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Evaluation of the Child With Suspected Immunodeficiency
Evaluation of the Child With Suspected Immunodeficiency
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SECTION R: Infections in Patients With Deficient Defenses
of the Child With Suspected 101 Evaluation Immunodeficiency E. Stephen Buescher
Although primary immunodeficiency disorders are uncommon, referral for evaluation of these conditions in children with frequent infections is common. Epidemiologic studies show that children aged <2 years have an average of 5 to 6 acute respiratory tract illnesses per year, with a range up of to 11 or 12 per year.1,2 Infections such as otitis media and gastroenteritis occur with similar frequencies in children <2 years of age, with up to 14 episodes per year at the far end of the normal spectrum.3 Attendance at group childcare and exposure to secondhand smoke further increase frequency of these infections.4 An approach that includes a carefully obtained history, a thorough physical examination, and selected laboratory tests often is required to differentiate the uncommon, immunologically abnormal child who requires more extensive evaluation from the common, “normal but unlucky” child.5 Because normal children can experience large numbers of infections, criteria other than the number of illnesses should be considered. These include (1) a history of documented, deep infections at multiple sites; (2) abnormal growth or development; (3) abnormal morphology or physiology between infections; or (4) a family history of immunodeficiency. Further investigation is warranted in children with one or more of these characteristics and focuses on categorizing patients as to the likely cause for their recurrent infections.
TABLE 101.1 Anatomic and Physiologic Abnormalities That Predispose to Recurrent Infections Type of Infection
Predisposing Abnormality
Bloodstream infection
Asplenia Cardiac valve abnormality Intravascular cannula or thrombus Neutropenia
Bone infection
Foreign body Orthopedic device
Meningitis
Cochlear implant Dura mater (meningeal) defect Midline dermal sinus Mondini defect of inner ear Neuroenteric fistula Occult skull fracture Ventricular cannula
Pneumonia
Abnormal cough reflex Atelectasis
ANATOMIC AND PHYSIOLOGIC ABNORMALITIES
Bronchiectasis
A variety of anatomic abnormalities can alter natural host defenses and predispose a child to recurrent infections (Table 101.1). Anatomy-related infections often localize with recurrent infections at or near the site of the abnormality. In instances of congenital malformation, infections usually begin during infancy. Compared with the incidence of primary immunodeficiency disorders, congenital malformation as a cause of recurrent infections is common.
Extrinsic airway compression
Endotracheal intubation Foreign body Gastroesophageal reflux Polyps Pulmonary cyst, fistula Pulmonary sequestration Tracheal web
UNDERLYING CONDITIONS
Tracheoesophageal fistula
The presence of underlying conditions, either natural or iatrogenic, can alter host defenses and predispose to recurrent infections or may be associated with an immunodeficiency (Box 101.1). In addition to the primary immunodeficiency syndromes, recurrent infections occur in more than 100 other syndromes, which include growth deficiencies, specific organ system dysfunctions, inborn errors of metabolism, and miscellaneous and chromosomal anomalies.6 Some underlying conditions only become serious diagnostic considerations when specific data are obtained during a detailed history. Some conditions are suspected when constellations of noninfectious signs and symptoms are revealed by history and physical examination. Recurrent infections associated with underlying conditions either can be localized or disseminated and may or may not respond well even when appropriate treatment is given. Compared with the incidence of primary immunodeficiency disorders, this category of causes of recurrent infections also is common.
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PRIMARY IMMUNODEFICIENCY DISORDERS Recurrent infections due to primary immunodeficiency disorders are rare in the general population and are relatively rare compared with other causes of recurrent infection (Table 101.2). Common characteristics in children with primary immunodeficiency disorders are shown in Box 101.2.
Tracheomalacia Vascular ring Soft tissue infection
Diminished sensation Foreign body Lymphedema Thermal injury
Urinary tract infection
Genitourinary tract duplication, cyst, fistula, or obstruction Nephrostomy Urinary catheter Vesicostomy
The relative frequency of primary immunodeficiency disorders is shown in Table 101.3.7,8 The list of recognized immunodeficiency conditions is ever-expanding, and the component due to recognized disorders of the innate immune system is growing.8 The International Union of Immunological Societies frequently publishes updates on the classification of primary immunodeficiencies, which include names of conditions, presumed pathogenesis, genetics, inheritance, immunologic parameters,
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PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION R Infections in Patients With Deficient Defenses
BOX 101.1 Underlying Conditions That Can Predispose to Recurrent Infections
BOX 101.2 Characteristics of Children Wth Primary Immunodeficiency Disorders
Asplenia syndromes/conditions Asthma Bone marrow and solid-organ transplantation Chemotherapy Collagen vascular diseases Congenital malformation Corticosteroid therapy Cystic fibrosis Dermatologic syndrome with immunodeficiency Diabetes mellitus Down syndrome Drug-induced cytopenia Galactosemia Gastrointestinal tract syndrome with immunodeficiency Genetic/metabolic conditions Glycogen storage disease type IB Growth deficiency/ immunodeficiency syndrome Hematopoietic/immunologic conditions Hemoglobinopathy Ichthyosis Immunosuppression Isovaleric acidemia
Infectious symptoms often begin in first days to weeks of life Therapeutic response is slow despite identification of a pathogen and administration of appropriate antimicrobial therapy Infection is suppressed rather than eradicated by appropriate therapy Common organisms cause severe manifestations or recurrent infection Unusual (sometimes sentinel) or “nonpathogenic” organisms cause infections Growth and development are delayed Multiple infections occur simultaneously Infection with common organisms leads to unexpected complications
Lymphohematopoietic malignancy Malnutrition α-Mannosidosis Methylmalonic aciduria Mucolipidosis II Myelokathexis (WHIM syndrome) Myotonic dystrophy Nephrotic syndrome Neurologic syndrome with immunodeficiency Newborn state Nutritional conditions Orotic aciduria Prematurity Propionic acidemia Protein-losing enteropathy Radiation therapy Renal conditions Renal failure Sarcoidosis Tumor necrosis factor antagonist therapy Werdnig-Hoffmann disease WHIM (warts, hypogammaglobulinemia, infections, myelokathexis)
associated features, and Online Mendelian Inheritance in Man (OMIM) reference numbers.9 More than 250 conditions presently are identified.9,10 Some are well characterized, their pathologic mechanisms are understood, and numerous affected patients have been described (e.g., chronic granulomatous disease, X-linked severe combined immunodeficiency syndrome, X-linked agammaglobulinemia, leukocyte adhesive deficiency type I, and adenosine deaminase deficiency).11–15 Other conditions remain incompletely characterized, are poorly understood, or have been observed in so few patients that they have not been studied extensively (e.g., lazy leukocyte syndrome, generalized pustular psoriasis, reticular dysgenesis).16–18
TABLE 101.2 Estimated Frequencies of Selected Chronic Underlying Illnesses, Primary Immunodeficiency Disorders, and HIV Infection
History A detailed history is the most powerful evaluation tool and should gather information using all available sources, including medical records, parent or patient interviews, radiographs, and laboratory test results. Information is assembled into a chronology of data and events to determine whether episodes of illness have been characterized well enough to confirm that the patient truly has had recurrent infections. Additional important considerations are whether treatment of infectious episodes was appropriate, response to treatment was as expected, or other explanations exist (e.g., fever from inflammatory rather than infectious disease).
