Porth's Essentials of Pathophysiology, 4e

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Infection and Immunity

U N I T 4

Immunodeficiency Disorders Immunodeficiency can be defined as an abnormality in one or more components of the immune system that renders a person susceptible to diseases normally pre- vented by an intact immune system. These disorders can be broadly classified into two groups: primary and secondary. 1 The primary or congenital immuno- deficiencies are genetic defects that result in increased susceptibility to infection that is frequently manifested early in life. Secondary or acquired immunodeficiency is not inherited but develops as a consequence of mal- nutrition, selective loss of immunoglobulins through the gastrointestinal or genitourinary tracts, treatment with immunosuppressant drugs, or human immuno- deficiency virus (HIV), the etiologic agent of acquired immunodeficiency syndrome (AIDS). Regardless of the cause, primary and secondary deficiencies can produce the same spectrum of disease. The severity and symp- tomatology of the various disorders depend on the type and extent of the deficiency. Until recently, little was known about the causes of primary immunodeficiency diseases. However, this has changed with recent advances in genetic technol- ogy. 1,32–35 To date, more than 180 primary immunode- ficiency syndromes have been identified, and specific molecular defects have been identified in more than one third of these diseases. 1 Most are transmitted as recessive traits, caused by mutations in genes on the X chromosome or autosomal chromosomes. Many of these disorders have been traced to mutations affect- ing signaling pathways (e.g., cytokines and cytokine signaling, receptor subunits, and metabolic pathways) that dictate immune cell development and function. Furthermore, it has been shown that the immune sys- tem is a carefully balanced system that is designed to distinguish between self and nonself; therefore, symp- toms of autoimmunity often are observed with primary immunodeficiency disease. Early detection, which is possible for most pri- mary immunodeficiency diseases, is critical for the success of some treatments and can be lifesaving. For infants with severe combined T- and B-cell immuno- deficiency, early diagnosis is essential in terms of not only preventing life-threatening infections, but also preventing administration of live attenuated virus vaccines (e.g., measles, mumps, rubella, varicella), which could prove fatal. 35 The first clinical clue for the diagnosis of a primary immunodeficiency disease is usually a history of infections that are persistent, difficult to treat, or caused by unusual microbes. The Jeffrey Modell Foundation/Immune Deficiency Foundation has developed a set of warning signs that serve as an excellent tool for determining what should be considered abnormal (Chart 16-2). 36 Because these Primary Immunodeficiency Disorders

CHART 16-2   TenWarning Signs of Primary Immunodeficiency

■■ Four or more new ear infections within 1 year ■■ Two or more serious sinus infections within 1 year ■■ Two or more months on antibiotics with little effect

■■ Two or more pneumonias within 1 year

■■ Failure of an infant to gain weight or grow normally

■■ Recurrent, deep skin or organ abscesses

disorders are frequently inherited, a positive family history is also a key diagnostic tool. The type of infec- tion can provide information regarding the type of defect that is present. Infections with bacterial organ- isms are frequently observed in cases of antibody defi- ciency, whereas severe viral, fungal, and opportunistic infections characterize T-cell deficiencies. Recurrent Streptococcus pneumoniae or Neisseria infections characterize persons with complement deficiencies, and recurrent infections with staphylococcal and other catalase-positive organisms indicate disorders of phagocytosis. Humoral (B-Cell) Immunodeficiency Disorders Of all the primary immunodeficiency diseases, those affecting antibody production and humoral immunity are the most common. 35 Antibody production depends on the differentiation of hematopoietic stem cells into mature B lymphocytes and the antigen-dependent gen- eration of immunoglobulin-producing plasma cells 37,38 (Fig. 16-6). This maturation cycle initially involves the production of surface IgM, migration from the bone marrow to the peripheral lymphoid tissue, and switching to the production of specialized IgM-, IgA-, IgD-, IgE-, or IgG-secreting plasma cells after antigenic stimulation. Primary humoral immunodeficiency disor- ders can interrupt the production of one or all of the immunoglobulins. Defects in humoral immunity increase the risk of recurrent pyogenic infections, including those caused by S. pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas species. Humoral immunity usually is not as important in defending against intracellular bacteria (mycobacteria), fungi, and protozoa. Viruses usually are handled nor- mally, except for the enteroviruses that cause gastroin- testinal infections. ■■ Persistent thrush in mouth or fungal infections of the skin ■■ Need for intravenous antibiotics to clear infections ■■ Two or more deep-seated infections including septicemia ■■ A family history of primary immunodeficiency These warning signs were developed by the Jeffrey Modell Foundation Medical Advisory Board. Consultation with primary immunodeficiency experts is strongly suggested. © Jeffrey Modell Foundation.