IMMUNODEFICIENCY DISORDERS: OBJECTIVES

1. THE STUDENT SHOULD KNOW THE TWO MAJOR CATEGORIES OF I.D. (PRIMARY AND SECONDARY) AND MAJOR EXAMPLES OF BOTH. The two main categories of immunodeficiency disorders are primary immunodeficiency and secondary immunodeficiency. The former manifests itself in infancy/childhood, as it is a result of an inherent genetic or congenital defect in the components of the immune system or its products. Many are as a result o X-linked inheritance; thus, greater percentage presenting in males. On the other hand, the latter is a result of the effects of environmental agents/external agents on a previously functional immune system. The secondary disorders are much more common than the primary disorders. However, a major example of a primary immunodeficiency is SCID. SCID is Severe Combined immunodeficiency. It affects both T and B cells. It is often fatal because the there is no resistance to disease and/or infection. An example of a secondary immunodeficiency is AIDS. Again, this disease illustrates the point that there was, previously, a functional immune system. In the secondary disorders, the immune system can be compromised by either host factors (age, severe stress, splenectomy, thymectomy, disease states/neoplasia), or environmental factors (malnutrition, infections, drugs, and/or radiation). In the case of AIDS, the immune system is weakened following the infection of the HIV. 2. FOR THE PRIMARY I.D., THE STUDENT SHOULD KNOW HOW THESE ARE SUBGROUPED, AND BE FAMILIAR WITH PRIMARY FEATURES, LABS, AND HISTOLOGICAL FEATURES Primary immunodeficiency disorders can be grouped in a way to distinguish what arm of the immune system is faulty. For example, here are some of the following categories: a. B cell (antibody) deficiencies: 50-70% b. T cell deficiencies: 30% c. Combined B and T cell- very problematic d. Phagocyte defects- 18% e. Complement System defects- 2% To evaluate all deficiencies, you want to take a detailed H and P. The routine screening tests include a CBC with differential and platelet count, IG levels, assessment of antibody response, and evaluation of infections and/or underlying diseases that might be present to paint this particle clinical picture. Specific lab tests are as follows: a. B cell deficiency- IG levels, Isoagglutinin titers, and response to vaccines b. T cell deficiency- Lymphocyte count and morphology, DTHR, Chest X-Ray c. Phagocyte Deficiency- WBC count and morphology, NBT dye test, and IgE level d. Complement Deficiency- CH 50 levels, along with C3 and C4 levels. B cell Deficiency Disorders/Diseases Q: A 5 month old boy comes into clinic with recurrent pyogenic infections of the lungs, sinuses, and bones. Most of the bugs that have been cultured have been of pneumococcal, haemophilus, and streptococcus nature. There is a little bit of IgG, but there is a marked absence of IgM, A, D, and E. There are also low/absent B cells in the periphery. What is it? A: Brutons/X-linked agammaglobulinemia

Q: A child is brought in by her mother. She has had recurrent respiratory and chronic diarrhea. You measure her Ig titers and she has a marked reduction in her serum IgA. All the other IgG are within normal limits. What is it? A: Isolated IgA deficiency Q: An adult presents to clinic with significant HX of otitis media and pneumonia. His current medical condition is sclerosing cholangitis. He also complains that he has had some trouble with fighting off viral infections; they tend to last a little bit longer than usual. When serum/blood is taken, his neutrophil levels are lower than normal (neutropenia), as well as the fact that he has low levels of Ig A, IgG. However, his levels of IgM are elevated. What is it? A: Hyper IgM deficiency Q: A 25 year-old female presents to clinic with significant history of respiratory infections in the last two years. She is currently taking antibiotics to treat S pneumonia and is not feeling any better. You draw blood and find that she has no plasma cells and her IgG level is 100. In her chart, you note that she also has IgA deficiency. What is her DX? A: Acquired aggamaglobulimenia T cell Deficiency Diseases Q: A 1 year-old boy presents to clinic with significant history of viral infections. His chart notes that he has hypoparathyroidism and that he has a VSD (Ventricle Septal Defect). His appearance is markedly different. He has low and misshapen ears, as well as the fact that he has fish-like mouth. A lymph node biopsy shows hypoplastic T-cell dependent areas in lymph nodes. What is your diagnosis? A: DiGeorges Syndrome Q: A 3 year-old girl presents to clinic with significant history of Candida infections. Her mother informs you that the majority of these infections have affected her eyelids and nails. Her mom does not remember if she has had any endocrinopathy associated with the infections. Her PPD test is negative, and, when measured, her antibody levels to Candida are within normal limits. What is her DX? A: Chronic mucocuteneaous candidiasis Combined T cell and B cell deficiency disorders Q: When performing an autopsy on a 3 month old boy, the chary notes that the child had had both persistent bacterial and viral infections. The lamina propia of the S.I. was greatly damaged and resulted in chronic diarrhea. What is your DX? A: SCID Of note, there are congenital autosomal recessive or X-linked variants of this disease, which do not necessarily lead to a failure to thrive. Phagocyte Defects: Q: An 18 month year-old boy presents to clinic with significant history of widespread granulomatous lesions of the skin and lymph nodes. Upon CBC and Antibody levels examination, there is marked anemia and hypergammaglobulinemia. What is your diagnosis? A: Chronic granulomatous disease

