Allergy and Immunology

Allergy and Immunology

Abbreviations

ABPA	Allergic bronchopulmonary aspergillosis
APC	Antigen-presenting cell
AIRE	Autoimmune regulator
APS	Autoimmune polyglandular syndrome
AR	Autosomal recessive
CGD	Chronic granulomatous disease
C1INH	C1 esterase inhibitor
CVID	Common variable immunodeficiency
EBV	Epstein-Barr virus
ELISA	Enzyme-linked immunosorbent assay
FESS	Functional endoscopic sinus surgery
HIM	Hyperimmunoglobulin M
HIV	Human immunodeficiency virus
HLA	Human leukocyte antigen
ICF	Immunodeficiency centromeric instability and facial anomalies
ICOS	Inducible T-cell costimulator gene
IFN	Interferon
IL	Interleukin
IVIG	Intravenous immunoglobulin (IgG)
LAD	Leukocyte adhesion deficiency
LPS	Lipopolysaccharide
MCP	Monocyte chemoattractant protein
MHC	Major histocompatibility complex
NARES	Nonallergic rhinitis with eosinophilia syndrome
NK	Natural killer
NSAID	Nonsteroidal anti-inflammatory drug
PAMP	Pathogen-associated molecular patterns
PCP	Pneumocystis jiroveci pneumonia
PSS	Progressive systemic sclerosis
RANTES	Regulated on activation, normal T-cell expressed, and secreted chemokine
SADNI	Specific antibody deficiency with normal immunoglobulins
SCID	Severe combined immunodeficiency
TACI	Transmembrane activator, calcium modulator, and cyclophilin ligand interactor
TLR	Toll-like receptor
UP	Urticaria pigmentosa
WHIM	Warts, hypogammaglobulinemia, infection, myelokathexis
XLA	X-linked agammaglobulinemia
XLP	X-linked lymphoproliferative syndrome

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Definitions

Define the following:
Innate immunity	Hard-wired responses encoded by host germ-line genes that recognize patterns on many foreign microbes (nonspecific immunity)
Adaptive immunity	Responses encoded by gene elements that have undergone rearrangement resulting in assembly of antigen-binding structures with high specificity for unique microbial antigens (specific immunity)
Chemokines	Small molecules that induce chemotaxis through G protein–coupled receptors
Antigen	A protein (or carbohydrate) recognized by the immune system
Immunoglobulins	Protein products of mature plasma cells
Antibodies	Immunoglobulins that recognize specific antigens
MHC	The major histocompatibility complex (MHC), or HLA in humans, is the genetic region housing the loci of genes encoded on chromosome 6 (HLA I, II, III). They are responsible for generating cell surface glycoproteins that bind peptides made in cells (MHCI) or ingested by cells and processed (MHCII). These glycoproteins are necessary for the presentation of foreign proteins to T lymphocytes. The absence of MHC may cause a severe immunodeficiency. The presence of different forms (polymorphisms) is associated with the potential for specific disease states (e.g., HLA-B27 and ankylosing spondylitis).

