Nancy B. Kuemmerle Our immune system is the result of millions of years of evolution all leading to one overarching goal: to protect us from our environment. When working properly, immunity enables us to conduct all the normal affairs of running the human body, such as taking in nutrients, breathing air potentially contaminated with microorganisms or pollutants, and eliminating organisms that could potentially do us harm. When immunity develops abnormally (primary or inherited immunodeficiency) or later becomes compromised by any mechanism (secondary or acquired immunodeficiency), the result can prove catastrophic for the affected individual. One need only recall the images of David Vetter, also known as the Bubble Boy, who lived with severe combined immunodeficiency disease (SCID) for almost all of his 12 years in a sterile enclosure, to understand the precarious situation caused by lack of a functional immune system. Fortunately, conditions such as David Vetter’s are uncommon, probably affecting fewer than 1 in 100,000 live births, although the exact incidence is unknown.1 More common primary immunodeficiencies, such as isolated immunoglobulin (Ig) A deficiency, can affect 1 in 500 to 1 in 300 individuals.2 All told, immunodeficiency is seen in around 1 in 1200 live births in the United States; of these individuals, about 1 in 2000 are diagnosed before the age of 18.1,2 More than 180 primary immunodeficiencies have been described since Colonel Ogden Bruton first discovered agammaglobulinemia in 1952.2,3 Acquired immunodeficiencies tend to be more common than inherited forms, and even the newest health care practitioner understands the toll that human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), the most common secondary immunodeficiency in the United States, can take on patients, families, and the health care system. Acquired immunodeficiency is discussed in Chapter 230 and is not covered in detail here. In general, whether inherited or acquired, most immunodeficiencies manifest as an unusual susceptibility to infection. The complications of immunodeficiency include, in addition to infection, autoimmune processes, unregulated inflammation, malignancies, and the complications of pharmacologic or other therapeutic interventions.4 The type of infection can often provide a clue to the underlying mechanism of disease and to its potential treatment.5 Although recurrent infections can frequently be masked with antibiotics, other allergic or autoimmune symptoms can also be clues that the patient may have an underlying deficiency. Consultation with an allergist or clinical immunologist is indicated for all patients with suspected immunodeficiency disorders. Primary immunodeficiencies are by definition congenital, and many arise from single-gene defects, although others come under the influence of multiple genes. As more is learned about the processing and maturation of cells of the immune system, it becomes apparent that mutations in any of a number of genes along a specific pathway can effect an immunodeficiency.6 Immunodeficiencies can be linked to sex chromosomes, or they can be caused by mutations in somatic genes, in which case they are usually recessive; however, germline mutations can also be dominant acting.6 Most appear by the age of 6 years, but milder forms may never cause enough morbidity to facilitate diagnosis or are discovered serendipitously. Understanding how the immune system is structured can provide clues to the underlying mechanisms of a suspected immunodeficiency as well as allow its classification. The immune system is composed of two main divisions. The innate immune system is the section that provides nonspecific defense. Examples of innate immunity include physical barriers such as intact skin and mucus in the lungs, which block entry of harmful bacteria, viruses, and fungi; immune cells (macrophages, neutrophils), which recognize and target primitive protein sequences common to most nonself organisms; and finally protein components (such as complement or cytokines), which circulate throughout the blood, ready to latch onto foreign proteins. Whether a lowly snail or a sprinting cheetah, all living organisms, including humans, possess some of these innate tactics for fighting off the environment. The adaptive immune system, on the other hand, is an evolutionary advance that we share only with fellow vertebrates. Here, foreign proteins (antigens) are recognized and processed by immune effector cells. This process, called immune priming, induces changes in the development and maturation of other cells (B and T cells), which then specifically target subsequent invaders for destruction. The respective cell lines produce antigen-specific antibodies (through B cells, or humoral immunity) or target the antigen for cell-mediated destruction (through T cells, or cell-mediated