Evaluacion De Inmunodefiencia En Adultos

The American Journal of Medicine (2007) 120, 764-768

OFFICE MANAGEMENT: ALLERGY AND IMMUNOLOGY Richard D. deShazo, Speciality Editor

Evaluation of the Adult with Suspected Immunodeficiency Antoine E. Azar, MD, Zuhair K. Ballas, MD Division of Allergy/Immunology, Department of Internal Medicine, University of Iowa and the Iowa City VA Medical Center, Iowa City. ABSTRACT Several primary immunodeficiencies may have their initial presentation in adulthood. Although recurrent infections are the hallmark of an underlying immunodeficiency, they need not be the presenting manifestation. This review highlights aspects of infections, as well as noninfectious diseases, that should prompt a high index of suspicion for an underlying immune disorder. The office tests that can be obtained for initial screening and their interpretation are detailed. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Antibody deficiency; Common variable immunodeficiency; Failure to thrive; Hypogammaglobulinemia; Immune deficiency; Opportunistic organisms; Recurrent infections

This article is not intended as a review of the various immunodeficiencies that can be seen in adults. Our objective here is to provide the primary care physician with a practical approach as to when to suspect, and how to screen for, an immunodeficiency in adult patients. A significant part of the evaluation can be done in the office setting. A detailed history can yield abundant clues as to the nature of a potential immune abnormality. Initial screening tests are relatively simple, inexpensive, and widely available. Abnormal results obtained on initial screening may indicate the nature of the immune disorder or the need for consultation with an allergist/immunologist for further evaluation.

A BRIEF OVERVIEW OF THE IMMUNE SYSTEM The main task of the immune system is the differentiation of “self” from “non-self.” “Non-self” is considered harmful and should be eliminated, whereas “self” is tolerated. Microorganisms are the major “non-self” that the immune system attempts to neutralize on a daily basis. A suboptimal immune system is not able to effectively contain microorganisms, resulting in frequent infections. Also, an abnormal immune system might not be tolerant of “self,” resulting in autoimmune diseases. Some immune disorders, therefore,

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may present with increased incidence of infections and autoimmune diseases. Each major class of microorganisms is recognized predominantly by a specific immune mechanism: Gram-negative bacteria are recognized by neutrophils and macrophages. Neutrophils recognize any of several molecules, such as mannose, that are present on the cell wall of the gram-negative bacteria. Encapsulated bacteria have a polysaccharide capsule, and thus their cell wall molecules are hidden. The immune system responds to these organisms by generating antibodies against the capsule. The antigen–antibody complex then activates the complement cascade. Complement fragments (C3b) and the antigen–antibody complex result in optimal opsonization to the macrophages that then phagocytose and eliminate the bacteria. A properly functioning antibody response and complement cascade are needed for optimal defense against these organisms. Intracellular organisms such as viruses and mycobacteria require T lymphocytes and natural killer (NK) cells for their elimination. The immune response against gram-negative bacteria and encapsulated organisms centers on facilitating phagocytosis. This strategy does not work for intracellular organisms because they thrive inside the cell. T lymphocytes and NK cells are responsible for defense against such organisms and function by activating the macrophages (in the case of mycobacteria) or by directly killing the infected cells (in the case of viruses).

Azar and Ballas Table 1

Adult Immunodeficiencies

765

Selected Pathogens Associated with Immunodeficiency Disorders in Adults

Host Defense Affected

Clinical Examples

Common Pathogens

B cells

Common variable immunodeficiency

T cells

AIDS, chronic mucocutaneous candidiasis

Neutrophils

Neutropenia, chronic granulomatous disease

Complement

Terminal complement deficiency (C5-C9) Early complement deficiency (C2, C4, C3) NK cell deficiency

Encapsulated organisms Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Giardia Campylobacter Fungi Candida Cryptococcus Pneumocystis Viruses Cytomegalovirus Herpes simplex Varicella zoster Mycobacteria Staphylococcus aureus Aspergillus Nocardia Gram-negative bacteria Escherichia coli Serratia marcescens Burkholderia Pseudomonas Neisseria meningitidis, Neisseria gonorrhea Encapsulated organisms (same as B-cell deficiency) Herpes viruses; human papilloma virus

NK cells

AIDS ⫽ acquired immune deficiency syndrome; NK ⫽ natural killer.