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Basic Immunology

What makes the basic function of the immune system possible?	Recognition of self from nonself by key effector systems
List four nonspecific components of the innate immune system	Physical barriers (e.g., skin) Complement Phagocytic cells, many with TLRs that recognize microbial patterns Cytokines
Where do lymphocytes arise?	All lymphocytes arise in bone marrow; 85% are T cells.
Where do lymphocytes undergo maturation?	T cells mature in the thymus and B cells mature in the fetal liver and adult bone marrow.
What is the function of T cells (cell-mediated immunity)?	To facilitate resistance to intracellular microorganisms (e.g., mycobacteria, viruses, fungi, and parasites) and tumors and to regulate specific antibody production by B cells
What is the difference between CD4+ and CD8+ T cells?	Located on the cell surface, CD4 and CD8 receptors are important in determining the recognition of antigen. T cells bearing CD4 can recognize only antigen embedded in MHC class II, which is found only on the surface of a few specialized cells (APCs). T cells bearing CD8 recognize antigen on MHC class I, which is found on all nucleated cells.
What cell markers might be useful clinically?	CD3, a marker used for all T cells. CD4, a marker for T-helper cells. It generally defines 60% to 70% of T cells in the peripheral blood and lymphoid tissue and is the receptor for HIV. CD8, a marker for cytotoxic T cells. CD19 or CD20, B-cell markers. CD16 and 56, markers for NK cells.
What is the difference between T- and B-cell markers?	T-cell markers (e.g., CD4 and CD8) have functional significance, whereas B-cell markers (e.g., CD19 and CD20) are primarily of maturational significance.
What is the function of B cells (humoral immunity)?	To mature into plasma cells and produce antibody. They can also act as macrophages and APCs.
What are the five major classes (isotypes) of immunoglobulins?	IgA, IgD, IgE, IgG, and IgM
What is the basic structure of immunoglobulins?	A combination of two heavy chains and two light chains
What are the two types of light chains?	Kappa and lambda
What is the role of immunoglobulin?	Recognition and binding of specific extracellular antigens and activation of cells or of the complement-binding system
What are the three phases of the immune response?	Recognition, amplification, and response
Describe each phase of the immune response:
Recognition	Foreign antigen patterns (e.g., bacterial LPSs) are recognized by the innate immune system.
Amplification	Signals are generated leading to the release of cytokines that attract other immune components to the site of foreign invasion.
Response	The stimulating antigen is cleared from the system by effector mechanisms such as inflammation, further innate effector mechanisms (e.g., phagocytosis), and initiation of the adaptive immune response.
What are the basic mast cell products?	Granule-associated mediators (e.g., histamine, tryptase, heparin), lipid derived mediators (e.g., leukotrienes), cytokines/chemokines (e.g., IL-5)
What are the effectors of an IgE-mediated response?	Mast cells, basophils, and eosinophils. Mast cells and basophils are the source of histamine and leukotrienes released in an allergic response. Eosinophils are important in the IgE-mediated killing of helminths. IgE and eosinophils are both produced in response to cytokines expressed by Th2 cells.
What does complement do?	Complement, a component of the innate immune system, lyses pathogens via the membrane activation complex (MAC) in the absence of specific immunity, opsonizes pathogens to target them for destruction, and recruits other cells and proteins to help with target destruction.

