Immune Deficiency Disorders
Tracy B. Fausnight
E. Scott Halstead
Sachin S. Jogal
Jennifer A. Mcarthur
KEY POINTS
Primary immunodeficiency disease, once thought to be a rare occurrence, is more common than originally thought. The pediatric critical care provider needs a sound working knowledge of primary immunodeficiency, as prompt identification and diagnosis of these disorders allows for early institution of appropriate therapy and, potentially, improved outcomes among these high-risk patients.
The intensivist should recognize a child presenting with a second invasive bacterial infection, an opportunistic infection, and/or an infection slow to respond to conventional therapy as a patient in need of an immunologic workup.Disorders Predominantly Affecting Immunoglobulins
Antibody defects are the most prevalent primary immune deficiency; thus, laboratory evaluation should generally first focus on the possibility of humoral deficiency.
Antibody defects most commonly predispose patients to sinopulmonary infections with encapsulated organisms.
An early clue to an immunoglobulin deficiency is the finding of a low total protein level in the presence of a normal albumin level on routine blood analysis.
Immunoglobulin replacement may be helpful in the control and clearance of severe infections in patients with known immunodeficiency, and IV administration at physiologic replacement doses of 400-500 mg/kg is most appropriate.Disorders Predominantly Affecting Cellular Function
Although less common than antibody defects, predominantly cellular immune defects may also be encountered by the pediatric intensivist. The cardinal clinical features of T-cell dysfunction are fungal infections, chronic viral infections, opportunistic infections, autoimmune disorders, and malignancies.
Dysgammaglobulinemia is a frequent consequence of T-cell dysfunction, given the necessary role of T-cell signaling for immunoglobulin class switching and affinity maturation.
Infants with DiGeorge syndrome (DGS) and velocardiofacial syndrome have a characteristic 22q11.2 deletion and frequently manifest T-cell deficiency. The 22q11.2 deletion syndrome is the most common cellular immune defect that is likely to present to the pediatric intensivist as a result of congenital heart disease and/or hypocalcemia.Immunodeficiency with Cytotoxic Defects
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are both characterized by uncontrolled inflammation.
MAS is typically seen in patients with autoimmune disease and often resolves with aggressive treatment of the underlying autoimmune disorder.
Immunodeficiency with Combined Antibody and Cellular Defects
Combined antibody and cellular immune deficiencies are generally characterized by the early onset of viral and fungal infections, usually resulting in growth failure.
The intensive care of an infant suspected or known to have severe combined immunodeficiency (SCID) should include strict isolation and the use of only irradiated, CMV-negative, and leukocyte-depleted blood products.
The infant with SCID may benefit from aggressive antiviral therapies in addition to antibiotics and intravenous immunoglobulin (IVIG). An immunologist or hematologist should be involved early in the care of these infants to facilitate arrangements for HSCT, the most successful therapy for SCID.
Early recognition of a combined immunodeficiency is extremely important not only for treating the infections but in directing care, as there is no uniform approach to treating these disorders.Disorders Affecting Phagocyte Function
Primary neutrophil disorders may also be encountered by the intensivist and may be divided into two broad categories: diseases associated with decreased numbers of neutrophils (neutropenia) and those with impaired neutrophil function.
Complement Deficiency
Complement deficiencies are likely to present to the intensivist in the form of invasive infections (most notably meningococcal disease), hereditary angioedema (HAE), or rheumatologic disorders, especially systemic lupus erythematosus (SLE).
In addition to deficits in the classical complement pathway, deficiencies in mannan-binding lectin (MBL) may also contribute to disease states relevant to the pediatric critical care provider, including sepsis, Kawasaki disease, and autoimmune disorders.
C1 esterase inhibitor concentrate infusion therapy can be lifesaving for children with acute upper airway obstruction or severe gastrointestinal symptoms secondary to HAE.Innate Immune Signaling Defects
Primary immunodeficiencies associated with impaired toll-like receptor (TLR) signaling have been described; infections can range from mild to severe, including herpes encephalitis.Immunodeficiency and Cancer Predisposition
Several primary immune deficiencies, including Wiskott-Aldrich syndrome (WAS), ataxia telangiectasia, SCID, Kostmann syndrome, and X-linked lymphoproliferative disease (XLP) are associated with an increased risk of cancer.
The mechanisms contributing to this association are not completely understood and are likely multifactorial in origin.Immunologic Effects of Cancer and Its Treatment
Most cancer patients are immunocompromised as a result of their underlying disease and/or their antineoplastic therapy.