Medical History A description of each infectious episode is obtained, specifically: (1) date, duration, and site of infection; (2) how the diagnosis was established (i.e., specific cultures and diagnostic tests performed and their results); (3) severity of the episode (shock, tissue destruction, ventilator support, end-organ damage); (4) what treatment (need for parenteral or prolonged) was used and responses to specific treatments; (5) need for surgical intervention and quality of wound healing; and (6) temporal relationships to previous episodes. This level of detail often necessitates a prolonged interview but is crucial for establishing whether an immunodeficiency is likely. Additional helpful details of the patient’s history include immunizations administered and any clinical illnesses associated with them, pattern of growth and development, medications given (including long-term antibiotic use) and their effect on course of disease, compliance with treatments, presence of conditions that can predispose to or masquerade as infections, unusual blood phenotypes (e.g., McLeod phenotype in chronic granulomatous disease, Bombay phenotype in leukocyte adhesion deficiency type II), and healing pattern after skin and soft tissue infection, injuries, or surgery. If infections have
Condition
Frequency
Asthma26
1 in 26
IgA deficiency
1 in 500 to 700
Diabetes mellitus26
1 in 556
HIV infection
1 in 1000
Sickle cell disease26
1 in 2200
TABLE 101.3 Relative Frequency of Primary Immunodeficiency Disorders
Cystic fibrosis27
1 in 2500
Factors
Acute lymphocytic leukemia26
1 in 9000
B lymphocytes
50–70
26
Percentage
1 in 10,000
T lymphocytes
20–30
Agammaglobulinemia26
1 in 50,000 to 100,000
T and B lymphocytes
10–15
Severe combined immunodeficiency
1 in 100,000 to 500,000
Phagocytic cells
15–20
Chronic granulomatous disease28
1 in 255,000
Complement
Phenylketonuria
HIV, human immunodeficiency virus; IgA, immunoglobulin A.
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CLINICAL APPROACH TO THE CHILD WITH RECURRENT INFECTIONS
Other innate immunity factors
2–5 <1
Evaluation of the Child With Suspected Immunodeficiency
TABLE 101.4 Sentinel Pathogens of Infections and Associated Conditions Infectious Agent
Condition
Mucoid Pseudomonas aeruginosa
Cystic fibrosis
Nocardia spp., Aspergillus spp.
Chronic granulomatous disease
Burkholderia cepacia pneumonia
Chronic granulomatous disease, cystic fibrosis
Recurrent Neisseria spp. infections
Terminal complement component deficiency
Escherichia coli bloodstream infection
Galactosemia
Deep Candida spp. infection
Myeloperoxidase deficiency
Disseminated Mycobacterium spp. infection
T-lymphocyte deficiency, IFNγ receptor deficiency, IL-12 defects
Pneumocystis jirovecii
T-lymphocyte deficiency
Recurrent/severe Streptococcus pneumoniae bloodstream infection
Asplenia, hemoglobinopathy, agammaglobulinemia, mannosebinding lectin deficiency, IRAK4 deficiency
Recurrent/severe Staphylococcus aureus infection
Chronic granulomatous disease, hyper-IgE/recurrent infection syndrome, Chédiak-Higashi syndrome, IRAK4 deficiency
IFNγ, interferon γ; IgE, immunoglobulin E; IL, interleukin; IRAK4, interleukin 1 receptor−associated kinase 4.
been localized around an anatomic site, details should be obtained to focus on foreign body aspiration, injuries or surgery at the site, medical problems involving the site, and timing of onset of infections relative to other events. Historical details that decrease concern for a primary immunodeficiency are rapid responses to appropriate therapy, rapid resolution (vs. suppression) of infected foci, healing without scarring, and inability to document infection. Details that are difficult to assess are poorly documented “infections,” “infections” in the presence of allergic inflammation, and infections occurring in association with underlying conditions. The category of microorganisms (and certain sentinel organisms) causing infections can suggest specific disorders (Table 101.4). Recurrent infections with extracellular, encapsulated microorganisms or chronic sinopulmonary infections frequently occur in people with asplenia, antibody deficiency conditions, or pattern recognition molecule (e.g., mannose-binding lectin or toll-like receptor) dysfunction. Deep fungal infections, multiple liver abscesses, or osteomyelitis suggests a phagocytic cell disorder. Recurrent infections accompanied by autoimmune symptoms or recurrent infections with Neisseria meningitidis suggest complement deficiencies. Recurrent infections due to opportunistic viral, protozoal, bacterial, mycobacterial, or fungal agents suggest T-lymphocyte deficiency. Unusual susceptibility to human papillomavirus infections occurs in WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome and severe and disseminated mycobacterial infections are seen in defects related to interferon γ production and signaling.
Family History Specific questions regarding the parents’ ethnic heritage, the likelihood of parental consanguinity, early childhood deaths in the two previous generations, and gender bias in medical problems should be asked. Survival and significant illnesses and hospitalizations in all family members within two previous generations, as well as occurrence of peculiar infections or certain syndromes (e.g., collagen vascular diseases and lymphoreticular malignancy), should be documented. Consanguinity or close ethnic heritage of the parents, occurrence of multiple early childhood deaths (particularly of male sex) in the family, serious infections in other family
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members, or presence of recognized syndromes in other family members (e.g., discoid lupus in heterozygous carriers for X-linked chronic granulomatous disease) heighten concern. Collagen vascular diseases in family members (associated with some complement deficiency states) and the presence of lymphoreticular malignancies (associated with a variety of immunodeficiency diseases) are noteworthy.19
Birth History Both congenital anatomic malformations and primary immunodeficiency disorders can manifest within days to weeks of birth. History is sought about the mother’s prenatal care, prenatal illnesses, and exposures as well as the infant’s length of gestation and peripartum problems, delayed separation of the umbilical stump (leukocyte adhesion deficiency type I), requirement for blood transfusion (graft-versus-host disease), and need for ventilator support. Historical details of concern include lack of prenatal care, maternal drug use or multiple sexual partners (human immunodeficiency virus or other congenital infection), presence of congenital malformations, absence of a thymic shadow on a neonatal chest radiograph, perinatal blood transfusion, perinatal ventilator therapy (resulting in chronic lung disease), onset of infection in the first days of life, intracranial hemorrhage (resulting in dysfunction of hypothalamic temperature regulation), prenatal exposure to a teratogen, and the need for surgical removal of the umbilical stump. Separation of the umbilical stump normally occurs within 14 days, and failure to separate is associated with leukocyte adhesion deficiency type 1. Of note, assiduous umbilical cord care (aggressive application of triple dye and isopropyl alcohol to “keep the cord stump clean”) can lead to its desiccation and resultant failure to separate in normal infants.
