Chapter 116 Evaluation of Suspected Immunodeficiency
Primary care physicians must have a high index of suspicion if defects of the immune system are to be diagnosed early enough that appropriate treatment can be instituted before irreversible damage develops. Diagnosis is difficult because primary immunodeficiency diseases are not screened for at any time during life and most affected do not have abnormal physical features. Screening for SCID (T-cell lymphopenia) has become incorporated as part of the newborn screening programs in a few states. Extensive use of antibiotics may mask the classic presentation of many primary immunodeficiency diseases. Evaluation of immune function should be initiated in those rare infants or children who do have clinical manifestations of a specific immune disorder and in all who have unusual, chronic, or recurrent infections such as (1) 1 or more systemic bacterial infections (sepsis, meningitis); (2) 2 or more serious respiratory or documented bacterial infections (cellulitis, abscesses, draining otitis media, pneumonia, lymphadenitis) within 1 yr; (3) serious infections occurring at unusual sites (liver, brain abscess); (4) infections with unusual pathogens (Pneumocystis jiroveci, Aspergillus, Serratia marcescens, Nocardia, Burkholderia cepacia); and (5) infections with common childhood pathogens but of unusual severity (Table 116-1). Additional clues to immunodeficiency include: failure to thrive with or without chronic diarrhea, persistent infections after receiving live vaccines, and chronic oral or cutaneous moniliasis. Certain clinical features suggestive of immunodeficiency syndromes are noted in Tables 116-2 and 116-3.
Table 116-2 CHARACTERISTIC CLINICAL PATTERNS IN SOME PRIMARY IMMUNODEFICIENCIES
| FEATURES | DIAGNOSIS |
|---|---|
| IN NEWBORNS AND YOUNG INFANTS (0 TO 6 MONTHS) | |
| Hypocalcemia, unusual facies and ears, heart disease | DiGeorge anomaly |
| Delayed umbilical cord detachment, leukocytosis, recurrent infections | Leukocyte adhesion defect |
| Persistent thrush, failure to thrive, pneumonia, diarrhea | Severe combined immunodeficiency |
| Bloody stools, draining ears, atopic eczema | Wiskott-Aldrich syndrome |
| Pneumocystis jiroveci pneumonia, neutropenia, recurrent infections | X-linked hyper-IgM syndrome |
| IN INFANCY AND YOUNG CHILDREN (6 MONTHS TO 5 YEARS) | |
| Severe progressive infectious mononucleosis | X-linked lymphoproliferative syndrome |
| Recurrent staphylococcal abscesses, staphylococcal pneumonia with pneumatocele formation, coarse facial features, pruritic dermatitis | Hyper-IgE syndrome |
| Persistent thrush, nail dystrophy, endocrinopathies | Chronic mucocutaneous candidiasis |
| Short stature, fine hair, severe varicella | Cartilage hair hypoplasia with short-limbed dwarfism |
| Oculocutaneous albinism, recurrent infection | Chédiak-Higashi syndrome |
| Abscesses, suppurative lymphadenopathy, antral outlet obstruction, pneumonia, osteomyelitis | Chronic granulomatous disease |
| IN OLDER CHILDREN (OLDER THAN 5 YEARS) AND ADULTS | |
| Progressive dermatomyositis with chronic enterovirus encephalitis | X-linked agammaglobulinemia |
| Sinopulmonary infections, neurologic deterioration, telangiectasia | Ataxia-telangiectasia |
| Recurrent neisserial meningitis | C6, C7, or C8 deficiency |
| Sinopulmonary infections, splenomegaly, autoimmunity, malabsorption | Common variable immunodeficiency |
Modified from Stiehm ER, Ochs HD, Winkelstein JA: Immunologic disorders in infants and children, ed 5, Philadelphia, 2004, Elsevier/Saunders.
Table 116-3 COMMON CLINICAL FEATURES OF IMMUNODEFICIENCY
| Usually present | Recurrent upper respiratory infections |
| Severe bacterial infections | |
| Persistent infections with incomplete or no response to therapy | |
| Paucity of lymph nodes and tonsils | |
| Often present | Persistent sinusitis or mastoiditis (Streptococcus pneumoniae, Haemophilus, Pneumocystis jiroveci, Staphylococcus aureus, Pseudomonas spp.) |
| Recurrent bronchitis or pneumonia | |
| Failure to thrive or growth retardation for infants or children; weight loss for adults | |
| Intermittent fever | |
| Infection with unusual organisms | |
| Skin lesions: rash, seborrhea, pyoderma, necrotic abscesses, alopecia, eczema, telangiectasia | |
| Recalcitrant thrush | |
| Diarrhea and malabsorption | |
| Hearing loss due to chronic otitis | |
| Chronic conjunctivitis | |
| Arthralgia or arthritis | |
| Bronchiectasis | |
| Evidence of autoimmunity, especially autoimmune thrombocytopenia or hemolytic anemia | |
| Hematologic abnormalities: aplastic anemia, hemolytic anemia, neutropenia, thrombocytopenia | |
| History of prior surgery, biopsy | |
| Occasionally present | Lymphadenopathy |
| Hepatosplenomegaly | |
| Severe viral disease (e.g., EBV, CMV, adenovirus, varicella, herpes simplex) | |
| Chronic encephalitis | |
| Recurrent meningitis | |
| Deep infections: cellulitis, osteomyelitis, organ abscesses | |
| Chronic gastrointestinal disease, infections, lymphoid hyperplasia, sprue-like syndrome, atypical inflammatory bowel disease | |
| Autoimmune disease such as autoimmune thrombocytopenia, hemolytic anemia, rheumatologic disease, alopecia, thyroiditis, pernicious anemia | |
| Pyoderma gangrenosum | |
| Adverse reaction to vaccines | |
| Delayed umbilical cord detachment | |
| Chronic stomatitis or peritonitis |
EBV, Epstein-Barr virus; CMV, cytomegalovirus.
