Page 683 - Clinical Immunology_ Principles and Practice ( PDFDrive )

656 ParT FivE Allergic diseases

histamine release from mast cells without IgE involvement, in heparin and PF4. These immune complexes activate platelets,
a dose-dependent fashion. releasing PF4 and causing platelet destruction. Mild throm-
bocytopenia can occur in up to 5% of patients treated with
heparin, and 10% develop paradoxical thrombosis, which can be
CLiNiCaL PEarLS life-threatening.
Vancomycin Red Man Syndrome Type III Reactions
• Presents as erythema, flushing, rarely hypotension Immune complexes form during normal immune responses
• Histamine elevated in urine and blood without any clinical consequences. Immune complexes can also
• Direct mast cell activation and release of histamine be formed during treatment with drugs that form hapten–carrier
• Can be potentiated by mast cell activation agents (e.g., opioids) complexes or with chimeric or humanized proteins, such as mAbs.
• Treatment: slow infusion, dose reduction, and antihistamines
These immune complexes are typically cleared by binding to
the FcγRI or complement receptor CR1 on reticuloendothelial
cells. Decreased clearance because of high levels complement
Type II Reactions: IgG-Mediated Cytotoxic Reactions defects or aberrant FcγRI function can lead to type III reac-
Type II and type III reactions result from the formation of tions. Recently a low copy number of FcγRIII was shown to
complement-fixing IgG antibodies, typically of the IgG1 and be associated with glomerulonephritis. Type III reactions can
IgG3 subclasses, which bind to Fcγ receptors (FcγRI, IIa, and present as small vessel vasculitis and/or serum sickness. Serum
IIIa) on macrophages, natural killer (NK) cells, granulocytes, sickness was first described when heterologous serum or foreign
and platelets, or form immune complexes and interact with serum was used for passive immunization. Antibodies appear
complement receptors on these cells. In type II reactions, the in 4–10 days and react with drug antigens, forming soluble
antibody is directed against antigens on the cell membrane, or circulating immune complexes. These immune complexes capture
immune complex activation occurs on the cell surface. Both complement and are deposited in postcapillary venules, attract-
events can lead to cell destruction or sequestration; affected cells ing leukocytes by interacting with FcγRIII, eventually inducing
include erythrocytes, leukocytes, platelets, and bone marrow the release of proteolytic enzymes and tissue damage. Non-
precursor cells. The development of type II reactions requires protein drugs, such as cefaclor, trimethoprim-sulfamethoxazole,
an IgG immune response to a drug hapten–carrier complex after cephalexin, amoxicillin, NSAIDs, and diuretics, are the most
high-dose and prolonged treatment, as is seen in penicillin and commonly implicated drugs, but these reactions can also occur
cephalosporin reactions, where the reaction is caused by comple- with protein drugs, such as mAbs.
ment fixation. IgM antibodies are sometimes implicated, as well The incidence of hypersensitivity vasculitis is 10–30 cases
as autoantibodies reactive to the carrier molecule. These immune per million per year. The presentation can include fever, skin
reactions can persist after cessation of the drug. Another type rash, myalgia, arthralgia, and lymphadenopathy. Palpable
of type II reaction occurs when the drug or its metabolites adhere purpura may be present in legs, with lesions that can coalesce
to the erythrocyte or platelet surface, creating a new antigenic and ulcerate. The GI tract, kidneys, and joints can be affected:
complex with the cell membrane. Quinine-induced thrombo- the prognosis depends on the extent of systemic involvement.
cytopenia occurs when IgG or IgM antibodies react with Patients taking systemic steroids may present with a milder form
membrane epitopes, such as GPIIb/IIIa (fibrinogen receptor) or of reaction, with fewer manifestations. Renal biopsy reveals
GPIb/IX (von Willebrand factor receptor); this only happens IgA-containing immune complexes, similar to those found in
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when the drug in present in soluble form. This interaction IgA nephropathy.
results in platelet destruction and thrombocytopenia. Similar
reactions occur with sulfonamides and quinidine. The antibody- Type IV Reactions
coated cells can be sequestered in the liver and spleen by Fcγ or Cell-mediated reactions are now subdivided on the basis of the
complement receptor binding. Rarely, intravascular destruction cytokines produced by T cells and the type of effector immune
occurs via complement-mediated lysis. cells induced by these cytokines, such as eosinophils and
Penicillin, cephalosporins, levodopa, methyldopa, quinidine, neutrophils.
and some antiinflammatory drugs can induce hemolytic anemia, Type IVa reactions correspond to classic T helper 1 (Th1)–type
which presents with fatigue, pallor, shortness of breath, tachy- immune reactions, in which Th1 cells activate macrophages by
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cardia, and dark urine. Direct and indirect Coombs tests are secreting interferon-γ (IFN-γ) and other cytokines (TNF-α,
positive, unconjugated levels of bilirubin are elevated, haptoglobin IL-12). These Th1 cells drive the production of the complement-
is decreased, and hemoglobinuria is present. Thrombocytopenia fixing antibodies involved in types II and III reactions and are
can occur with quinine, quinidine, sulfonamide antibiotics, and costimulators of pro-inflammatory responses, and CD8 T-cell
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mAbs. Drug-induced thrombocytopenia usually occurs after responses. Examples of type IVa reactions include tuberculin
5–8 days of exposure but may occur after a single exposure reactions, contact dermatitis (with activated CD8 cells) and
in a sensitized patient. The typical presentation is petechial sarcoidosis (with granuloma formation and monocyte
hemorrhages in skin and mucosal bleeding, sometimes associated activation).
with GI and urinary bleeding. Intracranial bleeding is rare, and Type IVb reactions correspond to type 2 immune responses
the platelet count returns to normal 3–5 days after the drug is with IL-4, IL-13, and IL-5 cytokines, which promote IgE- and
discontinued. In heparin-induced thrombocytopenia, FcγRIIa IgG4-producing B cells, mast cells, and eosinophils. IL-5 produc-
receptors on platelets bind IgG and IgM immune complexes tion leads to eosinophilic inflammation, which is seen in many
of heparin and platelet factor 4 (PF4), a CXC chemokine drug-induced hypersensitivity reactions, including DRESS. Type
usually stored in platelet α-granules. About 50% of patients I reactions are linked to these reactions since IgE is produced
treated for >7 days with heparin develop antibodies against as a result of IL-4 and IL-13 secretion by Th2 cells. Maculopapular