Volume 2 Issue 1 August 2000 I SSUES AND I NFORMATION O N CURRENT TOPICS The Clinical Presentation of Primary Editor: Howard Lederman, MD, PhD Immunodeficiency Diseases Medical Advisory Committee Jerry Winkelstein, MD Chairman Johns Hopkins University School of Medicine Howard M. Lederman, M.D., Ph.D. Baltimore, MD Table 2: Associate Professor of Pediatrics Douglas J. Barrett, MD University of Florida, Gainesville, FL Clinical Features of Johns Hopkins University R. Michael Blaese, MD Immunodeficiency Kimeragen , Newton, PA School of Medicine Rebecca H. Buckley, MD Baltimore, Maryland Duke University School of Medicine Durham, NC • Increased susceptibility to infection Mary Ellen Conley, MD Chronic/recurrent infections without other St. Jude Children's Research Hospital The primary immunodeficiency diseases were originally Memphis, TN explanation Max Cooper, MD viewed as rare disorders, characterized by severe clini- University of Alabama School of Medicine Birmingham, AL cal expression early in life. However, it has become Infection with organism of low virulence Charlotte Cunningham-Rundles, MD, PhD clear that these diseases are not as uncommon as origi- Mt. Sinai Medical Center Infection of unusual severity New York, NY nally suspected, that their clinical expression can some- Erwin W . Gelfand, MD • Autoimmune or inflammatory disease National Jewish Center For Immune and Respiratory Medicine times be relatively mild, and that they are seen nearly as Denver, CO Robert Good, MD, PhD • Syndrome complex often in adolescents and adults as they are in infants University of South Florida All Children's Hospital St. Petersburg, FL and children (Table 1). In fact, immunodeficiency may Richard Hong, MD University of Vermont School of Medicine present so subtly that the diagnosis will be made only if Burlington, VT This article will review the most common clinical Richard B. Johnston, Jr., MD National Jewish Medical & Research Center signs and symptoms of primary immunodeficiency dis- Denver, CO Table 1: Alexander R. Lawton, III, MD eases, and discuss the most useful screening laboratory Vanderbilt University School of Medicine Primary Immunodeficiency D3237 Medical Center North, Nashville, TN 37232 tests. Stephen Miles, MD All Seasons Allergy, Asthma & Immunology Center Woodlands, TX • Is Not Rare Clinical Manifestations Hans D. Ochs, MD • May Present at Any Age University of Washington School of Medicine Patients with primary immunodeficiency diseases Seattle, WA • Does Not Always Present with Severe Infections Fred Rosen, MD most often are recognized because of their increased The Center for Blood Research Boston, MA susceptibility to infection, but these patients may also Andrew Saxon, MD the physician is alert to that possibility. UCLA School of Medicine present with a variety of other clinical manifestations Los Angeles, CA Early diagnosis of immunodeficiency is important William T. Shearer, MD (Table 2). In fact, non-infectious manifestations, such so that appropriate therapy can be instituted before Texas Children's Hospital Houston, TX as autoimmune disease, may be the first or the pre- there has been end-organ damage. Furthermore, E. Richard Stiehm, MD UCLA School of Medicine dominant clinical symptoms of the underlying immun- because some primary immunodeficiency diseases are Los Angeles, CA odeficiency. Other immunodeficiency diseases may be John L. Sullivan, MD inheritable, early diagnosis is essential for making University of Massachusetts Medical Center diagnosed because of their known association with syn- Worcester, MA genetic information available to the families of affected Diane W . Wara, MD drome complexes. UCSF Medical Center individuals. San Francisco, CA Immune Deficiency Foundation, the national nonprofit organization devoted to research and education for Immune the primary immune deficiency diseases, publishes other materials for physicians and healthcare professionals (eg. Deficiency Physician’s Primer and Guide for Nurses) and for patients (eg.Patient and Family Handbook, Our Immune System, and Foundation Newsletter). For Information about our programs, patient groups and publications, call 1-800-296-4433. 40 West Chesapeake Avenue Suite 308 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 Towson, MD 21204