When evaluating a patient with frequent infections, the type of organism responsible for these infections should give a clue as to which aspect of the immune system might not be functioning properly (Table 1).1

PRIMARY VERSUS SECONDARY IMMUNODEFICIENCY Primary immunodeficiency disorders (PIDs) are reported to have an estimated prevalence of 1:10,000 in the general population. This is probably an underestimate because the prevalence of selective immunoglobulin (Ig)A deficiency is estimated at 1:300 to 1:700 (in the United States). Approximately one third of patients with selective IgA deficiency have frequent infections, thus making the prevalence of clinically relevant primary immunodeficiency much more common than 1:10,000. In addition to IgA deficiency, the most common PIDs diagnosed in adulthood include common variable immunodeficiency (CVID) and certain complement deficiencies.2 Conditions leading to secondary immune dysfunction are far more common in adults than PIDs. These should always be ruled out first when a patient is being evaluated for suspected immunodeficiency (Table 2). Infections recurring at the same site may suggest an anatomic abnormality, such as a urethral stricture in a patient with recurrent urinary tract infection.

WHEN TO SUSPECT AN IMMUNODEFICIENCY Although recurrent infections are a hallmark of immunodeficiency, this is not always the case. In thinking about immunodeficiency, the key word is “unusual” (Table 3). An unusual organism, an unusual duration, an unusual complication, or an unusual severity of a “usual” infection should

Table 2

Common Causes of Secondary Immunodeficiency

● ● ● ● ●

Malnutrition HIV Malignancy Immunosuppressive drugs Immunomodulatory agents: ● Rituximab (affecting B cells) ● Infliximab, etanercept, adalimumab, anakinra (affecting cellular immunity) ● Drug-induced hypogammaglobulinemia: ● Certain antiepileptics (eg, diphenylhydantoin, carbamazepine, valproate) ● Protein loss (especially if presenting with low IgG but normal IgA and IgM): ● Nephrotic syndrome, protein-losing enteropathy, severe burns ● Metabolic disease: ● Diabetes, severe liver disease, uremia HIV ⫽ human immunodeficiency virus; Ig ⫽ immunoglobulin.

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Table 3 Clues Suggesting the Presence of an Immunodeficiency Aspects of Infections: ● Unusual frequency ● Unusual severity ● Unusual duration ● Unusual complications ● Unusual organisms Noninfectious Clues ● Premature loss of dentition ● Poor wound healing ● Unexplained bronchiectasis ● Chronic diarrhea or malabsorption ● Autoimmunity, especially if more than one (eg, hypothyroidism and alopecia or vitiligo) ● Hematologic disorders (hemolytic anemia, neutropenia, thrombocytopenia) ● “Failure to thrive”

prompt suspicion of an immunodeficiency. For example, an upper respiratory tract infection that progresses to pneumonia or empyema in an otherwise healthy individual may indicate an underlying immune dysfunction. The frequency of infection need not be on a monthly or annual basis. One documented pneumonia every 5 years in an otherwise healthy, nonsmoking, young adult might be considered an increased frequency of infection.3 Certain noninfectious presentations might suggest an underlying immunodeficiency. Premature loss of dentition or recurrent gingivitis may occur in individuals with antibody deficiency or impaired phagocytic function. Poor or delayed wound healing can be indicative of antibody deficiency. Skin or genital warts, especially when extensive and disseminated, suggest a deficient cellular immunity. Immune deficiency disorders also are frequently associated with autoimmune conditions, such as thyroiditis, autoimmune hemolytic anemia, thrombocytopenia, neutropenia, pernicious anemia, inflammatory bowel disease, celiac disease, vitiligo, and connective tissue disorders. A family history of immunodeficiency, frequent infections, or autoimmune disorders also may heighten the suspicion of an immune deficiency.

EVALUATION OF THE PATIENT WITH SUSPECTED IMMUNODEFICIENCY History As in any disease investigation, a thorough history is the most important initial step in evaluation. Detailed information should be obtained about the nature and site of the infections, their frequency, their complications, their documentation (cultures, imaging), and their treatment. Treatment features that might suggest a less than optimal host defense include the need to use intravenous antibiotics, the need for multiple antibiotics, and the need for multiple courses of antibiotics.

History should be obtained regarding premature loss of dentition, poor or delayed wound healing, warts, chronic diarrhea, and bronchiectasis. A history of recurrent aphthous ulcers may be the only clue for the presence of neutropenia. Current and recent medications, especially immunosuppressive and antiepileptic drugs, should be reviewed in detail (Table 2).

Family History Many PIDs are inherited in an autosomal recessive or Xlinked pattern. Consanguinity raises the possibility of an autosomal recessive disorder. CVID and selective IgA deficiency do not have a definitive pattern of inheritance but tend to cluster in families. It is not unusual to have a patient with CVID whose sibling may have IgA deficiency, rheumatoid arthritis, systemic lupus erythematosus, pernicious anemia, or other autoimmune disorders. A small subset of patients with CVID have an autosomal recessive mutation.

