IMMUNODEFICIENCY DISORDERS

Increased susceptibility to usual or unusual infections (opportunistic infections) is the clinical hallmark of immunodeficiency disorders. These disorders may involve qualitative or quantitative deficiency of any one or more component of the immune system (Table 8.1).

a. Primary immunodeficiency disorders (PID) are rare genetic defects with overall frequency of ~1#8725;10,000 children, including B-cell defects (50%), T-cell defects (3O%), phagocytic disorders (18%) and complement disorders (lt;2%). Family history of similar illness or consanguinity is often present in these cases. Till date over 400 PIDs are known and the list is expanding. Table 8.2 lists warning signs for suspecting PIDs in children.

b. Secondary immunodeficiency states are relatively more common and usually involve more than one component of immune system. Viral infections, e.g. measles, malnutrition and steroid therapy are three important causes of transient immunodeficiency, while more severe and persistent defects are seen in HIV/AIDS, splenic dysfunction and malignancies. Common congenital immunodeficiency disorders

are discussed here, while acquired defects have been discussed in relevant chapters on primary diseases.

• Four or more new ear infections within one year

• Two or more serious sinus infections within one year

• Two or more months on antibiotics with little effect

• Two or more pneumonias within one year

• Failure of an infant to gain weight or grow normally

• Recurrent, deep skin or organ abscesses

• Persistent thrush in mouth or fungal infection on skin

• Two or more deep-seated infections including septicemia

• Family history of primary immunodeficiency (PID)

I. Phagocytic Disorders

Phagocytic disorders include quantitative phagocytic cell deficiency, e.g.

Clinically, these defects usually present with recurrent mucus membrane infections, e.g. gingivitis, or superficial/ deep abscesses due to pyogenic or gram-ve organisms. Absence of pus formation despite severe infection is a hallmark of leukocyte migration defect. Other indicators of phagocytic disorders are poor wound healing and delayed separation of umbilical cord in newborn.

Diagnosis of phagocytic defects depends on: (a) abnor­mal neutrophil count and morphology, (b) nitroblue tetrazolium test for intracellular phagocytic capacity, and

(c) in vitro tests for neutrophil functions, e.g. chemotaxis, phagocytosis and microbiocidal activity.

Persistent neutrophilia or persistent neutropenia are indicative of leukocyte adhesion deficiency-I or severe congenital neutropenia-II important phagocytic defects, respectively.

Management of these disorders include: (a) Long-term antibiotic prophylaxis or recombinant interferon (IFN-#947;) therapy, (b) colony stimulating factors (G-CSF, GM-CSF) in leukopenic states, and (c) stem cell transplantation in selected cases.

Some important inherited phagocytic disorders are as follows:

Chronic granulomatous disease of childhood (CGDC) is an X-linked or autosomal recessive disorder, characte­rized by defective intracellular killing of microbes within phagocytes due to abnormal oxidative metabolic responses. Most cases present in early infancy with: (a) serious, recurrent or persistent infections, (b) perioral/ anal eczema, and (c) hepatosplenomegaly.

Chediak-Higashi syndrome is an autosomal recessive disorder of defective chemotaxis, degranulation and intracellular killing. Apart from recurrent infections in early childhood, these cases are associated with: (a) oculocutaneous albinism, (b) neurological abnormalities, e.g. mental retardation, pyramidal/cerebellar signs, peripheral neuropathy, etc. and (c) neutrophils with giant cytoplasmic granules.

Cyclic neutropenia is an autosomal dominant disorder, characterized by Cyclicalfluctuations in peripheral neutrophil counts between normal and neutropenic values (lt;500/ mm³) with mean oscillatory period of 21 days. During neutropenic phase, child may suffer from mild problems, e.g. oral ulcers, pharyngitis, lymphadenopathy, etc. or more serious infections, e.g. pneumonia. Cycles become less noticeable with advancing age, changing into chronic neutropenia.

Hyper IgE syndrome (Job's syndrome) is a rare disorder of chemotaxis and opsonization, characterized by elevated IgE levels (gt;2000 mg/dl), eosinophilia, recurrent staphylococcal abscesses of skin/deeper tissues and atopic dermatitis.

Lazy leukocyte syndrome is a rare disorder of chemotaxis and neutrophil migration from bone marrow, despite adequate bone marrow reserves.

II. Complement Disorders

Complement disorders are rarely congenital, seen more commonly as acquired defects due to:

• Deficient production, e.g. in newborns, PEM and chronic liver diseases,

• Defective function, e.g. in sickle cell disease,

• Increased consumption or loss, e.g. in septicemia, burns, SLE and nephrotic syndrome.

Clinically, these cases present with recurrent pyogenic or neisserial infections, frequently associated with immune complex disorders (lupus-like illness) and vasculitis syndromes.

Diagnosis is established by assessing CH₅₀ activity with control or direct C₃-C₄ immunoassays. Genetic workup is needed to identify inherited complement disorders, most of whom are autosomal recessive except properdin deficiency (X-linked).