Social History Because the frequency of infection in small children mirrors frequency of exposure, details are sought of the patient’s contacts with other children (e.g., siblings, classmates, playmates in childcare, nursery school, playgroups) that increase the frequency of exposures. In addition, exposure to tobacco smoke or other environmental pollutants affects infection rates and symptomatology, particularly in association with underlying atopy. Review of the patient’s dietary habits should include estimates of caloric intake and whether raw egg ingestion occurs (excessive intake of avidin can lead to nutritional biotin deficiency). The length of time at the current residence, the type and duration of parental employment, and the child’s daily activities or school performance can yield insights into the continuity of medical care. The effect that “recurrent infections” has had on the child and family gives a measure of their severity.
Review of Systems The review of systems should focus on infection by organ systems involved. Skin, mouth, nasopharynx, lungs, and gastrointestinal tract are sites of constant contact with the microbially contaminated external environment and are common sites of infection. The liver, spleen, and lungs provide defenses against systemic spread of infection and as a result can become sites of infection. The occurrence of cutaneous abscesses and extent of scarring when wounds heal, rashes (e.g., discoid lupus), rhinitis, dermatitis (generalized or localized, particularly behind the ears and in the diaper area), and paronychia provide clues to underlying disorders and the integrity of skin defenses. Questions about sinusitis, seasonal allergies, allergic shiners, snoring, and sleep disturbance (i.e., upper airway obstruction) explore the possibility of an allergic diathesis. Gingivitis, periodontal disease, retained primary teeth, and aphthous stomatitis can be associated with specific primary immunodeficiency disorders. Focused questioning about pneumonia, diarrhea, perirectal or pararectal abscess, liver abscess, lymphadenitis, and bloodstream infections can reveal details sometimes missed in general review of systems.
Physical Examination Points to be addressed by the physical examination are (1) the physical status of the patient, (2) the presence of physical findings that confirm
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PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION R Infections in Patients With Deficient Defenses
BOX 101.3 Specific Considerations During the Physical Examination Reconcile vital signs with historical details (e.g., normal pulse and respiratory rate despite significant lung disease infers physiologic compensation and, therefore, chronicity) Assess general habitus, growth, and development (chronically ill versus robust; developmental delay; dysmorphism suggesting a genetic syndrome) Seek markers for atopy, nasopharyngeal lymphoid hyperplasia, or both Identify lymphoid tissue (absence of palpable or visible lymphoid tissue suggesting T-lymphocyte deficiency) Examine for midline defects in the head, neck, spine, or sacrum; or the presence of glucose-containing rhinorrhea Examine for scarring of tympanic membranes Examine for gingivitis, ulcerations, tooth loss, or periodontal disease (typical of immunodeficiency) Identify cutaneous stigmata: ■ Petechiae (suggesting Wiskott-Aldrich syndrome) ■ Skin or conjunctival telangiectases (ataxia-telangiectasia syndrome) ■ Eczematoid rash (Wiskott-Aldrich syndrome, hyperimmunoglobulinemia E [hyper-IgE] syndrome) ■ Seborrhea-like dermatitis localized behind the ears (chronic granulomatous disease) ■ Generalized seborrhea-like dermatitis (Langerhans histiocytosis, graft-versus-host disease, or T-lymphocyte deficiency) ■ Nose-tip dermatitis (chronic granulomatous disease) ■ Alopecia (graft-versus-host disease) ■ Ectodermal dysplasia (anhidrotic ectodermal dysplasia with immunodeficiency) ■ Cutaneous scars, with thin/poor formation at site of previous surgery or with tissue loss at site of previous infection (leukocyte defects) Seek markers for chronic lung disease (pulmonary osteoarthropathy) Assess for acute or chronic sinus disease Identify the size of the liver and spleen Examine for pararectal inflammation, scarring from previous infections, or persistent inflammation Examine exhaustively any anatomic site where infections repeatedly localize, assessing normalcy of local anatomy and physiology
points of history, and (3) previously unrecognized but significant physiologic or anatomic abnormalities. Specific considerations during the physical examination are shown in Box 101.3.
LABORATORY FINDINGS AND DIAGNOSIS
TABLE 101.5 Screening Laboratory Tests and Their Purposes in the Evaluation of Immunodeficiency Disorders Test
Purposes
Complete blood count differential
Assess numbers and morphology of cellular blood elements: leukopenia, leukocytosis, anemia, neutropenia, lymphopenia, Howell-Jolly bodies, bizarre erythrocyte forms, leukocyte morphology, thrombocytopenia
Total lymphocyte, T-lymphocyte, and B-lymphocyte quantification
CD3 marker is used to estimate total lymphocyte number by flow cytometry; CD4 and CD8 markers are used to estimate T-lymphocyte subsets; B-lymphocyte numbers are estimated using surface Ig expression or CD19 or CD20 markers
Skin testing
Simple assessment of cell-mediated immunity (T-lymphocyte function)
Serum immunoglobulin quantification (IgA, IgG, IgM, IgE)
Assess for hypergammaglobulinemia, hypogammaglobulinemia, or agammaglobulinemia
IgG subclass determinations
Assess for specific subclass deficiency
Specific antibody determinations
Assess production of antibody in responses to tetanus or diphtheria toxoid immunization as well as boosting; assess quantitative isohemagglutinin levels
Assess for Underlying Conditions
Test
Cystic fibrosis
Sweat test
HIV
HIV serology (and PCR testing, depending on patient age)
Sickle cell disease, thalassemia
Hemoglobin electrophoresis
If the history and physical findings are consistent with an anatomic cause of infection or the presence of an underlying condition, laboratory evaluation of the patient is directed at either defining the anatomic problem or diagnosing the underlying condition. If the history and physical findings do not point to a cause for recurrent, significant infections, a screening laboratory analysis provides a reasonable first evaluation (Table 101.5).
Multiple congenital and acquired anomalies/conditions
Assess chest radiograph for chronic lung disease, foreign body, presence of thymus, situs inversus, anatomic abnormality, or end-organ damage If anatomic definition is inadequate, consider chest computed tomography
Further Assessment
Terminal complement component deficiency
Total hemolytic complement activity (CH50)a
After the history, physical examination, and a screening laboratory evaluation have been completed, either the diagnosis will be clear and a plan of action can be proposed, or a diagnosis will be lacking and the decision must be made as to whether further, more detailed evaluation is appropriate. This decision is based on an overall impression of the severity,
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end-organ effects, documentation, and pathogens of the child’s recurrent infections, family history, and physical findings. In the absence of repeated, documented infections in a patient in whom physical findings, growth and development, and appetite and activity are normal and the screening laboratory examination are unrevealing, the likelihood of a predisposing condition or immunodeficiency is remote and the child is assessed as “normal but unlucky.” Prospective observation and documentation should be planned and reassurance given. Problems may resolve spontaneously, or documentation of continuing problems may reveal their cause or lead to a need for specialized evaluation. If there are major incongruities between physical findings, historical details, and laboratory results, or when an unexplained lack of continuity in patient care is obvious, Munchausen syndrome or Munchausen syndrome by proxy should be considered.20
a Test performance is altered easily and unpredictably by inappropriate specimen handling and/or poor laboratory technique. CD, cluster designation (for antigens); CH50, 50% hemolyzing dose of complement; HIV, human immunodeficiency virus; Ig, immunoglobulin; PCR, polymerase chain reaction.