Physical Examination Physical examination gives valuable hints to the underlying disease process. Examination of the head and neck may reveal signs of sinusitis, which is common in patients with antibody defects. Tympanic membrane scarring or perforation suggests recurrent otitis media. Oral examination should include evaluation for aphthous ulcers and oral thrush. Rales or rhonchi may indicate bronchiectasis or chronic bronchitis. Hepatosplenomegaly is seen in a significant subset of patients with CVID. Lymphadenopathy also is common in CVID (reactive lymphadenopathy is the most frequent histologic picture, although lymphoma is also markedly increased). Skin may reveal verrucae, furuncles or abscesses, severe scars (suggestive of possible repeated

Table 4 Initial Screening Tests for Secondary Causes of Immunodeficiency ● CBC with differential and smear: Leukocytosis (infection, leukemia) Neutropenia (medications, infections, malignancy) Lymphopenia (HIV, malignancy) Eosinophilia (allergic disorders, lymphoma) Anemia (chronic disease, malabsorption, hemolysis) Macrocytosis (alcoholism, pernicious anemia) Thrombocytopenia (bone marrow infiltration, autoimmunity) ● Creatinine, electrolytes, liver function tests, blood glucose ● Urinalysis (proteinuria) ● Total serum protein, albumin, globulin ● HIV (ELISA or PCR) ● Imaging to document sinusitis or bronchiectasis, if indicated ● Appropriate cultures if indicated CBC ⫽ complete blood count; HIV ⫽ human immunodeficiency virus; ELISA ⫽ enzyme-linked immunosorbent assay; PCR ⫽ polymerase chain reaction.

Azar and Ballas Table 5

Adult Immunodeficiencies

767

Immunologic Screening Tests

Office-based Immunologic Screening Tests

● B cells Quantitative immunoglobulins (IgG, IgA, IgM, IgE)* Flow cytometry: enumeration of B cells Antibody response to pneumococcus, tetanus, and diphtheria vaccines ● T cells Flow cytometry: enumeration of T cells (CD3), T-helper cells (CD4), and cytotoxic T cells (CD8) ● Complement Total hemolytic complement (CH50) Selected complement levels as suggested by history ● Neutrophils/phagocytes CBC with differential Respiratory burst generation by flow cytometry (available in many reference laboratories) ● NK cells Flow cytometry: enumeration of NK cells (CD16/CD56) CBC ⫽ complete blood count; Ig ⫽ immunoglobulin; NK ⫽ natural killer. *IgG subclasses are not recommended as a screening test.

pyogenic infections), or vitiligo. Joint deformities suggest previous joint infections, or autoimmune inflammatory conditions, seen in antibody and complement deficiencies.4

Initial Diagnostic Evaluation After the history and physical examination, routine screening laboratory tests provide helpful information (Table 4). It is important to note that patients with a defect in antibody production may have false-negative results on tests that involve the measurement of antibodies. For example, to rule out hepatitis C or human immunodeficiency virus (HIV) infection in a patient with antibody deficiency, a viral load should be obtained rather than enzyme-linked immunosorbent assay. Microbiological information is critical for indicating the abnormal aspect of the immune system (Table 1).

Table 6

Initial immunologic screening tests are readily available and can be done in an office setting (Table 5).

Antibody Deficiency Quantitative evaluation of the humoral immune system starts with measurement of serum Igs (IgG, IgA, IgM, and IgE) (Table 6). An elevated IgE level might indicate further evaluation for allergic disorders. If the Ig levels are normal in the face of a strong clinical suspicion of an antibody deficiency, an assessment of functional activity of B cells should be undertaken. Some patients may have normal Ig levels (probably produced by memory B cells that developed before the acquisition of the immune abnormality) but are unable to mount a specific antibody on challenge. The definitive method for functional assessment of B cells consists of measuring specific antibodies after immunization. Both polysaccharide and protein vaccines are used. Antibodies should be measured before vaccine administration and repeated 4 weeks later. It is important to check the antibody levels before vaccination, because the interpretation of the results depends on the fold increase in antibody titers. Definitive criteria for an adequate antibody response have not been established, but a generally accepted rule is a 4-fold increase in antibody titers. Interpretation becomes more difficult in patients who have protective titers before immunization and who subsequently may not adequately respond to the vaccine. Common protein vaccines used are tetanus and diphtheria; a common polysaccharide vaccine used is the 23valent pneumococcal vaccine, which provides the potential for measuring the immune response to different pneumococcal serotypes. The consensus is that normal individuals mount a 4-fold antibody titer increase in response to 70% of pneumococcal serotypes.2 The utility of measuring IgG subclasses is questionable. Although IgG subclasses can be selectively low,

Interpretation of Serum Immunoglobulin Levels*

Immunoglobulin Level IgG

IgA

IgM

Differential Diagnosis

Nl

2

Nl

Nl or 1

2

2

2

Nl

Nl

2 2

2 or Nl 2

2 or Nl Nl or 1

Selective IgA deficiency (if IgA is nondetectable) Anti-epileptics Monoclonal IgG production Common variable immunodeficiency patient on replacement therapy Protein loss (nephrotic syndrome, protein-losing enteropathy) Antibody deficiency Common variable immunodeficiency (low IgA and/or low IgM) Monoclonal gammopathy (Waldenstrom, monoclonal gammopathy of unknown significance, multiple myeloma) Hyper-IgM syndrome

Nl ⫽ normal; 2 ⫽ decreased; 1 ⫽ increased; Ig ⫽ immunoglobulin. *Any elevated immunoglobulin level should be followed by immunofixation electrophoresis to look for a monoclonal band.