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Immunodeficiency

How are primary immunodeficiencies involving known molecular defects classified?	Antibody/B cell deficiencies [Bruton's X-linked agammaglobulinemia, AR agammaglobulinemia, CVID (ICOS and TACI deficiencies), HIM (AR), ICF syndrome] Cellular deficiencies (IFN-γ/IL-12 axis, APS type 1, defective NK function) Combined [SCID, Wiskott-Aldrich, DiGeorge, ataxia telangiectasia, HIM (AR), XLP syndrome, WHIM syndrome, caspase 8 deficiency] Complement Phagocytic (CGD, Chediak-Higashi syndrome, LAD, specific granule deficiency, cyclic neutropenia, X-linked neutropenia)
What are some common primary immunodeficiencies with no known molecular defect?	Selective IgA deficiency CVID SADNI Hyper-IgE syndrome Cartilage hair hypoplasia Idiopathic CD4 lymphocytopenia (Nezelof syndrome)
What are common causes of secondary immunodeficiency?	Immunosuppression (chemotherapy, steroids, immunomodulators, antilymphocyte antibodies) Infections (HIV, herpes, parasites) Malignancy (Hodgkin's, leukemia, myeloma) Autoimmune disease (diabetes, lupus) Malnutrition Environmental exposure (radiation, chemical) Other (uremia, intestinal lymphangiectasia, pregnancy, aging, stress, hyposplenism)
In general, what does a history of contact dermatitis (e.g., poison ivy) suggest?	Intact cellular immunity
What is a simple test for T-cell function?	The “anergy” panel skin test (e.g., PPD, Candida, Trichophyton, tetanus toxoid, saline control) is a measure of delayed-type hypersensitivity; a positive test requires intact T-cell function.
What interferes with an anergy panel?	Corticosteroids (topical or higher-dose systemic) Anticoagulants (induration is the result of fibrin deposition) Technique (failure to place antigen intradermally) Infection (HIV, EBV, TB, leprosy) Autoimmune disease (sarcoid, lupus, rheumatoid arthritis) Malnutrition Pregnancy Malignancy (e.g., Hodgkin's lymphoma)
What assays are available to test for T cells?	Flow cytometry for CD3, CD4, CD8, CD45, T-cell receptor
What assays are available to test for B cells?	CD19, CD20, CD21, Ig-associated
What assays are available to test for NK cells?	CD16/CD56
What assays are useful in the evaluation of patients with borderline IgG levels or recurrent sinopulmonary bacterial infections?	Pre- and postimmunization pneumococcal, diphtheria, tetanus titers, isohemagglutinins
What is the treatment for IgA deficiency?	Antibiotics for specific infections and, sometimes, prophylactic antibiotics. IgA-deficient patients who are unable to mount a response to polysaccharide vaccines are occasionally given IVIg.
Are blood transfusions safe in patients with IgA deficiency?	No. Some IgA-deficient patients with anti-IgA antibodies are at increased risk of a severe reaction to trace IgA from IVIg and from blood transfusions (washed packed cells should be given if transfusion is needed).
What constitutes the diagnosis of CVID?	Total serum IgGs are reduced to >2 standard deviations below the age-adjusted mean as well as impaired production of specific antibodies (isohemagglutinins or poor response to vaccines above).
What infections are seen in IgG deficiencies?	Most common, sinopulmonary infections Common, central nervous system, joint, and gastrointestinal tract infections
What organisms are the most common causes of infection in patients with IgG deficiencies?	Most common, encapsulated bacteria such as Haemophilus influenzae or Streptococcus pneumoniae Common, Staphylococcus aureus, meningococci, Pseudomonas, Campylobacter, Ureaplasma, and Mycoplasma, Giardia
Are persons with IgG deficiencies more susceptible to viral infections?	As a rule, no. However, IgG-deficient patients are susceptible to polioviruses (and should not receive live virus vaccine) and to hepatitis B and C. In patients with XLA (but not CVID or HIM), a chronic meningoencephalitis, which is ultimately fatal, can develop with enteroviruses (echovirus or coxsackie) infection.
What are the laboratory and radiographic findings in CVID?	Low IgG, IgA, IgE, variable IgM. B cells (CD19) are present in the peripheral blood and sometimes in exuberant lymphoid tissue. Commonly these patients (25%) have bronchiectasis on high-resolution computed tomography (CT) of the chest.
When are patients with agammaglobulinemia first seen?	Generally, boys with XLA are seen after the first 6 months of life (after maternal antibodies are gone) and within the first 2 years of life.
What are laboratory and radiographic findings in agammaglobulinemia?	XLA patients have essentially no B cells (CD19) in circulation and no discernible lymphoid tissue (a lateral neck view showing no adenoidal tissue is a diagnostic test in children).