TABLE 101.6 Specific Testing Approaches for Immunodeficiency Disorders Disorder
Possible Testing Approaches
Cytopenia
Bone marrow examination/histochemistry Cytokine, colony-stimulating factor levels
Antibody deficiency
In vitro antibody production (Ig isotypes and subclasses) Cytokine levels In vitro specific antibody production Bruton thymidine kinase gene
T-lymphocyte deficiency
Adenosine deaminase activity Nucleoside phosphorylase activity In vitro proliferation responses (mitogens and specific antigens) Cytokine, growth factor levels Skin biopsy, intestinal biopsy (graft-versus-host disease)
Phagocytic cell dysfunction
Bactericidal activity Respiratory burst activity (nitroblue tetrazolium reduction, superoxide, dihydrorhodamine 123 oxidation test, or H2O2 production) Chemotaxis
Complement deficiency
CH50 Individual complement component quantitation Serum opsonic activity
CH50, 50% hemolyzing dose of complement; Ig, immunoglobulin.
Specialized Testing If anatomic problems or underlying conditions are suspected, appropriate testing and imaging are pursued. If immunodeficiency is suspected or is likely, specialized, targeted testing is planned. Because the range of specialized testing is broad, an all-inclusive testing approach is both labor and time intensive, extremely costly, and inappropriate in most circumstances. Focused testing should be performed in a stepwise fashion, pursuing abnormalities uncovered by history, physical examination, and screening laboratory tests (Table 101.6).
Genetic Testing Genetic testing is a powerful diagnostic tool in primary immunodeficiency disorders. Current information on characteristics and genetics of most disorders is available at the OMIM website (www.omim.org). The genes responsible for all of the known X-linked and most of the known autosomal primary immunodeficiency disorders have been elucidated. For the X-linked disorders, approximately one third of new cases are due to new mutations, and two thirds are inherited.21 Carriers of some
X-linked conditions (e.g., X-linked severe combined immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome) sometimes can be identified through the use of X-chromosome inactivation analysis because cells expressing the normal X chromosome have a survival advantage over cells expressing the abnormal X chromosome.22–25 Carriers are recognized because of their homogeneous X-chromosome expression pattern (except in situations of “extreme” lyonization). In classical autosomal recessive conditions, recurrence risks follow mendelian inheritance. Well over 100 genes have now been associated with primary immunodeficiency diseases.9 Although the availability of appropriate gene probes or diagnostic methods for most currently recognized primary immunodeficiency syndromes makes their diagnosis easier than in the past, clinical suspicion remains the fulcrum for testing. In some instances, the suspicion only arises after the death of an index patient; if specimens of tissues are appropriately preserved, genetic testing can be performed postmortem.
MANAGEMENT When a child is identified with an anatomic abnormality, an underlying condition, or a primary immunodeficiency disorder, management is based on existing knowledge about the specific condition, as described in subsequent chapters. Management is more difficult for patients whose history or physical findings are suggestive of a defect but in whom diagnostic testing is unrevealing. Such patients often require management based more on skilled judgment and careful reassessment than on scientific knowledge. It is important to emphasize to parents that, although negative diagnostic test results cannot exclude all potential underlying conditions, they eliminate specific serious conditions; this information can be comforting and helpful. In addition, delineating a specific plan for ongoing observation communicates a commitment to the child’s well-being, which will help to ensure adherence to medically recommended interventions and continued contact with the patient. All references are available online at www.expertconsult.com.
KEY REFERENCES 5. Rubin BK. The evaluation of the child with recurrent chest infections. Pediatr Infect Dis J 1985;4:88–98. 9. Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunol, “Primary Immunodeficiencies”; Article #162, 2014;5:1–33. 10. Bousfiha AA, Jeddane L, Ailal F, et al. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol 2013;33:1078–1087. 13. Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clin Rev Allergy Immunol 2000;19:183–204. 28. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease: Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79:155–169.
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REFERENCES 1. Monto AS, Ullman BM. Acute respiratory illness in an American community: The Tecumseh Study. JAMA 1974;227:164–169. 2. Glezen P, Denny FW. Epidemiology of acute lower respiratory disease in children. N Engl J Med 1973;288:498–505. 3. Fosarelli PD, DeAngelis C, Winkelstein J, Mellits D. Infectious illnesses in the first two years of life. Pediatr Infect Dis J 1985;4:153–159. 4. Osterholm MT, Reves RR, Murph JR, Pickering LK. Infectious diseases and child day care. Pediatr Infect Dis J 1992;11(suppl):31–41. 5. Rubin BK. The evaluation of the child with recurrent chest infections. Pediatr Infect Dis J 1985;4:88–98. 6. Ming JE, Stiehm ER, Graham JM. Syndromes associated with immunodeficiency. Adv Pediatr 1999;46:271–351. 7. Stiehm ER. Immunodeficiency disorders: General considerations. In: Stiehm ER (ed) Immunologic Disorders in Infants and Children, 3rd ed. Philadelphia, WB Saunders, 1989, p 157. 8. Suhir H, Etzioni A. The role of toll-like receptor signaling in human immunodeficiencies. Clin Rev Allergy Immunol 2010;38:11–19. 9. Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunol, “Primary Immunodeficiencies”; Article #162, 2014;5:1–33. 10. Bousfiha AA, Jeddane L, Ailal F, et al. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol 2013;33:1078–1087. 11. Smith RM, Curnutte JT. Molecular basis of chronic granulomatous disease. Blood 1991;77:673–686. 12. Voss SD, Hong R, Sondel PM. Severe combined immunodeficiency, interleukin-2 (IL-2), and the IL-2 receptor: experiments of nature continue to point the way. Blood 1994;83:626–635. 13. Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clin Rev Allergy Immunol 2000;19:183–204. 14. Anderson DC, Schmalsteig FC, Finegold MJ, et al. The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis 1985;152:668–689.
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15. Hirschhorn R. Overview of the biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res 1993;33(suppl 1):S35–S41. 16. Miller ME, Oski FA, Harris MB. Lazy leukocyte syndrome: a new disorder of leukocyte function. Lancet 1971;1:665–669. 17. Kanazawa N, Nakamura T, Furukawa F. Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis. J Dermatol 2013;40:749–751. 18. Pannicke U, Hönig M, Hess I, et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat Genet 2009;41:101–105. 19. Leechawengwongs E, Shearer WT. Lymphoma complicating primary immunodeficiency syndromes. Curr Opin Hematol 2012;19:305–312. 20. Eminson DM, Postlethwaite RJ. Factitious illness: recognition and management. Arch Dis Child 1992;67:1510–1516. 21. Chase GA, Murphy EA. Risk of recurrence and carrier frequency for X-linked lethal recessives. Hum Hered 1973;23:19–26. 22. Puck JM, Stewart CC, Nussbaum RL. Maximum likelihood analysis of human T-cell X chromosome inactivation patterns: normal women vs. carriers of X-linked severe combined immunodeficiency. Am J Hum Genet 1992;50:742–748. 23. Fearon ER, Winkelstein JA, Civin CI, et al. Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome inactivation. N Engl J Med 1987;316:427–431. 24. Gealy WJ, Dwyer JM, Harley JB. Allelic exclusion of glucose-6- phosphate dehydrogenase in platelets and T-lymphocytes from a Wiskott-Aldrich syndrome carrier. Lancet 1980;1:63–65. 25. de Saint Basile G, Le Deist F, Caniglia M, et al. Genetic study of a new X-linked immunodeficiency syndrome. J Clin Invest 1992;89:861–866. 26. Gortmaker SL, Sappenfield W. Chronic childhood disorders: prevalence and impact. Pediatr Clin North Am 1984;31:3–18. 27. Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. In: Scrivner CL, Beaudet AL, Sly WS, Valle D (eds) The Metabolic Basis of Inherited Disease, 6th ed. New York, McGraw-Hill, 1989, p 2649. 28. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease: Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79:155–169.