2 Infectious Manifestations a patient who presents with infection caused by autoimmune thyroiditis), or may involve a An increased susceptibility to infection is Pneumocystis carinii or another opportunistic number of different target organs (e.g., vasculi- the hallmark of the primary immunodeficiency pathogen is likely to be immunodeficient even if tis, systemic lupus erythematosus, rheumatoid diseases. In most patients, the striking clinical it is his/her first recognized infection. arthritis). The autoimmune and inflammatory feature is the chronic or recurring nature of the The type of pathogen and the location of diseases are more commonly seen in particular the infection may give valuable insight into the primary immunodeficiency diseases, most Table 3: nature of the immunologic defect. Individuals notably common variable immunodeficiency, Autoimmune or Inflammatory with defects in cell-mediated immunity charac- selective IgA deficiency, chronic mucocutaneous Manifestations of Primary teristically have difficulty with viruses and fungi. candidiasis, and deficiencies of early compo- Immunodeficiency Individuals with antibody deficiencies are nents of the classical complement pathway (C1- unusually susceptible to encapsulated bacteria C4). Target Cells and enteroviruses. Patients with complement Occasionally a disorder that appears to be • Hemolytic anemia deficiencies most often present with bacteremia, autoimmune in nature may, in fact, be due to an • Immune thrombocytopenia septic arthritis and meningitis, caused by infectious agent. For example, the dermato- • Thyroiditis encapsulated bacteria. And finally, phagocytic myositis that is sometimes seen in patients with disorders are characterized by infections of the X-linked agammaglobulinemia is really a man- Target Tissues skin and reticuloendothelial system (lymph ifestation of chronic enterovirus infection and • Vasculitis nodes, spleen and liver). not autoimmune disease. • Systemic lupus erythematosus • Rheumatoid arthritis Autoimmune and Inflammatory Immunodeficiency Syndromes Manifestations Immunodeficiency can also be seen as one Associated Diseases Immunodeficient patients can present with part of a constellation of signs and symptoms in • Common variable immunodeficiency autoimmune or chronic inflammatory diseases. a syndrome complex. In fact, the recognition • Selective IgA deficiency It is thought that the basic abnormality leading that a patient has a syndrome in which immun- • Chronic mucocutaneous candidiasis to immunodeficiency may also lead to faulty odeficiency occurs may allow a diagnosis of • Complement pathway deficiencies discrimination between self and non-self, and immunodeficiency to be made before there are thus to autoimmune disease. The manifestations any clinical manifestations of that deficiency of these disorders (Table 3) may be limited to a infections rather than the fact that individual (Table 4). Children with the DiGeorge Syndrome single target cell or organ (e.g., autoimmune infections are unusually severe. It is difficult to are usually identified initially because of the hemolytic anemia or thrombocytopenia, assign a precise frequency of infections that neonatal presentation of congenital heart dis- defines increased susceptibility. As a guideline, immunodeficiency should be suspected when a Table 4: patient has more than one pneumonia per Examples of Immunodeficiency Syndromes decade, chronic sinusitis, chronic bronchitis without a history of smoking, increasing num- Syndrome Clinical Presentation Immunologic Abnormality bers of ear infections after early childhood, chronic diarrhea or recurrent bacteremia. In DiGeorge syndrome Congenital heart disease Thymic hypoplasia some instances the patient not only has recur- Hypoparathryroidism Abnormal facies rent infections, but one or more of these is either unusually severe (e.g., sepsis), leads to an Wiskott-Aldrich syndrome Thrombocytopenia Variable B- and T- unexpected complication (e.g., empyema or fis- Eczema lymphocyte dysfunction tula formation), or is caused by an organism of Ataxia-Telangiectasia Ataxia Variable B- and T- relatively low virulence (e.g., aspergillus). Telangiectasia lymphocyte dysfunction Not all immunodeficient patients are diag- nosed after recurrent infections. In some, the Ivemark syndrome Congenital heart disease Asplenia first infection may be unusual enough to raise Bilateral 3-lobed lungs the question of immunodeficiency. For example, Polyendocrinopathy syndrome Endocrine organ dysfunction Chronic mucocutaneous candidiasis
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