Complement Deficiency: Q: A 28 year-old African-American female presents to clinic with significant history of S.L.E. A: S.L.E. Associated with complement deficiency-lower levels because the demand is outweighing the supply. 3. FOR THE SECONDARY I.D., THE STUDENT SHOULD BE ABLE TO LIST THE GENERAL CAUSES AND GIVE EXAMPLES OF PARTICULAR DISORDERS, WITH LABS AND HISTOLOGICAL FEATURES The two major ones that she mentioned in her handouts/in class are AIDS and Malnutritionrelated Immunodeficiency. Two other secondary immunodeficiency disorders are related to splenic deficiency syndromes and drug/radiation related deficiency. AIDS is caused by the Human Immunodeficiency Virus, while the latter is related to malnutrition (of note: leading cause of infant and child death worldwide). The cells that are damaged in AIDS are mainly the CD4 T-cells, but also macrophages (long-term reservoir. In the case of malnutrition-related immunodeficiency, it is primarily a T-cell deficiency with cutaneous anergy (no DTHR), low T cell levels, poor proliferative responses to mitogens and antigens, and deficiency of interferon/lymphokines and cytotoxic activity. In both cases, the degree of immune impairment depends on duration of disorder and other underlying illnesses, infections, and/or diseases. However, in the case of malnutrition, the defect can be reversed with nutritional rehabilitation. This is not the case for AIDS. 4. THE STUDENT SHOULD KNOW WHAT IS INVOLVED WITH A BASIC EVALUATION FOR I.D., INCLUDING THE MAJOR CLINICAL LABS AND HISTOLOGICAL TECHNIQUES USED TO ASSESS THE IMMUNE FUNCTION IN EACH CASESEE ABOVE 5. FROM DE PALMAS LECTURE: THE STUDENT WILL KNOW THE BASIC NATURAL HISTORY OF HIV-INFECTION, ITS EFFECTS ON THE PERIPHERAL BLOOD CD4 LYMPHOCYE COUNT AND ON LYMPH NODE HISTOLOGY AND KNOW THE CRITERIA FOR DIAGNOSING AIDS HIV is the virus that causes AIDS. AIDS is a secondary immunodeficiency disorder. HIV is diagnosed in a 2 step mechanism. The first step is very sensitive test; it is a protein test, i.e. an ELISA test to the antibody produced against HIV. If it is positive, a second test is performed. This test is very specific in that it is a RNA and/or viral assay. There can be problems in this testing schematic depending on when the initial test is performed; there is a window period (the body has not started developing antibodies to the disease yet). AIDS is a definition. The CDC now looks predominately, or defines AIDS as opposed to being HIV +, as CD4 T-cell count less than 200 cells per micro-liter. However, AIDS used to be also defined by the presence of co-morbid conditions like P. carinii. Since AIDS patients are immunocompromised, there is a higher prevalence of TB (pandemic), MAC, and cytomegalovirus as co-morbid conditions. In AIDS, there is often no response to tests for CMI (anergy). Initially, there might be hyperplasia of lymph node (interfollicular hyperplasia). However, as the disease progresses, there is atrophy of the lymph nodes and lymphocytopenia (THINK SPARSE). However, there is a background of plasma cells and Russell bodies.