Immunodeficiency Disorders

Clinical History and Physical Examination

A thorough clinical history provides the primary clues in diagnosing a PIDD. Part of the first visit should include obtaining all previous medical records, including pathology reports or slides, and results of previous cultures and radiographs. The typical history includes recurrent, persistent infections or infections caused by unusual microbes. The clinician will be guided by the types of infection the patient has acquired. Patients with immunoglobulin deficiencies typically report an increased number of bacterial infections. Repeated viral, fungal, or other opportunistic infections are associated with T-cell immunodeficiencies. Patients with phagocytic defects usually report a history of infections with catalase-positive bacteria such as Staphylococcus spp. Complement deficiencies are most frequently associated with infections caused by encapsulated organisms such as Streptococcus pneumoniae or Neisseria spp. infections (see Fig. 52.1 ) ( ).

The physical examination in PIDD may reveal findings that are characteristic for that particular PIDD. Patients with PIDD may appear pale, lethargic, and chronically ill. Infants and young children affected with primary immunodeficiency disorders may present with failure to thrive, so monitoring height and weight is important. Small or absent peripheral lymph nodes, tonsils, or adenoids are indicative of X-linked agammaglobulinemia ( ). Hepatomegaly or splenomegaly may suggest presence of lymphoproliferation. In addition to respiratory infection, the infant may experience rhinitis; conjunctivitis; or hematologic, gastrointestinal, and autoimmune disorders ( ). In contrast, patients with chronic granulomatous disease (CGD) and common variable immunodeficiency present with normal or enlarged peripheral lymph nodes ( ). The genetic defect in Wiskott-Aldrich syndrome (WAS) causes immunodeficiency and thrombocytopenia, resulting in the combination of increased bruising, petechiae, and eczematous skin rashes ( ). Sparse hair and abnormalities of teeth and nails can be indications of ectodermal dysplasia seen in nuclear factor-kappa B essential modulator (NEMO) deficiency ( ). Skin rashes such as livedo reticularis, eczematous rash, ichthyosis, and erythroderma can be signs of various PIDDs.

Immune evaluation depends on several factors. Typical basic tests include complete blood count (CBC) with differential and immunoglobulins. However, based on patient’s signs and symptoms, initial tests may vary. For example, liver or perianal abscess caused by Serratia marcescens is suspicious for CGD, so the testing for CGD can be pursued as an initial test.

Complete Blood Count

The first test performed to examine the immune system is the CBC. A white blood count and differential will provide information on the morphology and number of small lymphocytes (diameter <10 μm). Normal parameters vary, based on the age of the patient, and therefore must be interpreted using age-appropriate reference ranges. Absolute cell counts can provide valuable information. Low absolute neutrophil count can point to immunodeficiencies associated with neutropenia. At a minimum, regardless of age, one expects more than 1500 small lymphocytes per cubic millimeter. Because few (∼10%) of the lymphocytes are B lymphocytes, an absolute lymphocyte deficiency primarily reflects T-cell deficiency. Absolute eosinophil count can be elevated in case of Omenn syndrome, autosomal dominant or autosomal recessive hyper-IgE syndrome (HIES), along with various other primary immunodeficiencies (Navabi & Upton, 2016). Absolute monocyte count can be low in GATA2 deficiency ( ). Anemia and thrombocytopenia can be associated with various PIDDs such as autoimmune lymphoproliferative syndrome, common variable immunodeficiency, and chromosome 22q11.2 deletion syndrome. Autoimmune hemolytic anemia can be seen in Wiskott-Aldrich syndrome. Peripheral smear evaluation can provide valuable information. Large vacuoles in neutrophils are seen in Chediak-Higashi syndrome. Small platelets can be seen in Wiskott-Aldrich syndrome. Howell-Jolly bodies can suggest functional asplenia.

Immunoglobulins

Because antibody deficiency diseases are more common than other immune defects, first emphasis should be placed on investigation of immunoglobulins and their production ( ; ). Quantitative immunoglobulin assays are readily available in all commercial and larger hospital laboratories and require only small volumes of serum to perform ( Chapter 20, Chapter 47 ). Because immunoglobulin values increase with age, comparison with age-matched normal ranges is necessary for correct interpretation ( ).

For the first few months of life, IgG is the major immunoglobulin found in infant serum and is maternal in origin. At approximately 3 months of age, dissipation of maternal IgG concentration, combined with a lag in production by the infant, creates a nadir in IgG levels at about 6 months of age. However, primarily IgM and secondarily IgA are synthesized by the infant; thus the absence of these two immunoglobulins may provide clues for a diagnosis of agammaglobulinemia, characterized by pan-hypogammaglobulinemia. The best understood cause of agammaglobulinemia is a defective BTK gene (known as X-linked agammaglobulinemia) causing arrest of maturing B cells and absence of mature B cells in circulation. Other autosomal recessive forms of agammaglobulinemia are now known to cause similar pan-hypogammaglobulinemia. Immunoglobulin G levels can be low due to primary immunodeficiency (antibody deficiencies such as XLA or common variable immunodeficiency or part of other combined immunodeficiencies) or secondary causes such as iatrogenic (medications such as corticosteroids, antiepileptics, B-cell–targeted therapy such as rituximab, radiation therapy), acute illness (e.g., sepsis), or protein losing conditions (protein losing enteropathy, protein losing nephropathy). While IgG level is most frequently used, IgG subclasses can be assessed (IgG1, IgG2, IgG3, IgG4) but their use is controversial and minimal. IgG3 has short half-life and can be used before 6 months of age to check if an infant can make antibodies (when the rest of the subclasses are maternal in origin).