Several cancer treatment-related factors, including neutropenia, loss of mucosal integrity, and T-cell dysfunction, contribute to this immunocompromised state.Immune Dysfunction Associated with Hematopoietic Stem Cell Transplant
Immune suppression is most severe among those patients who receive an allogeneic HSCT. The replacement of the functional lymphohematopoietic system of the host with that of a donor requires intense immunosuppression, often in a patient whose underlying disease has rendered him or her immunocompromised.
HSCT patients remain profoundly immunocompromised until effective immune reconstitution occurs, which is a complex and prolonged process that requires months to years.
Immune reconstitution following HSCT is influenced by patient-, disease-, and transplant-related factors. Importantly, cellular reconstitution does not necessarily correlate with functional recovery.
PRIMARY OR CONGENITAL IMMUNE DEFICIENCY DISORDERS
The pediatric intensivist is frequently confronted with severe and life-threatening infections. While the majority of these infections can be attributed to environmental risk factors and invasive monitoring, immune deficiency is a consideration in 
select cases. The incidence of congenital immune deficiency is estimated to be from 1 in 10,000 to 1 in 2000 live births (1), but these children are overrepresented at tertiary care centers where expert immunologic care is available. The intensivist should recognize a child presenting with a second invasive bacterial infection, an opportunistic infection or an infection slow to respond to conventional therapy as a patient in need of an immunologic 
workup. With antibody defects being the most prevalent type of immune deficiency, laboratory evaluation should generally focus first on the possibility of humoral defects. Specific pathogens and characteristic host responses, however, may indicate the likelihood of a cellular, phagocytic, or innate immune defect. A summary of the diseases addressed in this chapter can be found in Table 86.1. Excellent reviews of primary immune deficiency are readily available and have been published previously (2,3).
select cases. The incidence of congenital immune deficiency is estimated to be from 1 in 10,000 to 1 in 2000 live births (1), but these children are overrepresented at tertiary care centers where expert immunologic care is available. The intensivist should recognize a child presenting with a second invasive bacterial infection, an opportunistic infection or an infection slow to respond to conventional therapy as a patient in need of an immunologic workup. With antibody defects being the most prevalent type of immune deficiency, laboratory evaluation should generally focus first on the possibility of humoral defects. Specific pathogens and characteristic host responses, however, may indicate the likelihood of a cellular, phagocytic, or innate immune defect. A summary of the diseases addressed in this chapter can be found in Table 86.1. Excellent reviews of primary immune deficiency are readily available and have been published previously (2,3).DISORDERS PREDOMINANTLY AFFECTING IMMUNOGLOBULINS
Defects predominantly affecting antibody production and function comprise 65% of the congenital immunodeficient 
population (4). Included within this category are defects of questionable clinical significance, such as isolated IgM deficiency, isolated IgA deficiency, and IgG subclass deficiencies. Only the disorders involving quantitative total IgG deficiency and predictable immunologic consequences are discussed here. Antibody defects predispose patients to sino-pulmonary 
infections with encapsulated organisms, such as Streptococcus pneumoniae and Haemophilus influenzae. The patient presenting with severe pneumonia, which has been poorly responsive to antibiotic therapy, deserves quantitative assessment of immunoglobulin (IG) levels. Bacterial sepsis would be a less common presentation of an antibody defect, but poor responsiveness to therapy might again raise this concern.
population (4). Included within this category are defects of questionable clinical significance, such as isolated IgM deficiency, isolated IgA deficiency, and IgG subclass deficiencies. Only the disorders involving quantitative total IgG deficiency and predictable immunologic consequences are discussed here. Antibody defects predispose patients to sino-pulmonary infections with encapsulated organisms, such as Streptococcus pneumoniae and Haemophilus influenzae. The patient presenting with severe pneumonia, which has been poorly responsive to antibiotic therapy, deserves quantitative assessment of immunoglobulin (IG) levels. Bacterial sepsis would be a less common presentation of an antibody defect, but poor responsiveness to therapy might again raise this concern.X-linked Agammaglobulinemia
Since the original description of X-linked agammaglobulinemia (XLA) in 1952 by Colonel Ogden Bruton (5), significant advances have facilitated the accurate diagnosis and effective therapy of XLA. This defect occurs at an estimated incidence of 1 in 190,000 live male births based on birth rate data from a recent US XLA registry (6). Due to the persistence of maternal immunoglobulin, most XLA
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