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SECTION R: Infections in Patients With Deficient Defenses
of the Child With Suspected 101 Evaluation Immunodeficiency E. Stephen Buescher
Although primary immunodeficiency disorders are uncommon, referral for evaluation of these conditions in children with frequent infections is common. Epidemiologic studies show that children aged <2 years have an average of 5 to 6 acute respiratory tract illnesses per year, with a range up of to 11 or 12 per year.1,2 Infections such as otitis media and gastroenteritis occur with similar frequencies in children <2 years of age, with up to 14 episodes per year at the far end of the normal spectrum.3 Attendance at group childcare and exposure to secondhand smoke further increase frequency of these infections.4 An approach that includes a carefully obtained history, a thorough physical examination, and selected laboratory tests often is required to differentiate the uncommon, immunologically abnormal child who requires more extensive evaluation from the common, “normal but unlucky” child.5 Because normal children can experience large numbers of infections, criteria other than the number of illnesses should be considered. These include (1) a history of documented, deep infections at multiple sites; (2) abnormal growth or development; (3) abnormal morphology or physiology between infections; or (4) a family history of immunodeficiency. Further investigation is warranted in children with one or more of these characteristics and focuses on categorizing patients as to the likely cause for their recurrent infections.
TABLE 101.1 Anatomic and Physiologic Abnormalities That Predispose to Recurrent Infections Type of Infection
Predisposing Abnormality
Bloodstream infection
Asplenia Cardiac valve abnormality Intravascular cannula or thrombus Neutropenia
Bone infection
Foreign body Orthopedic device
Meningitis
Cochlear implant Dura mater (meningeal) defect Midline dermal sinus Mondini defect of inner ear Neuroenteric fistula Occult skull fracture Ventricular cannula
Pneumonia
Abnormal cough reflex Atelectasis
ANATOMIC AND PHYSIOLOGIC ABNORMALITIES
Bronchiectasis
A variety of anatomic abnormalities can alter natural host defenses and predispose a child to recurrent infections (Table 101.1). Anatomy-related infections often localize with recurrent infections at or near the site of the abnormality. In instances of congenital malformation, infections usually begin during infancy. Compared with the incidence of primary immunodeficiency disorders, congenital malformation as a cause of recurrent infections is common.
Extrinsic airway compression
Endotracheal intubation Foreign body Gastroesophageal reflux Polyps Pulmonary cyst, fistula Pulmonary sequestration Tracheal web
UNDERLYING CONDITIONS
Tracheoesophageal fistula
The presence of underlying conditions, either natural or iatrogenic, can alter host defenses and predispose to recurrent infections or may be associated with an immunodeficiency (Box 101.1). In addition to the primary immunodeficiency syndromes, recurrent infections occur in more than 100 other syndromes, which include growth deficiencies, specific organ system dysfunctions, inborn errors of metabolism, and miscellaneous and chromosomal anomalies.6 Some underlying conditions only become serious diagnostic considerations when specific data are obtained during a detailed history. Some conditions are suspected when constellations of noninfectious signs and symptoms are revealed by history and physical examination. Recurrent infections associated with underlying conditions either can be localized or disseminated and may or may not respond well even when appropriate treatment is given. Compared with the incidence of primary immunodeficiency disorders, this category of causes of recurrent infections also is common.
Tracheostomy
PRIMARY IMMUNODEFICIENCY DISORDERS Recurrent infections due to primary immunodeficiency disorders are rare in the general population and are relatively rare compared with other causes of recurrent infection (Table 101.2). Common characteristics in children with primary immunodeficiency disorders are shown in Box 101.2.
Tracheomalacia Vascular ring Soft tissue infection
Diminished sensation Foreign body Lymphedema Thermal injury
Urinary tract infection
Genitourinary tract duplication, cyst, fistula, or obstruction Nephrostomy Urinary catheter Vesicostomy
The relative frequency of primary immunodeficiency disorders is shown in Table 101.3.7,8 The list of recognized immunodeficiency conditions is ever-expanding, and the component due to recognized disorders of the innate immune system is growing.8 The International Union of Immunological Societies frequently publishes updates on the classification of primary immunodeficiencies, which include names of conditions, presumed pathogenesis, genetics, inheritance, immunologic parameters,
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PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION R Infections in Patients With Deficient Defenses
BOX 101.1 Underlying Conditions That Can Predispose to Recurrent Infections
BOX 101.2 Characteristics of Children Wth Primary Immunodeficiency Disorders
Asplenia syndromes/conditions Asthma Bone marrow and solid-organ transplantation Chemotherapy Collagen vascular diseases Congenital malformation Corticosteroid therapy Cystic fibrosis Dermatologic syndrome with immunodeficiency Diabetes mellitus Down syndrome Drug-induced cytopenia Galactosemia Gastrointestinal tract syndrome with immunodeficiency Genetic/metabolic conditions Glycogen storage disease type IB Growth deficiency/ immunodeficiency syndrome Hematopoietic/immunologic conditions Hemoglobinopathy Ichthyosis Immunosuppression Isovaleric acidemia
Infectious symptoms often begin in first days to weeks of life Therapeutic response is slow despite identification of a pathogen and administration of appropriate antimicrobial therapy Infection is suppressed rather than eradicated by appropriate therapy Common organisms cause severe manifestations or recurrent infection Unusual (sometimes sentinel) or “nonpathogenic” organisms cause infections Growth and development are delayed Multiple infections occur simultaneously Infection with common organisms leads to unexpected complications
Lymphohematopoietic malignancy Malnutrition α-Mannosidosis Methylmalonic aciduria Mucolipidosis II Myelokathexis (WHIM syndrome) Myotonic dystrophy Nephrotic syndrome Neurologic syndrome with immunodeficiency Newborn state Nutritional conditions Orotic aciduria Prematurity Propionic acidemia Protein-losing enteropathy Radiation therapy Renal conditions Renal failure Sarcoidosis Tumor necrosis factor antagonist therapy Werdnig-Hoffmann disease WHIM (warts, hypogammaglobulinemia, infections, myelokathexis)
associated features, and Online Mendelian Inheritance in Man (OMIM) reference numbers.9 More than 250 conditions presently are identified.9,10 Some are well characterized, their pathologic mechanisms are understood, and numerous affected patients have been described (e.g., chronic granulomatous disease, X-linked severe combined immunodeficiency syndrome, X-linked agammaglobulinemia, leukocyte adhesive deficiency type I, and adenosine deaminase deficiency).11–15 Other conditions remain incompletely characterized, are poorly understood, or have been observed in so few patients that they have not been studied extensively (e.g., lazy leukocyte syndrome, generalized pustular psoriasis, reticular dysgenesis).16–18
TABLE 101.2 Estimated Frequencies of Selected Chronic Underlying Illnesses, Primary Immunodeficiency Disorders, and HIV Infection
History A detailed history is the most powerful evaluation tool and should gather information using all available sources, including medical records, parent or patient interviews, radiographs, and laboratory test results. Information is assembled into a chronology of data and events to determine whether episodes of illness have been characterized well enough to confirm that the patient truly has had recurrent infections. Additional important considerations are whether treatment of infectious episodes was appropriate, response to treatment was as expected, or other explanations exist (e.g., fever from inflammatory rather than infectious disease).
