiency of cell-mediated immunity predis-poses individuals to develop infections causedby Pneumocystis carinii, other fungi and a vari-ety of viruses. Abnormalities of complementmost often lead to bacterial sepsis or immune

complex-mediated diseases, whereas phagocyticdysfunction should be suspected when patientshave recurrent skin infections or visceralabscesses.

Screening tests that should be performedin almost all patients include a complete bloodcount (CBC) with differential and quantitativemeasurement of serum immunoglobulins. Othertests should be guided by the clinical features ofthe patient (Table 6). Finally, whenever primaryimmunodeficiency is suspected, considerationmust also be given to secondary causes ofimmunodeficiency including HIV infection,therapy with anti-inflammatory medications(e.g., corticosteroids), and other underlying ill-nesses (e.g., lymphoreticular neoplasms).

Examination of the PeripheralBlood Smear

The CBC with examination of the bloodsmear is an inexpensive and readily availabletest that provides important diagnostic informa-tion relating to a number of immunodeficiencydiseases (Table 6). Neutropenia most oftenoccurs secondary to immunosuppressive drugs,

infection, malnutrition and autoimmunity, butmay be a primary problem (congenital or cyclicneutropenia). Persistent neutrophilia is charac-teristic of leukocyte adhesion molecule deficien-cy, and abnormal cytoplasmic granules may beseen in the peripheral blood smear of patientswith Chediak-Higaski Syndrome.

The blood is predominately a T cellorgan, i.e., the majority (50-70%) of peripher-al blood lymphocytes are T cells whereas only5-15% are B cells. Therefore, lymphopenia isoften a presenting feature of T cell or combinedimmunodeficiency disorders such as severecombined immunodeficiency disease andDiGeorge Syndrome.

Thrombocytopenia may occur as a sec-ondary manifestation of immunodeficiency, butis often a presenting manifestation of theWiskott-Aldrich Syndrome. A unique finding inthe latter group of patients is an abnormallysmall platelet volume, a measurement that iseasily made by automated blood counters.

Examination of red blood cell morphologycan yield clues about splenic function. Howell-Jolly bodies may be visible in peripheral blood

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Table 5:Patterns of Illness Associated with Primary Immunodeficiency

Disorder Illnesses

Infection Other

Antibody Sinopulmonary (pyogenic bacteria) Autoimmune diseaseGastrointestinal (enterovirus, giardia) (autoantibodies, inflammatory bowel disease)

Cell-mediated immunity Pneumonia (pyogenic bacteria,Pneumocystis carinii, viruses)

Gastrointestinal (viruses)Skin, mucous membranes (fungi)

Complement Sepsis and other blood-borne Autoimmune disease(streptococci, pneumococci, neisseria) (Systemic lupus erythematosis, glomerulonephritis)

Phagocytosis Skin, reticuloendothelial system, abscesses(staphylococci, enteric bacteria,fungi, mycobacteria)

4in cases of splenic dysfunction or asplenia.However, the converse is not always true andabsence of Howell-Jolly bodies does not guaran-tee that splenic function is normal.

Evaluation of Humoral ImmunityMeasurement of serum immunoglobulin

levels is an important screening test to detectimmunodeficiency for three reasons: (1) Morethan 80% of patients with primary disorders ofimmunity will have abnormalities of serumimmunoglobulins; (2) Immunoglobulin mea-surements yield indirect information about sev-eral disparate aspects of the immune systembecause immunoglobulin synthesis requires thecoordinated function of B lymphocytes, T lym-phocytes and monocytes; and (3) The measure-ment of serum immunoglobulin levels is readilyavailable, highly reliable and relatively inexpen-sive.

The initial screening test for humoralimmune function is the quantitative measure-ment of serum immunoglobulins. Neither serumprotein electrophoresis nor immunoelec-trophoresis is sufficiently sensitive or quantita-tive to be useful for this purpose. Quantitativemeasurements of serum IgG, IgA and IgM will

identify patients with panhypogammaglobuline-mia as well as those with deficiencies of an indi-vidual class of immunoglobulins, such as aselective IgA deficiency. Interpretation of resultsmust be made in view of the marked variationsin normal immunoglobulin levels with age.Therefore, age-related normal values mustalways be used for comparison.

A clue to immunodeficiency may be a lownormal IgG level in an individual with recurrentinfections. In such cases, it is critical to assessantibody function in addition to immunoglobu-lin level. Antibody levels generated in responseto childhood immunization with tetanus toxoidor the Hemophilus influenzae protein conjugatevaccines are usually the most convenient tomeasure. In children over the age of 18-24months, it is also important to assess antibodyresponses to polysaccharide antigens becausethese responses may be deficient in somepatients who respond normally to proteinantigens. Antibody can be measured afterimmunization with pneumococcal capsularpolysaccharide vaccine. (The pneumococcalpolysaccharide/protein conjugate vaccines arenot useful for this purpose.) Alternatively, sincethe ABO blood group antigens are polysaccha-

rides, anti-polysaccharide antibody can beassessed by quantitating isoagglutinin titers. Ineither case, anti-polysaccharide antibody mea-surements are generally useful only in childrenabove the age of 2 years, since normal childrenof younger age may not have significantresponses.

The role for IgG subclass measurements iscontroversial. There are four subclasses of IgG,and selective deficiencies of each of these havebeen described. However, the significance of anIgG subclass deficiency in the presence of nor-mal antibody responses to protein and polysac-charide antigens is not known. Many physicians,therefore, rely upon antibody measurements andfind that information about IgG subclass levelsadds to expense but not to diagnosis.

