1. Serum Sickness

2. Definition 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 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 Classic example of a systemic Gell and Coombs type III immunological reaction Serum sickness-like reactions are secondary to non- protein drugs but often cause indistinguishable reactions Serum sickness-like reactions are secondary to non- protein drugs but often cause indistinguishable reactions

3. History First described by Schick and VonPirquet in 1905 First described by Schick and VonPirquet in 1905 Horse anti-diptheria antitoxin Horse anti-diptheria antitoxin Reproducible syndrome in patients Reproducible syndrome in patients Fever, malaise, rash, tender lymphadenopathy, leukopenia, arthralgias, albuminuria and edema Fever, malaise, rash, tender lymphadenopathy, leukopenia, arthralgias, albuminuria and edema Occurred 8-13 days after first injection of horse sera Occurred 8-13 days after first injection of horse sera Incidence of symptoms related to amount of sera given Incidence of symptoms related to amount of sera given 5-15 cc of anti-toxin resulted in 5-10% incidence of serum sickness 5-15 cc of anti-toxin resulted in 5-10% incidence of serum sickness 100-200 cc of anti-toxin resulted in >85% incidence 100-200 cc of anti-toxin resulted in >85% incidence

4. Incidence Decreasing incidence of classic serum sickness Decreasing incidence of classic serum sickness Vaccination programs Vaccination programs Refined horse serum antitoxins Refined horse serum antitoxins Current use of human antiserums Current use of human antiserums Rabies Rabies Tetanus Tetanus Non-protein drugs now most common causes Non-protein drugs now most common causes

5. Incidence Directly related to amount and type of foreign serum injected 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 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%) Anti-rabies serum produces higher incidence (~16%) versus tetanus antitoxin (2.5-5%)

6. Current Use of Foreign Serum Botulism Botulism Diphtheria Diphtheria Tetanus – equine, human antitoxin Tetanus – equine, human antitoxin Snake bites (rattlesnakes,copper heads,cottonmouth) Snake bites (rattlesnakes,copper heads,cottonmouth) Black widow/Latrodectus species Black widow/Latrodectus species Scorpion Scorpion Antilymphocyte antibody Antilymphocyte antibody Digoxin immune FAB (Digibind) Digoxin immune FAB (Digibind)

7. Other Agents Causing Serum Sickness Allopurinol Allopurinol Anti-thymocyte globulin Anti-thymocyte globulin Arsenicals derivatives Arsenicals derivatives Barbituates Barbituates Bupropion Bupropion Captopril Captopril Carbamazepine Carbamazepine Cephalosporins Cephalosporins Cholecystographic RCM Cholecystographic RCM Ciprofloxin Ciprofloxin Dextran Dextran Fluoxetine Furazolidone Gold Salts Griseofulvin Halothane Hydralazine Iodides Indomethacin Infuenza Vaccine Itraconazole Methyldopa

8. Other Agents Causing Serum Sickness Mercurial derivatives Mercurial derivatives Metronidazole Metronidazole NSAIDs NSAIDs Penicillamine Penicillamine Penicillins Penicillins Phenylbutazone Phenylbutazone Phenytoin Phenytoin Piperazine Piperazine Procainamide Procainamide Propranolol Propranolol Rifampin Rifampin Quinidine Streptokinase Sulindac Sulfonamides Tetracycline Thiouracils

9. Still more causes Also… Also… Allergen extracts Allergen extracts Blood products Blood products Hormones Hormones Vaccines Vaccines Infectious agents Infectious agents Monoclonal antibodies Monoclonal antibodies Hymenoptera stings Hymenoptera stings Tick bites Tick bites

10. What is Going on? Foreign antigen introduced Foreign antigen introduced Antibodies develop and can form complexes with the antigen Antibodies develop and can form complexes with the antigen Depending on the size and amount of complexes, they may deposit on vascular wall Depending on the size and amount of complexes, they may deposit on vascular wall Smaller vessels more common Smaller vessels more common Leads to vasculitis, nephritis, and arthritis Leads to vasculitis, nephritis, and arthritis Fixation and activation of complement Fixation and activation of complement

11. What is Going on? Increase in Anaphylatoxins like C3a and C5a Increase in Anaphylatoxins like C3a and C5a Causes mast cells to degranulate Causes mast cells to degranulate Leads to PMNs influx to area of inflammation Leads to PMNs influx to area of inflammation Endothelial cells increase expression of adhesion molecules (like ICAM) Endothelial cells increase expression of adhesion molecules (like ICAM) Proinflammatory cytokines are released by monocytes and macrophages Proinflammatory cytokines are released by monocytes and macrophages Proteolytic enzymes are released and mediate damage (and symptoms) Proteolytic enzymes are released and mediate damage (and symptoms)

12. Mast Cell Mediators Preformed mediators Preformed mediators Histamine Histamine Proteases Proteases Tryptase Tryptase Acid hydrolases Acid hydrolases Proteoglycans Proteoglycans Cytokines (TNF-α, IL-4) Cytokines (TNF-α, IL-4) Newly formed mediators Newly formed mediators Prostaglandins Prostaglandins Leukotrienes Leukotrienes Thromboxanes Thromboxanes Platelet activating factor Platelet activating factor