Medical History A description of each infectious episode is obtained, specifically: (1) date, duration, and site of infection; (2) how the diagnosis was established (i.e., specific cultures and diagnostic tests performed and their results); (3) severity of the episode (shock, tissue destruction, ventilator support, end-organ damage); (4) what treatment (need for parenteral or prolonged) was used and responses to specific treatments; (5) need for surgical intervention and quality of wound healing; and (6) temporal relationships to previous episodes. This level of detail often necessitates a prolonged interview but is crucial for establishing whether an immunodeficiency is likely. Additional helpful details of the patient’s history include immunizations administered and any clinical illnesses associated with them, pattern of growth and development, medications given (including long-term antibiotic use) and their effect on course of disease, compliance with treatments, presence of conditions that can predispose to or masquerade as infections, unusual blood phenotypes (e.g., McLeod phenotype in chronic granulomatous disease, Bombay phenotype in leukocyte adhesion deficiency type II), and healing pattern after skin and soft tissue infection, injuries, or surgery. If infections have
Condition
Frequency
Asthma26
1 in 26
IgA deficiency
1 in 500 to 700
Diabetes mellitus26
1 in 556
HIV infection
1 in 1000
Sickle cell disease26
1 in 2200
TABLE 101.3 Relative Frequency of Primary Immunodeficiency Disorders
Cystic fibrosis27
1 in 2500
Factors
Acute lymphocytic leukemia26
1 in 9000
B lymphocytes
50–70
26
Percentage
1 in 10,000
T lymphocytes
20–30
Agammaglobulinemia26
1 in 50,000 to 100,000
T and B lymphocytes
10–15
Severe combined immunodeficiency
1 in 100,000 to 500,000
Phagocytic cells
15–20
Chronic granulomatous disease28
1 in 255,000
Complement
Phenylketonuria
HIV, human immunodeficiency virus; IgA, immunoglobulin A.
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CLINICAL APPROACH TO THE CHILD WITH RECURRENT INFECTIONS
Other innate immunity factors
2–5 <1
Evaluation of the Child With Suspected Immunodeficiency
TABLE 101.4 Sentinel Pathogens of Infections and Associated Conditions Infectious Agent
Condition
Mucoid Pseudomonas aeruginosa
Cystic fibrosis
Nocardia spp., Aspergillus spp.
Chronic granulomatous disease
Burkholderia cepacia pneumonia
Chronic granulomatous disease, cystic fibrosis
Recurrent Neisseria spp. infections
Terminal complement component deficiency
Escherichia coli bloodstream infection
Galactosemia
Deep Candida spp. infection
Myeloperoxidase deficiency
Disseminated Mycobacterium spp. infection
T-lymphocyte deficiency, IFNγ receptor deficiency, IL-12 defects
Pneumocystis jirovecii
T-lymphocyte deficiency
Recurrent/severe Streptococcus pneumoniae bloodstream infection
Asplenia, hemoglobinopathy, agammaglobulinemia, mannosebinding lectin deficiency, IRAK4 deficiency
Recurrent/severe Staphylococcus aureus infection
Chronic granulomatous disease, hyper-IgE/recurrent infection syndrome, Chédiak-Higashi syndrome, IRAK4 deficiency
IFNγ, interferon γ; IgE, immunoglobulin E; IL, interleukin; IRAK4, interleukin 1 receptor−associated kinase 4.
been localized around an anatomic site, details should be obtained to focus on foreign body aspiration, injuries or surgery at the site, medical problems involving the site, and timing of onset of infections relative to other events. Historical details that decrease concern for a primary immunodeficiency are rapid responses to appropriate therapy, rapid resolution (vs. suppression) of infected foci, healing without scarring, and inability to document infection. Details that are difficult to assess are poorly documented “infections,” “infections” in the presence of allergic inflammation, and infections occurring in association with underlying conditions. The category of microorganisms (and certain sentinel organisms) causing infections can suggest specific disorders (Table 101.4). Recurrent infections with extracellular, encapsulated microorganisms or chronic sinopulmonary infections frequently occur in people with asplenia, antibody deficiency conditions, or pattern recognition molecule (e.g., mannose-binding lectin or toll-like receptor) dysfunction. Deep fungal infections, multiple liver abscesses, or osteomyelitis suggests a phagocytic cell disorder. Recurrent infections accompanied by autoimmune symptoms or recurrent infections with Neisseria meningitidis suggest complement deficiencies. Recurrent infections due to opportunistic viral, protozoal, bacterial, mycobacterial, or fungal agents suggest T-lymphocyte deficiency. Unusual susceptibility to human papillomavirus infections occurs in WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome and severe and disseminated mycobacterial infections are seen in defects related to interferon γ production and signaling.
Family History Specific questions regarding the parents’ ethnic heritage, the likelihood of parental consanguinity, early childhood deaths in the two previous generations, and gender bias in medical problems should be asked. Survival and significant illnesses and hospitalizations in all family members within two previous generations, as well as occurrence of peculiar infections or certain syndromes (e.g., collagen vascular diseases and lymphoreticular malignancy), should be documented. Consanguinity or close ethnic heritage of the parents, occurrence of multiple early childhood deaths (particularly of male sex) in the family, serious infections in other family
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members, or presence of recognized syndromes in other family members (e.g., discoid lupus in heterozygous carriers for X-linked chronic granulomatous disease) heighten concern. Collagen vascular diseases in family members (associated with some complement deficiency states) and the presence of lymphoreticular malignancies (associated with a variety of immunodeficiency diseases) are noteworthy.19
Birth History Both congenital anatomic malformations and primary immunodeficiency disorders can manifest within days to weeks of birth. History is sought about the mother’s prenatal care, prenatal illnesses, and exposures as well as the infant’s length of gestation and peripartum problems, delayed separation of the umbilical stump (leukocyte adhesion deficiency type I), requirement for blood transfusion (graft-versus-host disease), and need for ventilator support. Historical details of concern include lack of prenatal care, maternal drug use or multiple sexual partners (human immunodeficiency virus or other congenital infection), presence of congenital malformations, absence of a thymic shadow on a neonatal chest radiograph, perinatal blood transfusion, perinatal ventilator therapy (resulting in chronic lung disease), onset of infection in the first days of life, intracranial hemorrhage (resulting in dysfunction of hypothalamic temperature regulation), prenatal exposure to a teratogen, and the need for surgical removal of the umbilical stump. Separation of the umbilical stump normally occurs within 14 days, and failure to separate is associated with leukocyte adhesion deficiency type 1. Of note, assiduous umbilical cord care (aggressive application of triple dye and isopropyl alcohol to “keep the cord stump clean”) can lead to its desiccation and resultant failure to separate in normal infants.