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one should not make any therapeutic decision on the basis of the level alone. Individuals with chromosomal deletions of IgG2 have been identified and had no clinical disease, probably because they were able to compensate by shifting their IgG response to the other subclasses. Current recommendations focus on evaluating specific antibody response with post-immunization titers rather than measuring IgG subclasses.

Cellular Immunity T-cell abnormalities result in infections with viral, fungal, or opportunistic organisms. Initial screening should always include HIV testing and enumeration of lymphocyte subsets. The cells tested are CD3 (T cells), CD4 (helper T cells), CD8 (cytotoxic T cells), CD19 or CD20 (B cells), and CD16 or CD56 (NK cells). Although an abnormal CD4:CD8 ratio may be important in HIV, its significance in the absence of HIV is not well established. A low CD4 count with negative HIV testing might indicate idiopathic CD4 lymphopenia, and the patient should be referred to an allergist/immunologist for further assessment.5 Delayed-type hypersensitivity is the major in vivo screening test for T-cell dysfunction. This is performed by using various antigens to which the patient has been exposed. However, administration and interpretation of such tests are fraught with difficulty, especially if an office does not routinely perform such tests. A major concern is the proper choice of antigens for the skin tests because there is no one single antigen to which 100% of the population responds. Therefore, several antigens have to be used before one can be confident that a negative test result indicates anergy. Because in vitro lymphocyte testing may be required in place of delayed skin testing, consultation should be considered when specific cell-mediated deficits are suspected.

Complement Patients with early complement component (C2, C4) deficiency present with collagen vascular disease and infections similar to patients with B-cell deficiency. Patients with C3 deficiency may be indistinguishable from those with antibody deficiency. Patients with terminal complement deficiency (C5, C6, C7, C8, C9) present with recurrent Neisserial infections. The most useful test for screening for complement deficiency is total hemolytic complement (CH50), which reflects the activity of all components of the classic complement pathway (C1 to C9) and the terminal components of the alternative pathway. If CH50 is low, the patient should be referred to an allergist/immunologist for further evaluation. Screening for abnormalities of the alternative complement pathway

can be done using rabbit eryhrocytes. The most common cause of a low CH50 is inappropriate handling of the serum sample.

Phagocytes Patients with phagocytic cell defects develop recurrent bacterial and fungal infections involving the skin, periodontal tissue, lung, liver, and bone. Neutropenia is the most commonly encountered disorder of phagocytes and is detected by doing complete blood cell count with differential. Most neutropenias are secondary to medications. An infection pattern suggestive of neutrophil deficit in the presence of normal neutrophil count should be followed by testing for superoxide generation (available in most reference laboratories using flow cytometry).

Natural Killer Cells NK cell deficiency, a rare entity, is associated with recurrent herpes viral infections, as well as severe human papilloma virus-associated disease, such as vaginal and cervical cancers or recurrent and disseminated warts. NK cell numbers can be assessed by flow cytometry. Functional assessment is available in reference libraries.

SUMMARY A heightened index of suspicion of immunodeficiency can lead to an early diagnosis and a favorable outcome. Recurrent infections, unusual aspects of usual infections, unexplained bronchiectasis, chronic diarrhea, autoimmune diseases, and “failure to thrive” should prompt screening for a potential immune abnormality. A considerable wealth of information can be obtained from screening tests done in a primary care setting. If initial assessment does not reveal any abnormality, and the clinician still suspects an immunodeficiency, referral to an allergist/immunologist for further evaluation is indicated.

References 1. Holland SM, Gallin JI. Evaluation of the patient with suspected immunodeficiency. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York, NY: Elsevier; 2005:149-160. 2. Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency.. Ann Allergy Asthma Immunol2005;94(5 Suppl 1):S1-S63. 3. Kavanaugh A. Evaluation of patients with suspected immunodeficiency. Am Fam Physician. 1994;49:1167-1172. 4. Ballow M, O’Neil KM. Approach to the patient with recurrent infections. In: Adkinson NF, Yunginger JW, Busse WW, Bochner BS, Holgate ST, Simons FE, eds. Middleton’s Allergy Principles and Practice.6th ed. Philadelphia, PA: Mosby; 2003:1043-1072. 5. Fleisher TA, Oliveira JB. Functional and molecular evaluation of lymphocytes. J Allergy Clin Immunol. 2004;114:227-234.