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Home , Immunodeficiency, Neutrophilia, Primary immunodeficiency, Thymic hypoplasia

Volume 2 Issue 1 August 2000

ISSUES AND INFORMATION ON CURRENT TOPICS

Editor: Howard Lederman, MD, PhD The Clinical Presentation of Primary Medical Advisory Committee Jerry Winkelstein, MD Chairman Johns Hopkins University School of Medicine Baltimore, MD Howard M. Lederman, M.D., Ph.D. Douglas J. Barrett, MD Associate Professor of Pediatrics Table 2: University of Florida, Gainesville, FL R. Michael Blaese, MD Johns Hopkins University Clinical Features of Kimeragen , Newton, PA School of Medicine Immunodeficiency Rebecca H. Buckley, MD Duke University School of Medicine Baltimore, Maryland Durham, NC Mary Ellen Conley, MD • Increased susceptibility to St. Jude Children's Research Hospital Chronic/recurrent without other Memphis, TN The diseases were originally Max Cooper, MD explanation University of Alabama School of Medicine viewed as rare disorders, characterized by severe clini- Birmingham, AL Infection with organism of low virulence Charlotte Cunningham-Rundles, MD, PhD cal expression early in life. However, it has become Mt. Sinai Medical Center New York, NY clear that these diseases are not as uncommon as origi- Infection of unusual severity Erwin W. Gelfand, MD nally suspected, that their clinical expression can some- National Jewish Center For Immune and Respiratory Medicine • Autoimmune or inflammatory Denver, CO times be relatively mild, and that they are seen nearly as Robert Good, MD, PhD University of South Florida All Children's Hospital often in adolescents and adults as they are in infants • Syndrome complex St. Petersburg, FL Richard Hong, MD and children (Table 1). In fact, immunodeficiency may University of Vermont School of Medicine Burlington, VT present so subtly that the diagnosis will be made only if Richard B. Johnston, Jr., MD This article will review the most common clinical National Jewish Medical & Research Center Denver, CO signs and symptoms of primary immunodeficiency dis- Alexander R. Lawton, III, MD Table 1: Vanderbilt University School of Medicine eases, and discuss the most useful screening laboratory D3237 Medical Center North, Nashville, TN 37232 Primary Immunodeficiency Stephen Miles, MD tests. All Seasons , Asthma & Center Woodlands, TX • Is Not Rare Hans D. Ochs, MD Clinical Manifestations University of Washington School of Medicine • May Present at Any Age Seattle, WA Patients with primary immunodeficiency diseases Fred Rosen, MD • Does Not Always Present with Severe Infections The Center for Research most often are recognized because of their increased Boston, MA Andrew Saxon, MD susceptibility to infection, but these patients may also UCLA School of Medicine the physician is alert to that possibility. Los Angeles, CA present with a variety of other clinical manifestations Early diagnosis of immunodeficiency is important William T. Shearer, MD (Table 2). In fact, non-infectious manifestations, such Texas Children's Hospital so that appropriate therapy can be instituted before Houston, TX as , may be the first or the pre- E. Richard Stiehm, MD there has been end-organ damage. Furthermore, UCLA School of Medicine dominant clinical symptoms of the underlying immun- Los Angeles, CA because some primary immunodeficiency diseases are John L. Sullivan, MD odeficiency. Other immunodeficiency diseases may be University of Massachusetts Medical Center inheritable, early diagnosis is essential for making Worcester, MA diagnosed because of their known association with syn- Diane W. Wara, MD genetic information available to the families of affected UCSF Medical Center drome complexes. San Francisco, CA individuals.