What infections are common in patients with agammaglobulinemia?	Sinopulmonary bacterial infections, enterovirus meningoencephalitis
Can a patient have an antibody deficiency with a normal total IgG level?	Yes, there have been reports of patients with B-cell immunodeficiency in spite of a normal total IgG level.
How are patients with B-cell immunodeficiency and normal total IgG level recognized?	Most of these patients have an inability to mount a response to polysaccharide antigens (pneumococcus or unconjugated Haemophilus).
How should patients with recurrent pneumonia or other serious bacterial infections be evaluated?	The patient should receive vaccination with unconjugated pneumococcal vaccine and tetanus toxoid; then prevaccination and postvaccination (3 to 4 weeks) titers of antibodies to at least 14 pneumococcal serotypes assayed simultaneously. An adequate response is a fourfold increase in antibody titers between the paired serums. Vaccination with H. influenzae (type b) conjugated to a protein may be useful for protecting these patients but is usually not helpful in diagnosis.
What is the treatment for IgG deficiencies?	Monthly infusions of pooled IVIg. The dose is generally begun at 200 to 400 mg/kg and is titrated to maintain an IgG trough level of >400 mg/dL obtained immediately before the next infusion (or sometimes to an adequate clinical response). Despite IgG infusions, many patients with CVID require prophylactic antibiotics.
Name some of the different types of SCID.	ADA deficiency (most common) PNP deficiency RAG1, RAG2 (Omenn syndrome) Defective cytokine signaling X-linked (common gamma chain) Autosomal recessive (IL2, IL7 receptor)
For each of the following, list the lymphocyte defect and major abnormalities:
DiGeorge syndrome	T cell; cardiac defects (great vessels) and hypocalcemia (failure of development of the parathyroids), absent thymus, abnormal ears, shortened philtrum, micrognathia, and hypotelorism
Idiopathic CD4 lymphocytopenia (Nezelof syndrome)	T cell; DiGeorge syndrome without the associated congenital anomalies; resembles HIV (failure to thrive, candidiasis, anemia, thrombocytopenia, cancer)
SCID	T and B cell; may be X-linked or autosomal recessive. Affected infants rarely survive the severe immunodeficiency state beyond 1 year. They often present with failure to thrive, diarrhea, respiratory infection, and disseminated infection.
ADA	Most common type of SCID; T and B cells; a form of SCID with deficient purine metabolism (adenosine deaminase)
PNP	Type of SCID; T cells; similar to ADA with deficient purine metabolism leading to toxic intracellular levels of deoxyguanosine triphosphate
Wiskott-Aldrich syndrome	T and B cell; low serum levels of IgM and increased levels of IgE; eczema, thrombocytopenia, repeated infections (encapsulated organisms), lymphoreticular malignancies, and anergy
Ataxia-telangiectasia	T and B cells; cerebellar ataxia and oculocutaneous telangiectasia (butterfly rash over the sclera, face, and ears), truncal ataxia, ovarian agenesis, sinopulmonary infections leading to bronchiectasis and lymphomas, and high levels of α-fetoprotein and carcinoembryonic antigen; highly susceptible to radiation-induced chromosomal injury and subsequent tumors.
Chronic mucocutaneous candidiasis (autoimmune polyglandular syndrome type I)	T cell; superficial candidiasis (not systemic) associated with single or multiple endocrinopathies, iron deficiency, and anergy; molecular defect in AIRE
Hyperimmunoglobulin E	Uncertain, with increased serum levels of IgE (up to 10 times normal); recurrent infections of the skin and sinopulmonary tract with S. aureus, H. influenzae, and Aspergillus; coarse facial features; delayed shedding of primary teeth; and chronic eczematous rashes
Do any of the T- and B-cell primary immunodeficiencies discussed occur in adults?	CVID; chronic mucocutaneous candidiasis and hyperimmunoglobulin E are disorders compatible with living to adulthood; the other T-cell or combined immunodeficiencies listed above are severe and generally present early in life; without bone marrow transplantation, they are generally fatal.
In general, how are T-cell and combined immunodeficiencies treated?	Bone marrow, fetal liver, and thymus transplantation may have a role. Gamma globulin infusions ± antibiotics may be given for patients who are IgG deficient or with SADNI. Fresh frozen plasma may be given for other immunoglobulin-deficient states. Good postural drainage helps prevent sinopulmonary infections. Live vaccines, blood transfusions, and x-rays avoided in patients with T-cell deficiencies. Splenectomy, chemotherapy, immunomodulators, antifungals, and antivirals are needed in rare cases.