Evaluation of Cell-MediatedImmunity

Testing for defects of cell-mediated immu-nity is relatively difficult because of the lack ofgood screening tests. Lymphopenia is suggestiveof T-lymphocyte deficiency because T lympho-cytes comprise the majority (50-70%) of periph-eral blood mononuclear cells. However, lym-phopenia is not always present in patients withT lymphocyte functional defects. Similarly, thelack of a thymus silhouette on chest x-ray israrely helpful in the evaluation of T lymphocytedisorders because the thymus of normal chil-dren may involute following stress and give theappearance of thymic hypoplasia.

Indirect information about T cell functionmay be obtained by enumerating peripheralblood T lymphocytes with appropriate mono-clonal antibodies (anti-CD2 or CD3 for total Tcells, anti-CD4 for T-helper cells, anti-CD8 forT-cytotoxic cells). Patients with severe combinedimmunodeficiency and DiGeorge Syndromegenerally have decreased numbers of both CD4and CD8 T lymphocytes. In contrast, patientsinfected with HIV typically have a selective defi-ciency of CD4 lymphocytes. All patients withreduced T lymphocyte function or reduced CD4lymphocyte number should be tested for HIVinfection.

Delayed type hypersensitivity (DTH) skin

Table 6:Screening Tests for Primary Immunodeficiency

Suspected Abnormality Diagnostic Tests

Antibody Quantitative immunoglobulins (IgG, IgA, IgM)

Antibody response to immunization

Cell-mediated immunity Lymphocyte count

T lymphocyte enumeration (CD4, CD8)

HIV serology

Delayed type hypersensitivity skin tests

Complement Total hemolytic complement (CH50)

Phagocytosis Neutrophil count

Nitroblue tetrazolium (NBT) dye test

to receive your FREE subscription to Clinical Focus on Primary Immune Deficiencies, send your mailing address with your request to:Immune Deficiency Foundation 40 West Chesapeake Avenue Suite 308 Towson, Maryland 21204 www.primaryimmune.org

SUGGESTED READINGConley, ME, Stiehm ER Immunodeficiency Disorders: General Considerations. In Stiehm ER (ed). Immunologic Disorders in Infants and Children, 4th ed.Philadelphia, WB Saunders Co, 1996, pp. 201-252.

Fischer A, Cavazzana-Calvo M, De Saint Basile G et al. Naturally occurring primary deficiencies of the immune system. Ann Rev Immunol. 1997; 15:93 124.

Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol. 1999.118 (Suppl 1) 1-28.

Puck JM. Primary immunodeficiency diseases. JAMA. 1997; 278: 1835-1840.

Sicherer SH, Winkelstein. Primary immunodeficiency diseases in adults. JAMA. 1998; 279: 58-61.

REFERRAL TO A SPECIALIST: Patients should be sent for confirmatory or more specialized tests if screening tests are abnormal, or even if all screening tests are normal but the clinicalfeatures are highly suggestive of immune system dysfunction.

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testing with a panel of antigens is anotherscreening method for older children and adults.A standardized panel of antigens prepared forDTH testing should be used. The presence ofone or more positive delayed-type skin tests isgenerally indicative of intact cell-mediatedimmunity. However, there are significant limita-tions to this testing: (1) Prior exposure to anti-gen is a prerequisite; (2) Normal patients mayhave transient depression of DTH with acuteviral infections such as infectious mononucleo-sis; (3) A positive skin test to some antigens doesnot insure that the patient has normal cell-mediated immunity to all antigens (e.g.,patients with chronic mucocutaneous candidia-sis have a limited defect in which cell-mediatedimmunity is generally intact except for theirresponse to candida); and (4) Normal childrenunder the age of 12 months frequently areunresponsive to all of the antigens in the panel.DTH skin tests are, therefore, generally nothelpful for evaluation of suspected T-lympho

cyte abnormalities that present early in life (e.g.,severe combined immunodeficiency orDiGeorge Syndrome).

Evaluation of the ComplementSystem

Most of the genetically determined defi-ciencies of complement can be detected with thetotal serum hemolytic complement (CH50) assay.Since this assay depends on the functionalintegrity of the classical complement pathway(C1 through C9), a severe deficiency of any ofthese components leads to a marked reductionor absence of total hemolytic complement activ-ity. Alternative pathway deficiencies (e.g., factorH, factor I and properdin) are extremely rare;they may be suspected if the CH50 is in the lowrange of normal and the serum C3 level is low.The final identification of the specific comple-ment component that is deficient usually restson both functional and immunochemical tests,and highly specific assays have been developedfor each of the individual components.

Evaluation of Phagocytic CellsEvaluation of phagocytic cells usually

entails assessment of both their number andtheir function. Disorders, such as congenitalagranulocytosis or cyclic neutropenia, that arecharacterized by a deficiency in phagocytic cellnumber, can be easily detected by using a whiteblood cell count and differential. Beyond that,assessment of phagocytic cell function is rela-tively specialized because it depends upon avariety of in vitro assays including measurementof directed cell motility (chemotaxis), ingestion(phagocytosis) and intracellular killing (bacte-ricidal activity). The most common of thephagocyte function disorders, chronic granulo-matous disease, can be identified by the nitrob-lue tetrazolium (NBT) dye test, that measuresthe oxidative metabolic response of neutrophilsand monocytes.

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