Management is non-specific, as complement replacement therapy is not available and includes: (a) prolonged antibiotic therapy during infections and (b) immunization against capsular organisms, e.g. pneumococci or meningococci.

Hereditary angioedema is an important autosomal dominant defect of C₁ inhibitor deficiency with unrestricted complement activity.

III. B-Cell Disorders

B-cell disorders, also termed humoral deficiency states, may involve all or selective antibody classes, either due to abnormal B-cell differentiation (quantitative) or inability to respond against a specific antigen (qualitative). Many cases are secondary to T cell defects.

Clinically, these cases present with variable severity of recurrent sinopulmonary infections or bacteremia, usually due to encapsulated organisms, e.g. S. pneumoniae, H. influenzae and Staph. aureus. These disorders do not manifest in first 3 months of life due to presence of transplacental antibodies from mother.

Diagnosis is usually established by measured nonspecific immunoglobulin levels or specific antibody titers after vaccination, e.g. DPT.

Management of these cases includes: (a) IVIG therapy (400-500 mg/kg/month) and (b) prophylactic antibiotics. Some important and common B-cell disorders are as follows:

Transient hypogammaglobulinemia indicates deve­lopmental delay in immunoglobulin production during early infancy, perhaps due to delayed maturation of T helper cells. This leads to accentuated physiological nadir in immunoglobulin levels at 3-5 months (lt;200 mg/dl), with spontaneous recovery by 18-24 months.

Bruton (X-linked) agammaglobulinemia, seen only in males, is a maturation defect from pre-B-cell stage to mature B-cell stage, characterized by severe hypogammaglobulinemia and absence/hypoplasia of lymphoid tissue, manifesting in late infancy or early childhood.

Common variable immunodeficiency disorder (CVID) is a maturation defect from mature B-cell stage to plasma cell differentiation, characterized by: (a) late onset after the first decade of life, (b) normal or enlarged lymphoid tissue, (c) frequently associated with splenomegaly, autoimmune disorders, e.g.

Selective IgA deficiency is commonest (1:600) but rarely a symptomatic B-cell defect, characterized by low serum IgA levels (lt;5-10 mg/dl). Symptomatic cases present with recurrent sinopulmonary infections, food allergy and autoimmune/rheumatologic disorders.

Hyper IgM syndrome is characterized by inability to produce antigen-specific antibody response despite elevated IgM and normal IgG/IgA levels, due to a genetic T-cell defect in activating B-cell response. Apart from sinopulmonary infections, hematologic autoimmune disorders or intracellular infections, e.g. tuberculosis are common.

IV. T-cell Disorders

T-cell defects present with widest clinical spectrum, due to their role in activating almost all immunological components.

Clinically, these patients usually present with: (a) fungal or intracellular infections, e.g. mycobacteria, due to defective phagocytic activation, (b) viral infections due to decreased NK-cell activity, and (c) opportunistic infections due to impaired B cell activation and immunoglobulin production.

Diagnosis of T cell defects depend on quantitative T cell and sub-cell counts, in vivo T-cell function tests, e.g. tuberculin test, candida skin test, phytohemagglutination assay (PHA), and in vitro tests, e.g. lymphokines assay, etc. Many of these defects may be diagnosed prenatally, e.g. Severe combined immunodeficiency disorders or Wiskott-Aldrich syndrome.

Treatment of choice for severe T-cell defects is bone marrow transplant, though gene therapy has been successful in some cases. IVIG therapy is indicated in cases with co-existing humoral immunodeficiency. Common T-cell defects are rarely isolated, usually associated with other immune disturbances and include:

DiGeorge syndrome is characterized by: (a) thymic aplasia due to 3^rd/4^th pharyngeal arch dysgenesis, (b) hypocalcemic tetany due to parathyroid dysgenesis, (c) cardiac cono-truncal or aortic arch abnormalities, e.g.

Severe combined immunodeficiency disorders (SCID) is a heterogeneous group of genetic disorders, characterized by: (a) absent T-and NK-cells in peripheral blood, (b) severe hypogammaglobulinemia despite normal B cell count, and (c) severe lymphoid hypoplasia. Most cases present since neonatal period with failure to thrive, severe bacterial infections, chronic mucocutaneous candidiasis, intractable diarrhea, opportunistic infections, e.g. Pneumocystis jiroveci pneumonia and eczematous skin disorders.

Wiskott-Aldrich syndrome is an X-linked defect of T-and B-cell dysfunction, associated with thrombocytopenia and eczema. IgE and IgA levels are raised, with low IgM levels. Most patients manifest in early infancy with severe bleeding or opportunistic/recurrent infections.

Chronic mucocutaneous candidiasis is an autosomal recessive defect of T-cell proliferation and function with normal B-cell count, presenting as chronic/recurrent mucocutaneous candidiasis in early childhood, with autoimmune endocrinopathies, e.g. Addison's disease or hypoparathyroidism.

8.3