HIV

See Chapter 7 (“Infectious Disease”) and Medicine Recall, 3rd ed. for more discussion of HIV.

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Complement Deficiency

Are complement deficiencies common?	No, they are rare (prevalence = 0.03%).
Name the most common complement deficiencies.	C2, C9, MBL
How are most inherited?	Autosomal recessive
What diseases are seen in patients with complement deficiency?	Autoimmune disease Recurrent infections
What is a common complement deficiency?	C2 deficiency is seen in approximately 1 in 25,000 Caucasians, in whom there is an increased tendency for autoimmune disease.
What immune issues do patients with complement deficiency have troubles with?	Persons are rarely clinically affected by a decreased ability to opsonize pyogenic bacteria.
In what ethnic groups are terminal complement deficiencies seen?	These deficiencies are probably more common in ethnic groups other than Caucasians.
What infections are most common with this problem?	People with terminal complement component deficiencies (C5 to C9) are predisposed to Neisseria infections.
What complement deficiency is associated with recurrent episodes of angioedema?	Deficiency of C1INH
What types of processes cause complement consumption?	Autoimmune disease (lupus, rheumatoid arthritis, vasculitis) Infections Serum sickness

Autoimmunity

See Medicine Recall, 3rd ed.

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Anaphylaxis

What is the acute treatment for anaphylaxis?	Stop the causative agent (e.g., penicillin infusion), provide basic life support, and: Epinephrine, intramuscular injections of 0.3 to 0.5 mL of 1:1000 every 5 minutes as necessary to control symptoms. IV fluids for hypotension. H1 blockers (diphenhydramine, >50 mg up to 300 mg/day) and H2 blockers (cimetidine, 4 mg/kg) intravenously. Glucagon, atropine, dopamine if patient is on beta blockers or refractory to epinephrine.
Why should patients who have had an anaphylactic reaction be monitored after successful therapy?	Episodes can recur for up to several hours after the event.
What are some of the drug and food causes of anaphylaxis?	Drugs: antibiotics (particularly beta lactams), protamine, insulin, muscle relaxants, general anesthetics, and vaccines Food: peanuts, tree nuts, fish, shellfish, milk, and eggs (including vaccines made from egg products, such as the influenza vaccine)
What are other common causes and causative agents of anaphylaxis?	Antitoxins, insect venom, latex, exercise, exercise within 4 to 6 hours of ingesting certain foods (e.g., wheat, celery), systemic mastocytosis, malignancy, semen, and unknown or idiopathic causes
How is the correct diagnosis of anaphylaxis made?	History is the major diagnostic modality (most cases present with urticaria and decreased blood pressure, increased heart rate). Specific IgE testing [either by skin testing or by IgE immunoassays (ELISA), formerly done with radiation and known as radioallergosorbent tests or RASTs] may be helpful when IgE is suspected. Skin testing should be performed more than 6 weeks after the event or else false-negative tests will be more common due to the anergic state of mast cells after anaphylaxis.
What blood test can be evaluated to confirm anaphylaxis?	Serum tryptase (within 3 to 4 hours of the event)
What is an anaphylactoid reaction and what agents usually cause them?	It is clinically similar to anaphylaxis but is not IgE-mediated. Agents such as radiocontrast media, NSAIDs, muscle relaxants, and paclitaxel cause direct stimulation of mast cells and basophils. Anaphylactoid reactions can often be prevented with glucocorticoids and antihistamines.
Can people with fish allergy tolerate IV contrast media?	Yes, there is no relationship between fish allergy and adverse reactions to contrast media.

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Urticaria and Angioedema

What are the causes of physical urticaria/angioedema?	Dermographism, cold, heat, sun, cholinergic stimulation, vibration, exercise
What are the complement-mediated causes of urticaria (and angioedema)?	Hereditary and acquired angioedema, necrotizing vasculitis, serum sickness, reactions to blood products, viral infections including hepatitis B and EBV, and pregnancy
What are the nonimmunologic (non–IgE mediated) causes of urticaria (and angioedema)?	Opiates (direct histamine release from mast cell), vancomycin, dextran, radiocontrast, acetylsalicylic acid, NSAID, azo dyes, and benzoates
What is the most common cause of chronic urticaria?	After excluding acute and physical urticarias, etiologies of chronic urticaria may be found in <2% of cases.
What factors should be considered in the evaluation of the patient with chronic urticaria?	Thyroid disease, physical urticarias, food sensitivity, drug reaction, chronic infections (sinus, dental, and genitourinary), systemic disease (vasculitides), and malignancy
What tests/labs should one evaluate for chronic urticaria?	CBC with differential, sedimentation rate, thyroid antibodies, thyroid function, liver function; consider autologous serum skin testing to demonstrate autoantibodies to Fc receptor; urinalysis if symptoms of UTI or history of recurrent UTI, skin biopsy for atypical urticaria (painful, residual bruising, if lesions last more than 24 to 48 hours, or other systemic complaints) to rule out vasculitis
What organs other than skin are affected in angioedema?	There is submucosal edema of the gastrointestinal system (lips, esophagus, gastrointestinal tract), nasopharynx, larynx, trachea, or urogenital system.
Is the differential diagnosis different for angioedema than for urticaria?	Yes; isolated angioedema is much less common than chronic urticaria with or without angioedema. Isolated angioedema suggests drug allergy; C1INH deficiencies, either hereditary or acquired; and vasculitis.
What are the causes of angioedema?	Same as urticaria with the addition of ACE inhibitors
What is the time course of ACE inhibitor–related angioedema?	This side effect is most commonly seen in the first week of treatment but may occur any time, affecting at least 3 in 1000 patients.
If a patient has a history of angioedema, must the ACE inhibitor be discontinued?	If the patient is taking an ACE inhibitor, it should be stopped, because the side effect of angioedema is life-threatening. Most patients with ACE inhibitor–related angioedema can tolerate angiotensin-receptor blockers (ARBs).
How is the cause of angioedema established?	If the C4 level is normal during an episode of angioedema, there is no problem with C1INH because C4 is used up in this process. If the C4 level is low or if a person is seen in an asymptomatic period, C1INH level and functional activity should be measured (to determine if it is HAE I or II), as should the C1q level. C1q levels are normal in hereditary angioedema and decreased in acquired C1INH deficiency. C2 is reduced during acute episodes. Acquired C1INH is associated with malignancy, particularly B-cell lymphomas.
What is the first-line therapy for urticaria and angioedema not related to C1INH deficiency?	H1 antihistamines (preferably long-acting; e.g., cetirizine, fexofenadine). If control is not achieved, H2 antihistamines (e.g., ranitidine) can be added or doxepin can be used, which has both H1 and H2 antihistaminic activity.
Where do steroids fit in the treatment of urticaria and angioedema not related to C1INH deficiency?	Daily steroids are to be avoided as they provide only short-term relief.
What other agents can also be used for the treatment of urticaria and angioedema not related to C1INH deficiency?	Leukotriene modifiers (montelukast, zileuton) can also be used. A short course of cyclosporine for those with autoimmune urticaria that is refractory to their medications may be beneficial. Epinephrine 1:1,000 IM is used if angioedema is threatening the airway.
What is the treatment for urticaria and angioedema secondary to C1INH deficiency?	C1INH deficiency is treated with attenuated androgenic steroids, which increase the production of C1INH. This is effective in patients with deficient production, deficient activity, and increased catabolism of C1INH. Epinephrine may not work in a crisis, and a tracheostomy is indicated for laryngeal edema. Antifibrinolytics (epsilon-aminocaproic acid or tranexamic acid) may be helpful.