Social History Because the frequency of infection in small children mirrors frequency of exposure, details are sought of the patient’s contacts with other children (e.g., siblings, classmates, playmates in childcare, nursery school, playgroups) that increase the frequency of exposures. In addition, exposure to tobacco smoke or other environmental pollutants affects infection rates and symptomatology, particularly in association with underlying atopy. Review of the patient’s dietary habits should include estimates of caloric intake and whether raw egg ingestion occurs (excessive intake of avidin can lead to nutritional biotin deficiency). The length of time at the current residence, the type and duration of parental employment, and the child’s daily activities or school performance can yield insights into the continuity of medical care. The effect that “recurrent infections” has had on the child and family gives a measure of their severity.
Review of Systems The review of systems should focus on infection by organ systems involved. Skin, mouth, nasopharynx, lungs, and gastrointestinal tract are sites of constant contact with the microbially contaminated external environment and are common sites of infection. The liver, spleen, and lungs provide defenses against systemic spread of infection and as a result can become sites of infection. The occurrence of cutaneous abscesses and extent of scarring when wounds heal, rashes (e.g., discoid lupus), rhinitis, dermatitis (generalized or localized, particularly behind the ears and in the diaper area), and paronychia provide clues to underlying disorders and the integrity of skin defenses. Questions about sinusitis, seasonal allergies, allergic shiners, snoring, and sleep disturbance (i.e., upper airway obstruction) explore the possibility of an allergic diathesis. Gingivitis, periodontal disease, retained primary teeth, and aphthous stomatitis can be associated with specific primary immunodeficiency disorders. Focused questioning about pneumonia, diarrhea, perirectal or pararectal abscess, liver abscess, lymphadenitis, and bloodstream infections can reveal details sometimes missed in general review of systems.
Physical Examination Points to be addressed by the physical examination are (1) the physical status of the patient, (2) the presence of physical findings that confirm
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PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION R Infections in Patients With Deficient Defenses
BOX 101.3 Specific Considerations During the Physical Examination Reconcile vital signs with historical details (e.g., normal pulse and respiratory rate despite significant lung disease infers physiologic compensation and, therefore, chronicity) Assess general habitus, growth, and development (chronically ill versus robust; developmental delay; dysmorphism suggesting a genetic syndrome) Seek markers for atopy, nasopharyngeal lymphoid hyperplasia, or both Identify lymphoid tissue (absence of palpable or visible lymphoid tissue suggesting T-lymphocyte deficiency) Examine for midline defects in the head, neck, spine, or sacrum; or the presence of glucose-containing rhinorrhea Examine for scarring of tympanic membranes Examine for gingivitis, ulcerations, tooth loss, or periodontal disease (typical of immunodeficiency) Identify cutaneous stigmata: ■ Petechiae (suggesting Wiskott-Aldrich syndrome) ■ Skin or conjunctival telangiectases (ataxia-telangiectasia syndrome) ■ Eczematoid rash (Wiskott-Aldrich syndrome, hyperimmunoglobulinemia E [hyper-IgE] syndrome) ■ Seborrhea-like dermatitis localized behind the ears (chronic granulomatous disease) ■ Generalized seborrhea-like dermatitis (Langerhans histiocytosis, graft-versus-host disease, or T-lymphocyte deficiency) ■ Nose-tip dermatitis (chronic granulomatous disease) ■ Alopecia (graft-versus-host disease) ■ Ectodermal dysplasia (anhidrotic ectodermal dysplasia with immunodeficiency) ■ Cutaneous scars, with thin/poor formation at site of previous surgery or with tissue loss at site of previous infection (leukocyte defects) Seek markers for chronic lung disease (pulmonary osteoarthropathy) Assess for acute or chronic sinus disease Identify the size of the liver and spleen Examine for pararectal inflammation, scarring from previous infections, or persistent inflammation Examine exhaustively any anatomic site where infections repeatedly localize, assessing normalcy of local anatomy and physiology
points of history, and (3) previously unrecognized but significant physiologic or anatomic abnormalities. Specific considerations during the physical examination are shown in Box 101.3.
LABORATORY FINDINGS AND DIAGNOSIS
TABLE 101.5 Screening Laboratory Tests and Their Purposes in the Evaluation of Immunodeficiency Disorders Test
Purposes
Complete blood count differential
Assess numbers and morphology of cellular blood elements: leukopenia, leukocytosis, anemia, neutropenia, lymphopenia, Howell-Jolly bodies, bizarre erythrocyte forms, leukocyte morphology, thrombocytopenia
Total lymphocyte, T-lymphocyte, and B-lymphocyte quantification
CD3 marker is used to estimate total lymphocyte number by flow cytometry; CD4 and CD8 markers are used to estimate T-lymphocyte subsets; B-lymphocyte numbers are estimated using surface Ig expression or CD19 or CD20 markers
Skin testing
Simple assessment of cell-mediated immunity (T-lymphocyte function)
Serum immunoglobulin quantification (IgA, IgG, IgM, IgE)
Assess for hypergammaglobulinemia, hypogammaglobulinemia, or agammaglobulinemia
IgG subclass determinations
Assess for specific subclass deficiency
Specific antibody determinations
Assess production of antibody in responses to tetanus or diphtheria toxoid immunization as well as boosting; assess quantitative isohemagglutinin levels
Assess for Underlying Conditions
Test
Cystic fibrosis
Sweat test
HIV
HIV serology (and PCR testing, depending on patient age)
Sickle cell disease, thalassemia
Hemoglobin electrophoresis
If the history and physical findings are consistent with an anatomic cause of infection or the presence of an underlying condition, laboratory evaluation of the patient is directed at either defining the anatomic problem or diagnosing the underlying condition. If the history and physical findings do not point to a cause for recurrent, significant infections, a screening laboratory analysis provides a reasonable first evaluation (Table 101.5).