Immune Immune Deficiency Foundation, the national nonprofit organization devoted to research and education for Deficiency the primary immune deficiency diseases, publishes other materials for physicians and healthcare professionals (eg. Foundation Physician’s Primer and Guide for Nurses) and for patients (eg.Patient and Family Handbook, Our , and 40 West Chesapeake Avenue Newsletter). For Information about our programs, patient groups and publications, call 1-800-296-4433. Suite 308 Towson, MD 21204 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 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 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 charac- selective IgA deficiency, chronic mucocutaneous Manifestations of Primary teristically have difficulty with and fungi. , and deficiencies of early compo- Immunodeficiency Individuals with deficiencies are nents of the classical complement pathway (C1- Target Cells unusually susceptible to encapsulated C4). • Hemolytic anemia and enteroviruses. Patients with complement Occasionally a disorder that appears to be • Immune deficiencies most often present with bacteremia, autoimmune in nature may, in fact, be due to an • Thyroiditis and , caused by infectious agent. For example, the dermato- encapsulated bacteria. And finally, phagocytic myositis that is sometimes seen in patients with Target Tissues disorders are characterized by infections of the X-linked agammaglobulinemia is really a man- • Vasculitis skin and reticuloendothelial system (lymph ifestation of chronic enterovirus infection and • Systemic lupus erythematosus nodes, and liver). not autoimmune disease. • Rheumatoid arthritis Autoimmune and Inflammatory Immunodeficiency Syndromes Manifestations Associated Diseases Immunodeficiency can also be seen as one Immunodeficient patients can present with • Common variable immunodeficiency part of a constellation of signs and symptoms in autoimmune or chronic inflammatory diseases. • Selective IgA deficiency a syndrome complex. In fact, the recognition It is thought that the basic abnormality leading • Chronic mucocutaneous candidiasis that a patient has a syndrome in which immun- to immunodeficiency may also lead to faulty • Complement pathway deficiencies odeficiency occurs may allow a diagnosis of 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 infections rather than the fact that individual of these disorders (Table 3) may be limited to a (Table 4). Children with the DiGeorge Syndrome infections are unusually severe. It is difficult to single target cell or organ (e.g., autoimmune are usually identified initially because of the assign a precise frequency of infections that hemolytic anemia or thrombocytopenia, 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 per Examples of Immunodeficiency Syndromes decade, chronic , chronic bronchitis without a history of smoking, increasing num- Syndrome Clinical Presentation Immunologic bers of ear infections after early childhood, Abnormality chronic or recurrent bacteremia. In DiGeorge syndrome Congenital heart disease some instances the patient not only has recur- Hypoparathryroidism rent infections, but one or more of these is Abnormal facies either unusually severe (e.g., ), leads to an Wiskott-Aldrich syndrome Thrombocytopenia Variable B- and T- unexpected complication (e.g., empyema or fis- Eczema dysfunction tula formation), or is caused by an organism of relatively low virulence (e.g., aspergillus). Ataxia-Telangiectasia Ataxia Variable B- and T- Not all immunodeficient patients are diag- Telangiectasia lymphocyte dysfunction nosed after recurrent infections. In some, the Ivemark syndrome Congenital heart disease first infection may be unusual enough to raise Bilateral 3-lobed the question of immunodeficiency. For example, Polyendocrinopathy syndrome Endocrine organ dysfunction Chronic mucocutaneous candidiasis 3 ease and/or hypocalcemic tetany. This should complex-mediated diseases, whereas phagocytic infection, and , but lead to T-lymphocyte evaluation prior to the dysfunction should be suspected when patients may be a primary problem (congenital or cyclic onset of opportunistic infections. Similarly, a have recurrent skin infections or visceral ). Persistent is charac- diagnosis of Wiscott-Aldrich Syndrome can abscesses. teristic of leukocyte adhesion molecule deficien- often be made in young boys with eczema and Screening tests that should be performed cy, and abnormal cytoplasmic granules may be thrombocytopenia even prior to the onset of in almost all patients include a complete blood seen in the peripheral blood smear of patients infections. count (CBC) with differential and quantitative with Chediak-Higaski Syndrome. measurement of serum immunoglobulins. Other The blood is predominately a “ LABORATORY tests should be guided by the clinical features of organ”, i.e., the majority (50-70%) of peripher- EVALUATION the patient (Table 6). Finally, whenever primary al blood are T cells whereas only Although immune system dysfunction can immunodeficiency is suspected, consideration 5-15% are B cells. Therefore, lymphopenia is be suspected by the clinician after careful must also be given to secondary causes of often a presenting feature of T cell or combined review of the history and physical exam, specific immunodeficiency including HIV infection, immunodeficiency disorders such as severe diagnoses are rarely evident without the use of therapy with anti-inflammatory medications combined immunodeficiency disease and the laboratory. However, the types of infections (e.g., corticosteroids), and other underlying ill- DiGeorge Syndrome. and other symptoms should help to focus the nesses (e.g., lymphoreticular ). Thrombocytopenia may occur as a sec- laboratory workup on specific parts of the ondary manifestation of immunodeficiency, but immune system (Table 5). Patients with anti- Examination of the Peripheral is often a presenting manifestation of the body deficiency typically have sinopulmonary Blood Smear Wiskott-Aldrich Syndrome. A unique finding in infections as a prominent presenting feature. The CBC with examination of the blood the latter group of patients is an abnormally Deficiency of cell-mediated immunity predis- smear is an inexpensive and readily available small platelet volume, a measurement that is poses individuals to develop infections caused test that provides important diagnostic informa- easily made by automated blood counters. by Pneumocystis carinii, other fungi and a vari- tion relating to a number of immunodeficiency Examination of morphology ety of viruses. Abnormalities of complement diseases (Table 6). Neutropenia most often can yield clues about splenic function. Howell- most often lead to bacterial sepsis or immune occurs secondary to immunosuppressive drugs, Jolly bodies may be visible in peripheral blood