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Mastocytosis

What is mastocytosis?	Mastocytosis is a disease of excess mast cells; it can be localized to the skin or may occur in systemic form.
How common is mastocytosis?	Approximately 1 in 5000 patients seen in dermatology clinics has mastocytosis. It is slightly more common in men than in women (1.5:1).
What is the most common lesion found on skin examination in mastocytosis?	Urticaria pigmentosa (UP)
What are symptoms and signs of mastocytosis?	Symptoms: pruritus, flushing, abdominal pain, fatigue, musculoskeletal pain, recurrent anaphylaxis Signs: skin lesions (UP), hepatosplenomegaly, ascites, bone lesions
What are the features of the seven categories of mastocytosis?	Cutaneous: includes UP, nodular or telangiectasia macularis, eruptive persistent, diffuse cutaneous Indolent systemic mastocytosis: involving skin and bone marrow only (UP and diffuse cutaneous) and systemic (marrow, gastrointestinal, and UP) Systemic: associated with a hematologic non–mast cell disorder (dysmyelopoietic syndrome, acute nonlymphocytic leukemia, myeloproliferative disorders, malignant lymphoma, chronic neutropenia) Aggressive systemic: lymphadenopathy and eosinophilia Mast cell leukemia Mast cell sarcoma Extracutaneous mastocytoma
How is the diagnosis of mastocytosis made?	One major diagnostic criterion + one minor criterion or three minor criteria Major criteria: Bone marrow biopsy and aspirate with dense infiltrates of mast cells Minor criteria: Spindle-shaped mast cells Detection of 816 c-kit mutation Flow cytometry with CD2, CD25, and CD117 expression Serum tryptase >20 µg/mL
What is the treatment for mastocytosis?	H1 antihistamines for pruritus, flushing, and tachycardia. H2 antihistamines for gastric hypersecretion. Epinephrine. Cromolyn (200 mg before meals and at bedtime) may help with gastrointestinal symptoms. Tricyclic antidepressants for headaches. Avoidance of ethanol, NSAIDs, opiates, friction, and physical exertion.
What is the prognosis for mastocytosis?	Those with the cutaneous form usually have high rates of spontaneous remission. The indolent form is usually associated with a normal life expectancy. The prognosis of patients with systemic disease and an associated hematologic non–mast cell disorder is determined by the hematologic abnormality. Aggressive systemic disease is the rarest and has the most fulminant course. Mast cell leukemia is rapidly progressive over 1 to 2 years.
What are the poor prognostic indicators for mastocytosis?	Constitutional symptoms, anemia, thrombocytopenia, abnormal liver function tests, lobulated mast cell nucleus, low percentage of fat cells in the marrow, associated hematologic disorder, absence of UP, male gender, absence of skin and bone symptoms, hepatosplenomegaly, and normal bone films
What therapies are available for more severe forms of systemic mastocytosis?	IFN-α (controversial), hydroxyurea (may reduce mast cell progenitors in type III disease), and other chemotherapy for leukemic forms (types II and IV)