Multiple congenital and acquired anomalies/conditions
Assess chest radiograph for chronic lung disease, foreign body, presence of thymus, situs inversus, anatomic abnormality, or end-organ damage If anatomic definition is inadequate, consider chest computed tomography
Further Assessment
Terminal complement component deficiency
Total hemolytic complement activity (CH50)a
After the history, physical examination, and a screening laboratory evaluation have been completed, either the diagnosis will be clear and a plan of action can be proposed, or a diagnosis will be lacking and the decision must be made as to whether further, more detailed evaluation is appropriate. This decision is based on an overall impression of the severity,
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end-organ effects, documentation, and pathogens of the child’s recurrent infections, family history, and physical findings. In the absence of repeated, documented infections in a patient in whom physical findings, growth and development, and appetite and activity are normal and the screening laboratory examination are unrevealing, the likelihood of a predisposing condition or immunodeficiency is remote and the child is assessed as “normal but unlucky.” Prospective observation and documentation should be planned and reassurance given. Problems may resolve spontaneously, or documentation of continuing problems may reveal their cause or lead to a need for specialized evaluation. If there are major incongruities between physical findings, historical details, and laboratory results, or when an unexplained lack of continuity in patient care is obvious, Munchausen syndrome or Munchausen syndrome by proxy should be considered.20
a Test performance is altered easily and unpredictably by inappropriate specimen handling and/or poor laboratory technique. CD, cluster designation (for antigens); CH50, 50% hemolyzing dose of complement; HIV, human immunodeficiency virus; Ig, immunoglobulin; PCR, polymerase chain reaction.
TABLE 101.6 Specific Testing Approaches for Immunodeficiency Disorders Disorder
Possible Testing Approaches
Cytopenia
Bone marrow examination/histochemistry Cytokine, colony-stimulating factor levels
Antibody deficiency
In vitro antibody production (Ig isotypes and subclasses) Cytokine levels In vitro specific antibody production Bruton thymidine kinase gene
T-lymphocyte deficiency
Adenosine deaminase activity Nucleoside phosphorylase activity In vitro proliferation responses (mitogens and specific antigens) Cytokine, growth factor levels Skin biopsy, intestinal biopsy (graft-versus-host disease)
Phagocytic cell dysfunction
Bactericidal activity Respiratory burst activity (nitroblue tetrazolium reduction, superoxide, dihydrorhodamine 123 oxidation test, or H2O2 production) Chemotaxis
Complement deficiency
CH50 Individual complement component quantitation Serum opsonic activity
CH50, 50% hemolyzing dose of complement; Ig, immunoglobulin.
Specialized Testing If anatomic problems or underlying conditions are suspected, appropriate testing and imaging are pursued. If immunodeficiency is suspected or is likely, specialized, targeted testing is planned. Because the range of specialized testing is broad, an all-inclusive testing approach is both labor and time intensive, extremely costly, and inappropriate in most circumstances. Focused testing should be performed in a stepwise fashion, pursuing abnormalities uncovered by history, physical examination, and screening laboratory tests (Table 101.6).
Genetic Testing Genetic testing is a powerful diagnostic tool in primary immunodeficiency disorders. Current information on characteristics and genetics of most disorders is available at the OMIM website (www.omim.org). The genes responsible for all of the known X-linked and most of the known autosomal primary immunodeficiency disorders have been elucidated. For the X-linked disorders, approximately one third of new cases are due to new mutations, and two thirds are inherited.21 Carriers of some
X-linked conditions (e.g., X-linked severe combined immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome) sometimes can be identified through the use of X-chromosome inactivation analysis because cells expressing the normal X chromosome have a survival advantage over cells expressing the abnormal X chromosome.22–25 Carriers are recognized because of their homogeneous X-chromosome expression pattern (except in situations of “extreme” lyonization). In classical autosomal recessive conditions, recurrence risks follow mendelian inheritance. Well over 100 genes have now been associated with primary immunodeficiency diseases.9 Although the availability of appropriate gene probes or diagnostic methods for most currently recognized primary immunodeficiency syndromes makes their diagnosis easier than in the past, clinical suspicion remains the fulcrum for testing. In some instances, the suspicion only arises after the death of an index patient; if specimens of tissues are appropriately preserved, genetic testing can be performed postmortem.
MANAGEMENT When a child is identified with an anatomic abnormality, an underlying condition, or a primary immunodeficiency disorder, management is based on existing knowledge about the specific condition, as described in subsequent chapters. Management is more difficult for patients whose history or physical findings are suggestive of a defect but in whom diagnostic testing is unrevealing. Such patients often require management based more on skilled judgment and careful reassessment than on scientific knowledge. It is important to emphasize to parents that, although negative diagnostic test results cannot exclude all potential underlying conditions, they eliminate specific serious conditions; this information can be comforting and helpful. In addition, delineating a specific plan for ongoing observation communicates a commitment to the child’s well-being, which will help to ensure adherence to medically recommended interventions and continued contact with the patient. All references are available online at www.expertconsult.com.
KEY REFERENCES 5. Rubin BK. The evaluation of the child with recurrent chest infections. Pediatr Infect Dis J 1985;4:88–98. 9. Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunol, “Primary Immunodeficiencies”; Article #162, 2014;5:1–33. 10. Bousfiha AA, Jeddane L, Ailal F, et al. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol 2013;33:1078–1087. 13. Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clin Rev Allergy Immunol 2000;19:183–204. 28. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease: Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79:155–169.
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15. Hirschhorn R. Overview of the biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res 1993;33(suppl 1):S35–S41. 16. Miller ME, Oski FA, Harris MB. Lazy leukocyte syndrome: a new disorder of leukocyte function. Lancet 1971;1:665–669. 17. Kanazawa N, Nakamura T, Furukawa F. Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis. J Dermatol 2013;40:749–751. 18. Pannicke U, Hönig M, Hess I, et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat Genet 2009;41:101–105. 19. Leechawengwongs E, Shearer WT. Lymphoma complicating primary immunodeficiency syndromes. Curr Opin Hematol 2012;19:305–312. 20. Eminson DM, Postlethwaite RJ. Factitious illness: recognition and management. Arch Dis Child 1992;67:1510–1516. 21. Chase GA, Murphy EA. Risk of recurrence and carrier frequency for X-linked lethal recessives. Hum Hered 1973;23:19–26. 22. Puck JM, Stewart CC, Nussbaum RL. Maximum likelihood analysis of human T-cell X chromosome inactivation patterns: normal women vs. carriers of X-linked severe combined immunodeficiency. Am J Hum Genet 1992;50:742–748. 23. Fearon ER, Winkelstein JA, Civin CI, et al. Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome inactivation. N Engl J Med 1987;316:427–431. 24. Gealy WJ, Dwyer JM, Harley JB. Allelic exclusion of glucose-6- phosphate dehydrogenase in platelets and T-lymphocytes from a Wiskott-Aldrich syndrome carrier. Lancet 1980;1:63–65. 25. de Saint Basile G, Le Deist F, Caniglia M, et al. Genetic study of a new X-linked immunodeficiency syndrome. J Clin Invest 1992;89:861–866. 26. Gortmaker SL, Sappenfield W. Chronic childhood disorders: prevalence and impact. Pediatr Clin North Am 1984;31:3–18. 27. Boat TF, Welsh MJ, Beaudet AL. Cystic fibrosis. In: Scrivner CL, Beaudet AL, Sly WS, Valle D (eds) The Metabolic Basis of Inherited Disease, 6th ed. New York, McGraw-Hill, 1989, p 2649. 28. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease: Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79:155–169.
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