immunity). Both these divisions are complex and are further regulated by added levels of intricacy. Failure of just one protein in one pathway can subsequently lead to partial or total deficiency of immune function. This is the pathophysiologic underpinning of immunodeficiency. Deficiencies in the innate immune system include barrier disorders (such as cystic fibrosis), neutrophil or phagocyte defects, and complement deficiencies. Disorders of the adaptive immune system usually manifest as B- or T-cell defects, antibody deficiencies, or SCIDs. Relative frequencies of various immune disorders can also help guide diagnosis. The most common disorders are antibody deficiencies (50%), followed by combined B- and T-cell deficiencies (20%), phagocytic defects (18%), cellular defects (10%), and complement deficiencies (2%).7 Immunodeficient patients are usually vulnerable to repeated, chronic, or unusual infections. Findings suggestive of immune dysfunction include the following8: • Recurrent, unusual, or difficult-to-treat infections • Poor growth or loss of weight • Recurrent pneumonia, ear infections, or sinusitis • Multiple courses of antibiotics, or intravenous antibiotics necessary to clear infections • Recurrent deep abscesses of the organs or skin • A family history of primary immunodeficiency disease (PIDD) In addition, serious or repeated infections with normally nonpathogenic organisms are a clue that immune dysfunction is a consideration. Knowing how the immune system is organized and how shortages of its various components will manifest clinically can often provide clues to the health care practitioner of an immunodeficiency. For example, recurrent sinopulmonary infections with encapsulated bacteria such as Streptococcus, Staphylococcus, or Haemophilus organisms can be suggestive of an antibody deficiency or B-cell disturbance because humoral immunity is generally responsible for dispatching these types of pathogens. However, wide use of antibiotics can mask or cloud the diagnosis of a specific immunodeficiency. Thus it is sometimes important to watch for common associations seen in these diseases. Common related conditions include chronic diarrhea, eczema, hepatosplenomegaly, hematologic disorders, autoimmune diseases, and failure to thrive in infants and children. An example is Wiskott-Aldrich syndrome (WAS), which like other humoral deficiencies, is characterized by recurrent infections with pneumococci. WAS is also associated with platelet maturation anomalies through the underlying genetic defect and thus could manifest with prolonged bleeding, easy bruising, and eczema. There is also a tendency in WAS for later development of T-cell anomalies. Primary T-cell disorders manifest as unusual sensitivity to viruses, fungi, some parasites, and other bacteria that are the targets of this class of cell. Common T-cell mutations can affect the manner in which T cells mature or become activated. However, cell-to-cell communication can also be impaired—that is, there can be defects in their receptors or cytokines. Even more severe are combined immunodeficiency disorders (CIDs) or SCIDs, which may knock out multiple immune cell pathways, usually as the result of an enzyme or early maturation defect. Both B- and T-cell lines can be affected, leading to early and devastating infections. Without prompt recognition and subsequent treatment with bone marrow transplantation or, more recently, gene therapy, these children’s lives are usually measured in days to months rather than years. Secondary immunodeficiencies are acquired or associated with underlying disorders and are not caused by intrinsic abnormalities in the development and function of the immune system. HIV and malnutrition are the most common causes of secondary immunodeficiency.8 Other causes include malignant disease, immunosuppressive agents, and systemic inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus.9 Obesity may also compromise the pathways of immune surveillance.10 There is some decrease in immunity that occurs with normal aging. Fewer T cells are produced; therefore, fewer are available to respond. Of course, malnutrition, common in the older adult, impairs immune responses.8 Secondary immunodeficiencies must be considered in the differential diagnosis of patients with multiple or recurrent infections. A careful history usually provides evidence that identifies the nature of the immune system defect. The history should include a detailed description of infections, including age at onset, sites, patterns of recurrence, response to treatment, and pathogens if known. More severe immunodeficiency disorders such as SCID, characterized by deficits in both B and T cells, can manifest with life-threatening infections in the first few weeks of life.2 Associated symptoms such as eczema, diarrhea, and arthritis should be noted. Risk