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Drug Allergies

How common are immune-mediated drug-induced allergic reactions?	Allergies account for 6% to 10% of all adverse drug reactions. The rest are commonly known, predictable pharmacologic actions of the drug.
Is skin testing helpful for patients with a history of hives to antibiotics?	Penicillin skin testing with penicillin major and minor is reliable for the diagnosis of immediate hypersensitivity. A negative test has a 99% negative predictive value, whereas a positive skin test indicates a high risk for immediate hypersensitivity reactions.
How common is antibiotic cross-reactivity in penicillin-sensitive patients?	The history of a reaction to penicillin carries a 5% to 15% risk of immediate hypersensitivity to first-generation cephalosporins (4% to second and 1% to 3% to third and fourth) and increases the risk of an adverse response to other, unrelated drugs eightfold. A positive penicillin skin test increases the risk of a reaction to cephalosporins (and probably imipenem).
What drugs interfere with immediate skin tests?	Most antihistamines if used within 3 days of the test (astemizole, 6 weeks) and tricyclic antidepressants
Are there skin tests for other antibiotics?	Clinically proven skin tests have not been developed for other pharmacologic agents. Testing is sometimes performed for other drugs, but a negative test must be interpreted with caution (poor negative predictive value). Nonirritating doses are available for testing which, if positive, suggest IgE-mediated sensitization. There are no prospective challenges published other than for beta lactams.
What if there is no alternative agent than the drug allergen?	Desensitization protocols decrease the risk of uncontrolled anaphylaxis. Once therapy is initiated, it cannot be interrupted without resuming the risk of anaphylaxis.
How does desensitization work?	It is not known for certain, but there may be a gradual cross linking of IgE by antigen, causing a controlled anaphylaxis.
Are drug rashes possible with a negative penicillin skin test?	Penicillin skin testing predicts only immediate IgE-mediated hypersensitivity. With a negative penicillin skin test, it is still possible for a non–IgE-mediated drug rash, serum sickness, mucocutaneous syndrome, or other adverse side effects to develop.
Which reactions are contraindications to drug use?	A history of serum sickness, Stevens-Johnson syndrome/toxic epidermal necrolysis, erythroderma, hemolytic anemia, interstitial nephritis, or exfoliative dermatitis

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Atopic Dermatitis (See Chapter 12, “Dermatology”)

Contact Hypersensitivity (See Chapter 12, “Dermatology”)

Rhinitis and Sinusitis

What is the differential diagnosis of chronic rhinitis?	Allergic Nonallergic Inflammatory [infectious, NARES, nasal polyps (NSAID allergy), atrophic rhinitis] Noninflammatory Vasomotor Systemic disease (hypothyroidism, diabetes) Rhinitis medicamentosa (oral contraceptives, topical decongestants, cocaine, ACE inhibitors) Chronic sinusitis Structural defects (trauma/cerebrospinal fluid rhinorrhea, tumor, foreign body) Pregnancy
What is chronic sinusitis?	Symptoms ≥12 weeks Requires two or more of the following: Anterior or posterior mucopurulent drainage Congestion Facial pain/pressure Decreased sense of smell Objective documentation: Rhinoscopy X-ray (sinus CT preferred)
How is the diagnosis of chronic sinusitis made?	Radiographically by sinus CT scan (plain films not very sensitive)
What is the treatment for acute sinusitis?	Antibiotics that cover beta lactamase–positive organisms for 10 to 21 days Promotion of nasal drainage Topical nasal decongestants for 3 to 5 days
What is the treatment for chronic sinusitis?	Nasal steroids Short course of oral steroids FESS (in certain patients—i.e., nasal polyps)
What are potential adverse effects of antihistamines?	Somnolence and a theoretical thickening of mucus, therefore possibly reducing clearance

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Asthma (See Also Chapter 10, “Pulmonology”)

What is the differential diagnosis for wheezing?

Asthma Pulmonary edema Airway obstruction (laryngospasm, tracheomalacia, vocal cord dysfunction, tracheal web, foreign body) Chronic obstructive pulmonary disease (COPD) Congestive heart failure Pulmonary embolus Primary eosinophilic lung disease (hypereosinophilic syndrome, eosinophilic pneumonia, Churg-Strauss syndrome) Secondary eosinophilic lung disease [allergic bronchopulmonary aspergillosis (ABPA), hypersensitivity pneumonitis, drugs, malignancy, collagen vascular disease, sarcoid] Bronchiolitis obliterans Interstitial lung disease

