Evaluation of the Child With Suspected Immunodeficiency

Acknowledgment

Substantial material from E. Stephen Buescher’s chapter in the previous edition has been used.

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 5–6 acute respiratory tract illnesses per year, with a range up of to 11 or 12 per year. ^, 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. Attendance at group childcare and exposure to secondhand smoke further increase frequency of these infections. 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. 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 of their recurrent infections.

Anatomic and Physiologic Abnormalities

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.

TABLE 101.1

Anatomic and Physiologic Abnormalities That Predispose to Recurrent Infections

Type of Infection	Predisposing Abnormality
Bloodstream infection	Asplenia, hemoglobinopathy Cardiac valve abnormality Intravascular cannula or thrombus Neutropenia
Bone infection	Foreign body Orthopedic device Injury Prior orthopedic surgery
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 Bronchiectasis Endotracheal intubation Extrinsic airway compression Foreign body Gastroesophageal reflux Polyps Pulmonary cyst, fistula Pulmonary sequestration Tracheal web Tracheoesophageal fistula Tracheomalacia Tracheostomy Vascular ring
Soft tissue infection	Diminished sensation Foreign body Lymphedema Traumatic injury Thermal injury
Urinary tract infection	Genitourinary tract duplication, cyst, fistula, or obstruction (posterior urethral valves) Nephrostomy Urinary catheter Vesicostomy

Underlying Conditions

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 >100 other syndromes, which include growth deficiencies, specific organ system dysfunctions, inborn errors of metabolism, and miscellaneous and chromosomal anomalies. 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.

BOX 101.1

Underlying Conditions That Can Predispose to Recurrent Infections

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
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
Lymphohematopoietic malignancy
Malnutrition
αMannosidosis
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
Trisomy 21
Tumor necrosis factor antagonist therapy
Werdnig-Hoffmann disease
WHIM (warts, hypogammaglobulinemia, infections, myelokathexis)

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 .

TABLE 101.2

Estimated Frequencies of Selected Chronic Underlying Illnesses, Primary Immunodeficiency Disorders, and HIV Infection

Condition	Frequency
Asthma	1 in 11–16
IgA deficiency	1 in 300–1,000
Diabetes mellitus	1 in 500
HIV infection	1 in 1,000
Sickle cell disease	1 in 2,200
Cystic fibrosis ²⁷	1 in 3,400
Phenylketonuria	1 in 10,000
Acute lymphocytic leukemia	1 in 13,000–29,000
Severe combined immunodeficiency	1 in 40,000–100,000
Agammaglobulinemia	1 in 100,000–250,000
Chronic granulomatous disease ²⁸	1 in 200,000–250,000

HIV, human immunodeficiency virus; IgA, immunoglobulin A.

BOX 101.2

Characteristics of Children With Primary Immunodeficiency Disorders

Infectious symptoms often begin in first days to weeks of life (pure B-cell defects may present later due to protection from passive maternal antibody).
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.

The relative frequency of primary immunodeficiency disorders is shown in Table 101.3 . ^, The list of recognized immunodeficiency conditions is ever-expanding, and the component due to recognized disorders of the innate immune system is growing exponentially. 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, associated features, and Online Mendelian Inheritance in Man (OMIM) reference numbers. More than 350 conditions presently are identified. ^, 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). 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).

TABLE 101.3

Relative Frequency of Primary Immunodeficiency Disorders

Factors	Percentage
B lymphocytes	50–70
T lymphocytes	20–30
T and B lymphocytes	10–15
Phagocytic cells	15–20
Complement	2–5
Other innate immunity factors	<1

Clinical Approach to the Child With Recurrent Infections

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