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SSUESANDNFORMATIONONCURRENTTOPICSVolume1August Patients with primary immunodeficiency diseasesmost often are recognized because of their increased(Table 2). In fact, non-infectious manifestations, suchodeficiency. Other immunodeficiency diseases may be Foundation40 West Chesapeake AvenueTowson, MD 21204Howard Lederman, MD, PhDMedical Advisory CommitteeJerry Winkelstein, MDChairmanDouglas J. Barrett, MDR. Michael Blaese, MDKimeragen , Newton, PA Table 1: y Immunodeficiency ¥ May Present at Any Age¥ Does Not Always Present with Severe Infections Table 2: Clinical F eatur es of Immunodeficiency ¥ Increased susceptibility to infection¥ Autoimmune or inflammatory disease Infectious Manifestations An increased susceptibility to infection isthe hallmark of the primary immunodeficiencydefines increased susceptibility. As a guideline,without a history of smoking, increasing num-bers of ear infections after early childhood,some instances the patient not only has recur-either unusually severe (e.g., sepsis), leads to antula formation), or is caused by an organism ofnosed after recurrent infections. In some, thethe question of immunodeficiency. For example,it is his/her first recognized infection.the infection may give valuable insight into theteristically have difficulty with viruses and fungi.and enteroviruses. Patients with complementdeficiencies most often present with bacteremia,encapsulated bacteria. And finally, phagocyticskin and reticuloendoth

elial system (lymph utoimmune and Inflammator y Manifestations Immunodeficient patients can present withautoimmune or chronic inflammatory diseases.thus to autoimmune disease. The manifestationsof these disorders (Table 3) may be limited to anumber of different target organs (e.g., vasculi-tis, systemic lupus erythematosus, rheumatoidarthritis). The autoimmune and inflammatoryprimary immunodeficiency diseases, mostnotably common variable immunodeficiency,selective IgA deficiency, chronic mucocutaneouscandidiasis, and deficiencies of early compo-autoimmune in nature may, in fact, be due to aninfectious agent. For example, the dermato-X-linked agammaglobulinemia is really a man- omes odeficiency occurs may allow a diagnosis of(Table 4). Children with the DiGeorge Syndromeare usually identified initially because of the Table 3: utoimmune or Inflammator y Manifestations of P rimar Target Cells¥ Hemolytic anemiaTarget Tissues¥ Vasculitis¥ Systemic lupus erythematosus¥ Rheumatoid arthritis¥ Selective IgA deficiency Table 4: omes Clinical P resentation DiGeorge syndromeCongenital heart diseaseThymic hypoplasiaHypoparathryroidismWiskott-Aldrich syndromeThrombocytopeniaVariable B- and T-Eczemalymphocyte dysfunctionAtaxia-TelangiectasiaAtaxiaVariable B- and T-Telangiectasialymphocyte dysfunctionIvemark syndromeCongenital heart diseaseAspleniaPolyendocrinopathy syndromeEndocrine organ dysfunctionChronic mucocutaneous 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 andLABORATORYEVALUATIONbe suspected by the clinician after carefulreview of the history and physical exam, specificthe 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 sinopulmonaryposes individuals to develop infections causedby Pneumocystis carinii, other fungi and a vari-most often lead to bacterial sepsis or immunedysfunction should be suspected when patientsin almost all patients include a complete bloodcount (CBC) with differential and quantitativetests should be guided by the clinical features ofthe patient (Table 6). Finally, whenever primarymust also be given to secondary causes oftherapy with anti-inflammatory medications eripheral Blood Smear diseases (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-cy, and abnormal cytoplasmic granules may beThe blood is predominately a ÒT cellal blood lymphocytes are T cells whereas only5-15% are B cells. Therefore, lymphopenia isoften a presenting feature of T cell or combinedThrombocytopenia may oc

cur as a sec-ondary manifestation of immunodeficiency, butis often a presenting manifestation of theWiskott-Aldrich Syndrome. A unique finding in Table 5: atterns of Illness Associated with P rimar y Immunodeficiency Disor Illnesses AntibodySinopulmonary (pyogenic bacteria)Autoimmune diseaseGastrointestinal (enterovirus, giardia)(autoantibodies, inflammatory bowel disease)Cell-mediated immunityPneumonia (pyogenic bacteria,Skin, mucous membranes (fungi)ComplementSepsis and other blood-borneAutoimmune disease(streptococci, pneumococci, neisseria)(Systemic lupus erythematosis, glomerulonephritis)PhagocytosisSkin, reticuloendothelial system, abscesses(staphylococci, enteric bacteria, in cases of splenic dysfunction or asplenia.However, the converse is not always true and than 80% of patients with primary disorders ofavailable, highly reliable and relatively inexpen-The initial screening test for humoraltive to be useful for this purpose. Quantitativemeasurements of serum IgG, IgA and IgM willidentify patients with panhypogammaglobuline-selective IgA deficiency. Interpretation of resultsTherefore, age-related normal values mustor the Hemophilus influenzae protein conjugatepatients who respond normally to proteinantigens. Antibody can be measured afternot useful for this purpose.) Alternatively, sincebeen described. However, the significance of anIgG subclass deficiency in the presence of nor-find that information about IgG subclass levelsadds to

expense but not to diagnosis. Immunity Testing for defects of cell-mediated immu-good screening tests. Lymphopenia is suggestiveof T-lymphocyte deficiency because T lympho-eral blood mononuclear cells. However, lym-T lymphocyte functional defects. Similarly, thelack of a thymus silhouette on chest x-ray israrely helpful in the evaluation of T lymphocytedren may involute following stress and give theblood T lymphocytes with appropriate mono-cells, anti-CD4 for T-helper cells, anti-CD8 forT-cytotoxic cells). Patients with severe combinedgenerally have decreased numbers of both CD4and CD8 T lymphocytes. In contrast, patientsciency of CD4 lymphocytes. All patients with Table 6: eening T ests for P rimar y Immunodeficiency Suspected Abnor mality Diagnostic T ests AntibodyQuantitative immunoglobulins (IgG, IgA, IgM)Cell-mediated immunityLymphocyte countComplementTotal hemolytic complement (CHPhagocytosisNeutrophil count to receive your 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.orgConley, ME, Stiehm ER Immunodeficiency Disorders: General Considerations. In Stiehm ER (ed). Immunologic Disorders in Infants aFischer A, Cavazzana-Calvo M, De Saint Basile G et al. Naturally occurring primary deficiencies of the immune system. Ann Rev IPrimary immunodeficiency diseases. Report of an IUIS S

cientific Committee. International Union of Immunological Societies. Clin Exp Immunol. 1999.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 te DTH testing should be used. The presence ofimmunity. However, there are significant limita-tions to this testing: (1) Prior exposure to anti-not insure that the patient has normal cell-sis have a limited defect in which cell-mediatedunder the age of 12 months frequently areunresponsive to all of the antigens in the panel.helpful for evaluation of suspected T-lympho System ciencies of complement can be detected with the) assay.Since this assay depends on the functional(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., factorrange of normal and the serum C3 level is low. entails assessment of both their number andagranulocytosis or cyclic neutropenia, that arenumber, can be easily detected by using a whitevariety of in vitro assays including measurementthe oxidative metabolic response of neutrophils NONPROFITORGU. S. POSTAGEPAIDELLICOTTCITY, MDPERMITNO. 70 Foundation25 West Chesapeake AvenueTowson, Maryland 212