Transcript Serum_Sickness

Serum Sickness
Definition
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A clinical syndrome that results from the injection
of heterologous foreign protein or serum that leads
to deposition of antibody-antigen complexes in the
blood vessel wall
Classic example of a systemic Gell and Coombs
type III immunological reaction
Serum sickness-like reactions are secondary to nonprotein drugs but often cause indistinguishable
reactions
History
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First described by Schick and VonPirquet in 1905
Horse anti-diptheria antitoxin
Reproducible syndrome in patients
Fever, malaise, rash, tender lymphadenopathy, leukopenia,
arthralgias, albuminuria and edema
Occurred 8-13 days after first injection of horse sera
Incidence of symptoms related to amount of sera given
 5-15 cc of anti-toxin resulted in 5-10% incidence of
serum sickness
 100-200 cc of anti-toxin resulted in >85% incidence
Incidence
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Decreasing incidence of classic serum sickness
Vaccination programs
 Refined horse serum antitoxins
 Current use of human antiserums
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Rabies
 Tetanus
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Non-protein drugs now most common causes
Incidence
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Directly related to amount and type of foreign
serum injected
In one study, 10% patients receiving 10ml tetanus
antitoxin developed serum sickness, whereas, all of
those receiving 80ml developed serum sickness
 Anti-rabies serum produces higher incidence (~16%)
versus tetanus antitoxin (2.5-5%)
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Current Use of Foreign Serum
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Botulism
Diphtheria
Tetanus – equine, human antitoxin
Snake bites (rattlesnakes,copper heads,cottonmouth)
Black widow/Latrodectus species
Scorpion
Antilymphocyte antibody
Digoxin immune FAB (Digibind)
Other Agents Causing Serum
Sickness
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Allopurinol
Anti-thymocyte globulin
Arsenicals derivatives
Barbituates
Bupropion
Captopril
Carbamazepine
Cephalosporins
Cholecystographic RCM
Ciprofloxin
Dextran
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Fluoxetine
Furazolidone
Gold Salts
Griseofulvin
Halothane
Hydralazine
Iodides
Indomethacin
Infuenza Vaccine
Itraconazole
Methyldopa
Other Agents Causing Serum
Sickness
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Mercurial derivatives
Metronidazole
NSAIDs
Penicillamine
Penicillins
Phenylbutazone
Phenytoin
Piperazine
Procainamide
Propranolol
Rifampin
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Quinidine
Streptokinase
Sulindac
Sulfonamides
Tetracycline
Thiouracils
Still more causes
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Also…
Allergen extracts
 Blood products
 Hormones
 Vaccines
 Infectious agents
 Monoclonal antibodies
 Hymenoptera stings
 Tick bites
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What is Going on?
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Foreign antigen introduced
Antibodies develop and can form complexes
with the antigen
Depending on the size and amount of
complexes, they may deposit on vascular wall
Smaller vessels more common
 Leads to vasculitis, nephritis, and arthritis
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Fixation and activation of complement
What is Going on?
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Increase in Anaphylatoxins like C3a and C5a
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Causes mast cells to degranulate
Leads to PMNs influx to area of inflammation
Endothelial cells increase expression of adhesion
molecules (like ICAM)
Proinflammatory cytokines are released by monocytes
and macrophages
Proteolytic enzymes are released and mediate damage
(and symptoms)
Mast Cell Mediators
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Preformed mediators
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Histamine
Proteases
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Tryptase
Acid hydrolases
Proteoglycans
Cytokines (TNF-α, IL-4)
Newly formed mediators
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Prostaglandins
Leukotrienes
Thromboxanes
Platelet activating factor
What is Going on?
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Increase in Anaphylatoxins like C3a and C5a
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Causes mast cells to degranulate
Leads to PMNs influx to area of inflammation
Endothelial cells increase expression of adhesion
molecules (like ICAM)
Proinflammatory cytokines are released by monocytes
and macrophages
Proteolytic enzymes are released and mediate damage
(and symptoms)
Why Does the Body do This?