factors for HIV should be assessed. A history of weight loss, enlarged lymph nodes, night sweats, fever, ecchymosis, pruritus, or epistaxis should be obtained. The past medical history should determine childhood illnesses, including developmental delay or failure to thrive, recurrent infections, autoimmune diseases, cancer, and history of splenectomy. A family history of unexplained death from infection may be significant. The patient’s immunization history and response to immunizations should be assessed. A history of normal response to smallpox vaccination or contact dermatitis from poison ivy suggests an intact cellular immunity. A complete physical examination should be performed with the goal of identifying the site and source of infection and any chronic indicators of immune dysfunction. It is important to review the growth parameters, such as height and weight, because failure to thrive is one of the more common features of adaptive immunodeficiency. Findings of ocular telangiectasia, tympanic membrane scarring, tonsillar absence, lymphadenopathy, periodontitis, dental erosions, gingivostomatitis, mucocutaneous candidiasis, eczema, vitiligo, oculocutaneous albinism, hepatosplenomegaly, clubbing or fungal infections of the nails, petechiae, and pallor can be associated with various immunodeficient states.5,7 Also, the tendency for immunodeficiency to be part of other congenital syndromes should cause the practitioner to look for body dysmorphisms. Examples of these include micrognathia, short philtrum, and ear abnormalities seen with DiGeorge syndrome; short-limbed dwarfism associated with some T-cell disorders; and prominent forehead, deep-set eyes, broad nasal bridge, and prognathism associated with hyperimmunoglobulinemia E syndrome.8 A full neurologic examination should also be performed. Broad-based gait in a young child could be the first sign of ataxia-telangiectasia before immunodeficiency becomes apparent.11 When an immunodeficiency disorder is suspected, initial laboratory work should include studies that are broadly informative, readily available, and cost-effective. A complete blood count (CBC) with differential is important for detection of neutropenia and relative levels of various leukocytes. A peripheral smear should be done concurrently to look for abnormal cell morphologies. These can help exclude neutropenia and lymphopenia. Thrombocytopenia can be consistent with WAS. Metabolic profiles can be helpful to exclude potential immune-modulating diseases such as diabetes mellitus. HIV testing should be performed. When possible, it is important to identify all organisms infecting the patient. To this end, blood, urine, sputum, and wound cultures as well as consultation with a serologist can be helpful. An erythrocyte sedimentation rate (ESR) and C-reactive protein level should be assessed for evidence of inflammation or lack thereof. Pulmonary function tests (PFTs) should be considered when the patient’s symptoms have a chronic respiratory component because immunodeficiencies can alter lung function over time. Immune testing should also begin broadly, but clinical symptoms can help guide which tests are ordered. Primary health care practitioners should obtain quantitative serum immunoglobulins as part of the initial screening because antibody disorders are the most common immunodeficiencies. Other specialized immune testing can be ordered and performed by the clinical immunologist. This includes examination of antibody production (e.g., IgE levels, antibody responses to protein or polysaccharide antigens, isohemagglutinins, IgG subclasses), T cells (functional assessment, quantification of T-cell subtypes), phagocytic function (nitroblue tetrazolium test, flow cytometry for diseased cell markers such as CD18), and complement deficiencies (complement levels C3, C4, CH50).5,7,12,13 Checking of sweat chloride and cystic fibrosis transmembrane regulator gene assays can help exclude cystic fibrosis. Further evaluations, including enzyme measurements, genetic and chromosomal studies, chemotaxis assays, and surgical biopsies (e.g., lymph nodes, colon) may also be considered by the clinical immunologist.7 Delayed-type hypersensitivity (DTH) skin testing is a common test of T-cell function, and positive reactions to common antigens such as Candida organisms, tetanus, and mumps can help rule out T-cell disorders in 85% of adults.7 There is more controversy in the use of DTH testing in infants and young children, who have not yet developed an exposure history adequate enough to turn a skin test result positive. Although some practitioners perform skin testing in children, there seems to be no usefulness in testing children younger than 1 year.
Immunodeficiency
Definition and Epidemiology
Pathophysiology
Clinical Presentation
Physical Examination
Diagnostics
Immunodeficiency
Chapter 225