Often, IgA is not present in significant amounts until 6 months of age; however, after 4 years of age, IgA levels that remain decreased indicate that this is a permanent defect ( ). Selective IgA-deficient patients may be asymptomatic or may have mild symptoms such as increased respiratory or gastrointestinal infection; however, patients may be at risk of developing severe or fatal anaphylactic reactions to plasma in blood products that contain IgA ( ). Such patients, once confirmed for IgA deficiency, would require plasma from other IgA-deficient individuals to avoid future anaphylactic reactions.

Hyper-IgM syndrome is characterized by normal to elevated levels of IgM with markedly low levels of IgA, IgG, and IgE ( ; ; ). Hyper-IgM syndrome is caused by defect in CD40 ligand, CD40, AID, UNG, INO80, and MSH6. In contrast, marked elevations of IgE can be a part of the hyper-IgE syndrome caused by STAT3 loss of function, DOCK8 deficiency, PGM3 defect, TGFBR, ZNF34I, ERBIN deficiency, CARD11 deficiency, interleukin-6 (IL-6) receptor deficiency or IL-6 signal transducer deficiency, and Comel Netherton syndrome ( ; ) but also are common in immunodysregulation, polyendocrinopathy, enteropathy, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), atypical complete DiGeorge syndrome, Wiskott-Aldrich syndrome, and Omenn syndrome ( ). WAS characteristically shows marked elevation of serum IgA combined with low IgM concentrations ( ). Patients with decreased levels of IgM are often found in the context of generalized immune deficiency/dysregulation and autoimmune diseases. While very low IgM levels have been noted in chromosome 22q11.2 deletion, reduced or lacking IgM+ B cells, or impaired IgG antibody responses against pneumococcus polysaccharides, it may be part of another immunodeficiency disorder ( ).

A simple way to assess functional antibody levels in children is to check for isohemagglutinins, commonly of the IgM isotype, directed against ABO antigens that the patient lacks (e.g., assessing anti-A antibodies in a patient with the B blood type), because their presence will indicate active functional antibody production ( ). Isohemagglutinins are naturally occurring antibodies that form at some point after 2 to 3 months of age; however, testing for these antibodies is not valid for children 4 to 6 months of age because of the persistence of maternal immunoglobulin. Additionally, because of relative immaturity, or perhaps inadequate exposure, children with normal immunity may have low concentrations of isohemagglutinins until 5 to 10 years of age ( ).

Radiologic Imaging

Radiographs, computed tomography (CT), and magnetic resonance imaging (MRI) studies can be helpful as adjunctive tests in assessing or in monitoring complications of immunodeficiencies. Chronic interstitial pneumonia is common in infants, children, and adults with T-cell deficiencies and should be confirmed on chest radiograph. With time, many patients with primary B-cell deficiency (agammaglobulinemia, common variable immunodeficiency) may develop chronic pulmonary fibrosis or bronchiectasis ( ; ). Chest CT in a patient who has recurrent respiratory tract infection is the best means of investigating for bronchiectasis; if these changes have developed, further investigation is clearly warranted.

In the past, lateral views of the neck were used to assess pharyngeal lymphoid tissue in children. However, radiographs are not recommended for evaluation of cervical lymphoid tissue because the information they provide is more easily obtained by alternative methods. Frontal views of the chest may reveal an absence of the thymic shadow in infants, but because the thymus can shrink easily because of stress, evaluation of thymic size by this method is not reliable. Bony abnormalities, however, can alert the radiologist to an immunologic problem presenting in childhood. A subset of patients with immunodeficiencies (e.g., cartilage hair hypoplasia) involving abnormalities of T cells, or both T and B cells, have short-limbed dwarfism. These patients show characteristic lesions, usually in the metaphyseal regions of the long bones. Patients with infant-onset adenosine deaminase deficiency show readily identifiable skeletal abnormalities of ribs and hips ( ). Bony abnormalities may be present in patients with HIES; these abnormalities include diffuse osteoporosis, fractures that occur with little trauma, craniosynostosis, and midline bony defects ( ).

Pulmonary Functions

Immunodeficiency, especially if it has persisted for some time, will often affect the pulmonary system and its function, as previously mentioned. Therefore complete lung volumes, with forced expiratory volumes and diffusing lung capacity for carbon monoxide (DLCO), should be tested even if the chest radiograph is normal. Patients with both T- and B-cell defects are subject to pulmonary infection, often resulting in bronchospasm, restrictive or obstructive disease, or combinations of these abnormalities. Those patients who are both IgA and IgG2 deficient have been shown to have significantly abnormal pulmonary function tests, and a causal relationship may be seen between these deficiencies and deterioration of lung function ( ).

Pathology

Hair microscopy can reveal pigmentation issues noted in familial hemophagocytic lymphohistiocytosis syndromes such as Chediak-Higashi syndrome, Hermansky-Pudlak syndrome, and Griscelli syndrome. Clumping of hair pigment can also be noted in cartilage hair hypoplasia.

Absence of plasma cells on biopsy of intestine can be noted in antibody deficiencies such as common variable immunodeficiency. Pulmonary alveolar proteinosis can be noted on bronchoalveolar lavage/lung biopsy in cases with GATA 2 deficiency or CSF2RB deficiency. Biopsy of any affected tissue may be helpful.