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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,
Requests for reprints should be addressed to Antoine E. Azar, MD, University of Iowa, Internal Medicine, 200 Hawkins Drive, Iowa City, IA 52242. E-mail address: firstname.lastname@example.org
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).
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.12.013
Azar and Ballas
Selected Pathogens Associated with Immunodeﬁciency Disorders in Adults Clinical Examples Common variable immunodeﬁciency Common Pathogens 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
Host Defense Affected B cells
AIDS, chronic mucocutaneous candidiasis
Neutropenia, chronic granulomatous disease
Complement NK cells
Terminal complement deﬁciency (C5-C9) Early complement deﬁciency (C2, C4, C3) NK cell deﬁciency
acquired immune deﬁciency syndrome; NK
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
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
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.
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.
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”
The American Journal of Medicine, Vol 120, No 9, September 2007 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).
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.
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.
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.
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.
Azar and Ballas
Ofﬁce-based Immunologic Screening Tests
Immunologic Screening Tests
Initial immunologic screening tests are readily available and can be done in an ofﬁce setting (Table 5).
● 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.
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,
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).
Interpretation of Serum Immunoglobulin Levels*
Immunoglobulin Level IgG Nl Nl or 1 2 2 2
IgA 2 2 Nl 2 or Nl 2
IgM Nl 2 Nl 2 or Nl Nl or 1
Differential Diagnosis 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.
The American Journal of Medicine, Vol 120, No 9, September 2007 can be done using rabbit eryhrocytes. The most common cause of a low CH50 is inappropriate handling of the serum sample.
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.
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).
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.
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.
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.
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
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