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Body’s way of dealing with some insults by complexing
them before they can elicit their damage
These complexes then cleared by RE system
Serum sickness is a systemic process whose symptoms
are determined by where immune complexes are
deposited
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There is localized serum sickness reaction called Arthus
reaction
Other human immune-complex diseases
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SLE, PAN, PSGN
Why Continued…
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Larger complexes are cleared more readily,
smaller complexes more apt to deposit
Complexes with cationic charge may bind
negative BM more readily
IgG more likely culprit in forming the
complexes that are seen in serum sickness
Amount and size of complexes based on the
amount of antigen versus antibody present in
system at the time (Zone of Equivalence)
• Formation of small antigenantibody complexes which are
soluble and poorly cleared
• Complex deposition may be
exacerbated by increased vascular
permeability caused by mast cell
activation via FcgammaRIII (CD16)
• The deposited immune complexes
trigger neutrophils to discharge their
granule contents with consequent
damage to the surrounding
endothelium and basement
membranes
Nick Holmes; Cambridge univerisity
Department of Pathology -Immunology
division
•The complexes may be deposited in
a variety of sites such as skin, kidney
and joints
Radio-labeled bovine serum albumin is injected intravenously
into normal rabbits at day 0, and sequence of immunologic
events is followed. At about day 8, immune complexes are
formed, complement levels fall, and rabbits become ill.
Complement
Antigen
Antibodies
Complexes
Zone of
Equivalence
Lawley TJ, Frank MM
In Parker C, editor:
Clinical immunology,
Philadelphia, 1980,
WB Saunders
Clinical Symptoms
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Occur 6-21 days after administration of foreign antigen
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Typically 7-14 days
Accelerated symptoms within 2-4 days in patients previously
sensitized
Often pain, pruritis, erythema and swelling at injection
site
Most cases resolve in a few days to a couple of weeks
Clinical Symptoms
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Fever
Mild to significant
 5-14 days after exposure
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Lymphadenopathy
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Can be regional (at site) or generalized
Arthralgias
More common in large joints like knees
 Metacarpal and TMJ also seen
 Pain often out of proportion
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Clinical Symptoms
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Arthritis less common
Some patients may feel chest pain or shortness
of breath
Edema may occur (especially face and neck)
Some patients may have visceral involvement
such as hepatomegaly
Cutaneous Eruptions
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Present in 95%
Urticaria - mediated by IgE and/or complement
Morbilliform eruption
Maculopapular exanthem
Erythema multiforme
Purpura
Angioedema, especially of face and neck
Skin rash in serum sickness
• Received equine anti-
thymocyte globulin therapy 12
days prior to rash
• Morbilliform and urticarial rash
began on the torso and back,
then spread to the extremities
• The rash was accompanied
by circulating immune
complexes
Cutaneous Eruptions
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Characteristic serpiginous erythematous,
purpuric eruption at the junction of palmar and
plantar skin and the dorsum of the hands and
feet
Reported in 75% of patients receiving
antithymocyte globulin in one study
Serpiginous Erythematous
(purpuric eruption at the junction of
palmar and plantar skin)
Other Manifestations
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Generalized vasculitis
Peripheral neuritis
Brachial Plexus most common
 Guillain-Barre rare
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Glomerulonephritis
Labs
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May see proteinuria or hematuria
May see a leukocytosis or leukopenia
May have eosinophilia
May have elevated ESR
Decreased complement (C3 and C4), increased
C3a
The Complement Pathways
Lectin pathway
Kuby, 336
Diagnosis
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Typical symptom complex in a patient given
foreign protein or drug within the appropriate
time interval
Symptoms have not lasted longer than one
month
No single laboratory test is confirmatory
Treatment
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Stop offending agent -should lead to resolution
of the signs and diagnosis within a period of
days to a few weeks
Symptoms are usually mild and spontaneously
resolve in a few days or weeks with symptomatic
therapy
Antihistamines and NSAID’s relieve the pruritis
and pain
Treatment of Severe Serum
Sickness
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Corticosteroids
Administered and tapered over 10-14 days
 Shorter courses are associated with relapses
 Relapses are more difficult to alleviate
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Prophylaxis
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Incidence of serum sickness may be reduced by
pretreatment with antihistamines
Negates the effect of vasoactive amines
 Decreases vascular permeability
 Reduces passive deposition of immune complexes
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