13. What is Going on? Increase in Anaphylatoxins like C3a and C5a Increase in Anaphylatoxins like C3a and C5a Causes mast cells to degranulate Causes mast cells to degranulate Leads to PMNs influx to area of inflammation Leads to PMNs influx to area of inflammation Endothelial cells increase expression of adhesion molecules (like ICAM) Endothelial cells increase expression of adhesion molecules (like ICAM) Proinflammatory cytokines are released by monocytes and macrophages Proinflammatory cytokines are released by monocytes and macrophages Proteolytic enzymes are released and mediate damage (and symptoms) Proteolytic enzymes are released and mediate damage (and symptoms)

14. Why Does the Body do This? Body’s way of dealing with some insults by complexing them before they can elicit their damage Body’s way of dealing with some insults by complexing them before they can elicit their damage These complexes then cleared by RE system These complexes then cleared by RE system Serum sickness is a systemic process whose symptoms are determined by where immune complexes are deposited Serum sickness is a systemic process whose symptoms are determined by where immune complexes are deposited There is localized serum sickness reaction called Arthus reaction There is localized serum sickness reaction called Arthus reaction Other human immune-complex diseases Other human immune-complex diseases SLE, PAN, PSGN SLE, PAN, PSGN

15. Why Continued… Larger complexes are cleared more readily, smaller complexes more apt to deposit Larger complexes are cleared more readily, smaller complexes more apt to deposit Complexes with cationic charge may bind negative BM more readily Complexes with cationic charge may bind negative BM more readily IgG more likely culprit in forming the complexes that are seen in serum sickness 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) Amount and size of complexes based on the amount of antigen versus antibody present in system at the time (Zone of Equivalence)

16. Formation of small antigen- antibody 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 The complexes may be deposited in a variety of sites such as skin, kidney and joints Nick Holmes; Cambridge univerisity Department of Pathology -Immunology division

17. 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. Lawley TJ, Frank MM In Parker C, editor: Clinical immunology, Philadelphia, 1980, WB Saunders Antigen Complexes Complement Antibodies Zone of Equivalence

18. Clinical Symptoms Occur 6-21 days after administration of foreign antigen Occur 6-21 days after administration of foreign antigen Typically 7-14 days Typically 7-14 days Accelerated symptoms within 2-4 days in patients previously sensitized Accelerated symptoms within 2-4 days in patients previously sensitized Often pain, pruritis, erythema and swelling at injection site Often pain, pruritis, erythema and swelling at injection site Most cases resolve in a few days to a couple of weeks Most cases resolve in a few days to a couple of weeks

19. Clinical Symptoms Fever Fever Mild to significant Mild to significant 5-14 days after exposure 5-14 days after exposure Lymphadenopathy Lymphadenopathy Can be regional (at site) or generalized Can be regional (at site) or generalized Arthralgias Arthralgias More common in large joints like knees More common in large joints like knees Metacarpal and TMJ also seen Metacarpal and TMJ also seen Pain often out of proportion Pain often out of proportion

20. Clinical Symptoms Arthritis less common Arthritis less common Some patients may feel chest pain or shortness of breath Some patients may feel chest pain or shortness of breath Edema may occur (especially face and neck) Edema may occur (especially face and neck) Some patients may have visceral involvement such as hepatomegaly Some patients may have visceral involvement such as hepatomegaly

21. Cutaneous Eruptions Present in 95% Present in 95% Urticaria - mediated by IgE and/or complement Urticaria - mediated by IgE and/or complement Morbilliform eruption Morbilliform eruption Maculopapular exanthem Maculopapular exanthem Erythema multiforme Erythema multiforme Purpura Purpura Angioedema, especially of face and neck Angioedema, especially of face and neck

22. Skin rash in serum sickness R eceived 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

23. Cutaneous Eruptions Characteristic serpiginous erythematous, purpuric eruption at the junction of palmar and plantar skin and the dorsum of the hands and feet 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 Reported in 75% of patients receiving antithymocyte globulin in one study

24. Serpiginous Erythematous (purpuric eruption at the junction of palmar and plantar skin)

25. Other Manifestations Generalized vasculitis Generalized vasculitis Peripheral neuritis Peripheral neuritis Brachial Plexus most common Brachial Plexus most common Guillain-Barre rare Guillain-Barre rare Glomerulonephritis Glomerulonephritis

26. Labs May see proteinuria or hematuria May see proteinuria or hematuria May see a leukocytosis or leukopenia May see a leukocytosis or leukopenia May have eosinophilia May have eosinophilia May have elevated ESR May have elevated ESR Decreased complement (C3 and C4), increased C3a Decreased complement (C3 and C4), increased C3a

27. The Complement Pathways Kuby, 336 Lectin pathway

28. Diagnosis Typical symptom complex in a patient given foreign protein or drug within the appropriate time interval Typical symptom complex in a patient given foreign protein or drug within the appropriate time interval Symptoms have not lasted longer than one month Symptoms have not lasted longer than one month No single laboratory test is confirmatory No single laboratory test is confirmatory

29. Treatment Stop offending agent -should lead to resolution of the signs and diagnosis within a period of days to a few weeks 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 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 Antihistamines and NSAID’s relieve the pruritis and pain

30. Treatment of Severe Serum Sickness Corticosteroids Corticosteroids Administered and tapered over 10-14 days Administered and tapered over 10-14 days Shorter courses are associated with relapses Shorter courses are associated with relapses Relapses are more difficult to alleviate Relapses are more difficult to alleviate

31. Prophylaxis Incidence of serum sickness may be reduced by pretreatment with antihistamines Incidence of serum sickness may be reduced by pretreatment with antihistamines Negates the effect of vasoactive amines Negates the effect of vasoactive amines Decreases vascular permeability Decreases vascular permeability Reduces passive deposition of immune complexes Reduces passive deposition of immune complexes