Gastroenterology

What is eosinophilic esophagitis/gastroenteritis?	An eosinophilic infiltrate of the bowel potentially involving all layers of the gut; symptoms include nausea, vomiting, diarrhea, malabsorption, weight loss, and dysphagia
How is the diagnosis of eosinophilic esophagitis/gastroenteritis made?	Biopsy shows >15 to 20 eosinophils per high-power field. Involvement is sporadic, so multiple biopsy samples may be required. Usually, about half of patients have a peripheral eosinophilia and some have high levels of IgE. IgE testing (skin test may be more sensitive than serum immunoassays) to foods should be performed. Patch testing is still experimental.
What is the treatment for eosinophilic esophagitis/gastroenteritis?	Treatment of coexisting acid reflux may relieve symptoms. Swallowed metered-dose-inhaler steroids; a trial of strict avoidance of any identified offending foods in esophagitis; an elemental diet in gastroenteritis or severe esophagitis; oral glucocorticoids in very severe cases.

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Transplantation Immunology

Are all grafts matched?	Although matching for intrafamilial transplants of all types is performed, nonfamilial cardiac, lung, and liver grafts are not MHC-matched because other factors such as size, location, and availability limit the transplants much more. Kidney transplantation, for which there is the potential for living related and unrelated donors, allows for matching. Bone marrow transplants must be matched, whereas matching in liver transplants may actually decrease survival.
What is hyperacute rejection?	Rejection mediated by preformed complement-fixing antibodies. It occurs in <24 hours and is irreversible.
What is accelerated rejection?	Rejection mediated by preformed but not complement-fixing antibodies. Onset is 3 to 5 days.
How is accelerated rejection treated?	Treatment is with antithymocyte or antilymphocyte globulin or newer anti–monoclonal antibodies against T-cell surface antigens (e.g., CD3). Treatment is successful in approximately 60% of cases.
What is acute rejection?	Rejection mediated by recipient T cells and antibodies as a primary response. It occurs 6 to 90 days after transplantation and is thought to be directed at passenger APCs. There is prominent infiltration of CD8 cells and polymorphonuclear neutrophils.
How is acute rejection treated?	Immunosuppression with pulse steroids and agents used in accelerated rejection is successful 80% to 90% of the time.
What is chronic rejection?	Mostly antibody deposition leading to hyperplasia and endothelial necrosis >60 days posttransplant. It is slowly progressive and does not respond well to treatment.
What is graft-versus-host disease?	Graft-versus-host disease is an immune response of the donor T cells against the recipient usually 6 or more days after transplant. It is a problem only when transplanting hematopoietic tissue (bone marrow, nonirradiated blood transfusions).
Why not purge the T cells from marrow before transplantation?	Sometimes the donor marrow is purged of T cells before transplant, but without T cells, engraftment is less often successful and the incidence of leukemia increases.
What immunosuppressive drugs specifically target T cells?	Antithymocyte globulin, antilymphocyte globulin, and anti–monoclonal antibody to T-cell antigens (CD3, OKT3), which, in part, bind with the activation sites of T cells via foreign proteins (horse, rabbit, or mouse) and are then selectively cleared by the host's immune system Calcineurin inhibitors (cyclosporine, tacrolimus) and anti–IL-2 receptor antibodies, which decrease IL-2 and interfere with growth and function
Should blood transfusion be avoided?	Yes, for persons likely to need a bone marrow transplant; however, it may enhance renal and cardiac allograft survival by selecting for patients who are hyporesponsive for antibody production. Transfusions with irradiated or filtered blood are usually safe, however.

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Tumor Immunology

What are common alterations that lead to cancer?	Increased activity of proto-oncogenes Decreased activity of suppressor genes Alterations in genes that regulate apoptosis Defect in genes that regulate DNA repair
What are causes of antigenic differences between normal and tumor cells?	Chemical carcinogens and ionizing radiation may alter protein synthesis. Viruses may introduce new DNA or RNA into cells. Malignant cells may revert to synthesis of fetal markers such as alpha fetoprotein, carcinoembryonic antigen, or other fetal proteins. Genetic mutation may lead to expression of inappropriate antigens such as ABO.
Why are antigenic differences potentially important?	If differences between normal cells and malignant cells can be found, immunotherapy may be effective in curing patients.
What immunotherapeutic agents are currently under investigation?	Interleukins and interferons, monoclonal antibodies, and antitumor vaccines
What are potential uses for monoclonal antibodies?	To direct action against tumors through antibody- or complement-dependent cytotoxicity To carry cytotoxic substances such as radiolabeled compounds, chemotherapeutic agents (e.g., methotrexate or doxorubicin), naturally existing toxins, or immunoconjugates (e.g., ricin)