Table 5: Patterns of Illness Associated with Primary Immunodeficiency Disorder Illnesses

Infection Other Antibody Sinopulmonary (pyogenic bacteria) Autoimmune disease Gastrointestinal (enterovirus, giardia) (, 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, ) (Systemic lupus erythematosis, glomerulonephritis)

Phagocytosis Skin, reticuloendothelial system, abscesses (staphylococci, enteric bacteria, fungi, mycobacteria) 4 in cases of splenic dysfunction or asplenia. identify patients with panhypogammaglobuline- rides, anti-polysaccharide antibody can be However, the converse is not always true and mia as well as those with deficiencies of an indi- assessed by quantitating isoagglutinin titers. In absence of Howell-Jolly bodies does not guaran- vidual class of immunoglobulins, such as a either case, anti-polysaccharide antibody mea- tee that splenic function is normal. selective IgA deficiency. Interpretation of results surements are generally useful only in children must be made in view of the marked variations above the age of 2 years, since normal children Evaluation of in normal immunoglobulin levels with age. of younger age may not have significant Measurement of serum immunoglobulin Therefore, age-related normal values must responses. levels is an important screening test to detect always be used for comparison. The role for IgG subclass measurements is immunodeficiency for three reasons: (1) More A clue to immunodeficiency may be a low controversial. There are four subclasses of IgG, than 80% of patients with primary disorders of normal IgG level in an individual with recurrent and selective deficiencies of each of these have immunity will have abnormalities of serum infections. In such cases, it is critical to assess been described. However, the significance of an immunoglobulins; (2) Immunoglobulin mea- antibody function in addition to immunoglobu- IgG subclass deficiency in the presence of nor- surements yield indirect information about sev- lin level. Antibody levels generated in response mal antibody responses to protein and polysac- eral disparate aspects of the immune system to childhood immunization with tetanus toxoid charide is not known. Many physicians, because immunoglobulin synthesis requires the or the Hemophilus influenzae protein conjugate therefore, rely upon antibody measurements and coordinated function of B lymphocytes, T lym- are usually the most convenient to find that information about IgG subclass levels phocytes and ; and (3) The measure- measure. In children over the age of 18-24 adds to expense but not to diagnosis. ment of serum immunoglobulin levels is readily months, it is also important to assess antibody available, highly reliable and relatively inexpen- responses to polysaccharide antigens because Evaluation of Cell-Mediated sive. these responses may be deficient in some Immunity The initial screening test for humoral patients who respond normally to protein Testing for defects of cell-mediated immu- immune function is the quantitative measure- antigens. Antibody can be measured after nity is relatively difficult because of the lack of ment of serum immunoglobulins. Neither serum immunization with pneumococcal capsular good screening tests. Lymphopenia is suggestive protein electrophoresis nor immunoelec- polysaccharide . (The pneumococcal of T-lymphocyte deficiency because T lympho- trophoresis is sufficiently sensitive or quantita- polysaccharide/protein conjugate vaccines are cytes comprise the majority (50-70%) of periph- tive to be useful for this purpose. Quantitative not useful for this purpose.) Alternatively, since eral blood mononuclear cells. However, lym- measurements of serum IgG, IgA and IgM will the ABO blood group antigens are polysaccha- phopenia is not always present in patients with T lymphocyte functional defects. Similarly, the lack of a silhouette on chest x-ray is Table 6: rarely helpful in the evaluation of T lymphocyte Screening Tests for Primary Immunodeficiency disorders because the thymus