Modified from Goldman L, Ausiello D: Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders, p 1598.
Children with defects in antibody production, phagocytic cells, or complement proteins have recurrent infections with encapsulated bacteria and may grow and develop normally despite their recurring infections, unless they develop bronchiectasis from repeated lower respiratory tract bacterial infections or persistent enteroviral infections of the central nervous system. Patients with only repeated benign viral infections (with the exception of persistent enterovirus infections) are not as likely to have an immunodeficiency. By contrast, patients with deficiencies in T-cell function usually develop opportunistic infections or serious illnesses from common viral agents early in life, and they fail to thrive (Table 116-4).
The initial evaluation of immunocompetence includes a thorough history, physical examination, and family history (Table 116-5). Most immunologic defects can be excluded at minimal cost with the proper choice of screening tests, which should be broadly informative, reliable, and cost-effective (Table 116-6 and Fig. 116-1). A complete blood count (CBC), manual differential count, and erythrocyte sedimentation rate (ESR) are among the most cost-effective screening tests. If the ESR is normal, chronic bacterial or fungal infection is unlikely. If an infant’s neutrophil count is persistently elevated in the absence of any signs of infection, a leukocyte adhesion deficiency should be suspected. If the absolute neutrophil count is normal, congenital and acquired neutropenias and leukocyte adhesion defects are excluded. If the absolute lymphocyte count is normal, the patient is not likely to have a severe T-cell defect, because T cells normally constitute 70% of circulating lymphocytes and their absence results in striking lymphopenia. Normal lymphocyte counts are higher in infancy and early childhood than later in life (Fig. 116-2). Knowledge of normal values for absolute lymphocyte counts at various ages in infancy and childhood (Chapter 708) is crucial in the detection of T-cell defects. At 9 mo of age, an age when infants affected with severe T-cell immunodeficiency are likely to present, the lower limit of normal is 4,500 lymphocytes/mm3. Absence of Howell-Jolly bodies or pitted erythrocytes by microscopic examination of erythrocytes rules against congenital asplenia. Normal platelet size or count excludes Wiskott-Aldrich syndrome. If a CBC and a manual differential were performed on the cord blood of all infants, severe combined immunodeficiency (SCID) could be detected at birth by the identification of lymphopenia, and lifesaving immunologic reconstitution could then be provided to all affected infants shortly after birth and before they become infected.
Table 116-5 SPECIAL PHYSICAL FEATURES ASSOCIATED WITH IMMUNODEFICIENCY DISORDERS
| CLINICAL FEATURES | DISORDERS |
|---|---|
| DERMATOLOGIC | |
| Eczema | Wiskott-Aldrich syndrome, IPEX |
| Sparse and/or hypopigmented hair | Cartilage hair hypoplasia, Chédiak-Higashi syndrome, Griscelli syndrome |
| Ocular telangiectasia | Ataxia-telangiectasia |
| Oculocutaneous albinism | Chédiak-Higashi syndrome |
| Severe dermatitis | Omenn syndrome |
| Recurrent abscesses with pulmonary pneumatoceles | Hyper-IgE syndrome |
| Recurrent organ abscesses, liver and rectum especially | Chronic granulomatous disease |
| Recurrent abscesses or cellulitis | Chronic granulomatous disease, hyper-IgE syndrome, leukocyte adhesion defect |
| Oral ulcers | Chronic granulomatous disease, severe combined immunodeficiency, congenital neutropenia |
| Periodontitis, gingivitis, stomatitis | Neutrophil defects |
| Oral or nail candidiasis | T-cell immune defects, combined defects, mucocutaneous candidiasis, hyper-IgE syndrome |
| Vitiligo | B-cell defects, mucocutaneous candidiasis |
| Alopecia | B-cell defects, mucocutaneous candidiasis |
| Chronic conjunctivitis | B-cell defects |
| EXTREMITIES | |
| Clubbing of the nails | Chronic lung disease due to antibody defects |
| Arthritis | Antibody defects, Wiskott-Aldrich syndrome, hyper-IgM syndrome |
| ENDOCRINOLOGIC | |
| Hypoparathyroidism | DiGeorge syndrome, mucocutaneous candidiasis |
| Endocrinopathies (autoimmune) | Mucocutaneous candidiasis |
| Growth hormone deficiency | X-linked agammaglobulinemia |
| Gonadal dysgenesis | Mucocutaneous candidiasis |
| HEMATOLOGIC | |
| Hemolytic anemia | B- and T-cell immune defects, ALPS |
| Thrombocytopenia, small platelets | Wiskott-Aldrich syndrome |
| Neutropenia | Hyper-IgM syndrome, Wiskott-Aldrich variant |
| Immune thrombocytopenia | B-cell immune defects, ALPS |
| SKELETAL | |
| Short-limb dwarfism | Short-limb dwarfism with T- and/or B-cell immune defects |
| Bony dysplasia | ADA deficiency, cartilage hair hypoplasia |
ADA, adenosine deaminase deficiency; AID, activation-induced cytidine deaminase; ALPS, autoimmune lymphoproliferative syndrome; GVHD, graft-versus-host disease; Ig, immunoglobulin; IPEX, X-linked immune dysfunction enteropathy polyendocrinopathy; SCID, severe combined immunodeficiency.
From Goldman L, Ausiello D: Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders, p 1599.