of normal chil- dren may involute following stress and give the Suspected Abnormality Diagnostic Tests appearance of thymic hypoplasia. Indirect information about T cell function Antibody Quantitative immunoglobulins (IgG, IgA, IgM) may be obtained by enumerating peripheral Antibody response to immunization blood T lymphocytes with appropriate mono- clonal (anti-CD2 or CD3 for total T Cell-mediated immunity Lymphocyte count cells, anti-CD4 for T-helper cells, anti-CD8 for T-cytotoxic cells). Patients with severe combined T lymphocyte enumeration (CD4, CD8) immunodeficiency and DiGeorge Syndrome HIV serology generally have decreased numbers of both CD4 Delayed type skin tests and CD8 T lymphocytes. In contrast, patients infected with HIV typically have a selective defi- ciency of CD4 lymphocytes. All patients with Complement Total hemolytic complement (CH50) reduced T lymphocyte function or reduced CD4 count lymphocyte number should be tested for HIV infection. Nitroblue tetrazolium (NBT) dye test Delayed type hypersensitivity (DTH) skin 5 testing with a panel of antigens is another cyte abnormalities that present early in life (e.g., Evaluation of Phagocytic Cells screening method for older children and adults. severe combined immunodeficiency or Evaluation of phagocytic cells usually A standardized panel of antigens prepared for DiGeorge Syndrome). entails assessment of both their number and DTH testing should be used. The presence of their function. Disorders, such as congenital one or more positive delayed-type skin tests is Evaluation of the Complement or , that are generally indicative of intact cell-mediated System characterized by a deficiency in phagocytic cell immunity. However, there are significant limita- Most of the genetically determined defi- number, can be easily detected by using a white tions to this testing: (1) Prior exposure to anti- ciencies of complement can be detected with the blood cell count and differential. Beyond that, gen is a prerequisite; (2) Normal patients may total serum hemolytic complement (CH50) assay. assessment of phagocytic cell function is rela- have transient depression of DTH with acute Since this assay depends on the functional tively specialized because it depends upon a viral infections such as infectious mononucleo- integrity of the classical complement pathway variety of in vitro assays including measurement sis; (3) A positive skin test to some antigens does (C1 through C9), a severe deficiency of any of of directed cell motility (), ingestion not insure that the patient has normal cell- these components leads to a marked reduction (phagocytosis) and intracellular killing (bacte- mediated immunity to all antigens (e.g., or absence of total hemolytic complement activ- ricidal activity). The most common of the patients with chronic mucocutaneous candidia- ity. Alternative pathway deficiencies (e.g., factor function disorders, chronic granulo- sis have a limited defect in which cell-mediated H, factor I and properdin) are extremely rare; matous disease, can be identified by the nitrob- immunity is generally intact except for their they may be suspected if the CH50 is in the low lue tetrazolium (NBT) dye test, that measures response to ); and (4) Normal children range of normal and the serum C3 level is low. the oxidative metabolic response of under the age of 12 months frequently are The final identification of the specific comple- and monocytes. unresponsive to all of the antigens in the panel. ment component that is deficient usually rests DTH skin tests are, therefore, generally not on both functional and immunochemical tests, helpful for evaluation of suspected T-lympho and highly specific assays have been developed for each of the individual components.

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 clinical features are highly suggestive of immune system dysfunction.

SUGGESTED READING Conley, 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.

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