Serum SicknessSerum Sickness

DefinitionDefinition A clinical syndrome that results from the A clinical syndrome that results from the

injection of heterologous foreign protein injection of heterologous foreign protein or serum that leads to deposition of or serum that leads to deposition of antibody-antigen complexes in the blood antibody-antigen complexes in the blood vessel wallvessel wall

Classic example of a systemic Gell and Classic example of a systemic Gell and Coombs type III immunological reactionCoombs type III immunological reaction

Serum sickness-like reactions are Serum sickness-like reactions are secondary to non-protein drugs but often secondary to non-protein drugs but often cause indistinguishable reactionscause indistinguishable reactions

History History

First described by Schick and VonPirquet in 1905First described by Schick and VonPirquet in 1905 Horse anti-diptheria antitoxinHorse anti-diptheria antitoxin Reproducible syndrome in patients Reproducible syndrome in patients Fever, malaise, rash, tender lymphadenopathy, Fever, malaise, rash, tender lymphadenopathy,

leukopenia, arthralgias, albuminuria and edemaleukopenia, arthralgias, albuminuria and edema Occurred 8-13 days after first injection of horse seraOccurred 8-13 days after first injection of horse sera Incidence of symptoms related to amount of sera Incidence of symptoms related to amount of sera

givengiven 5-15 cc of anti-toxin resulted in 5-10% incidence 5-15 cc of anti-toxin resulted in 5-10% incidence

of serum sicknessof serum sickness 100-200 cc of anti-toxin resulted in >85% 100-200 cc of anti-toxin resulted in >85%

incidenceincidence

IncidenceIncidence

Decreasing incidence of classic Decreasing incidence of classic serum sicknessserum sickness Vaccination programsVaccination programs Refined horse serum antitoxinsRefined horse serum antitoxins Current use of human antiserumsCurrent use of human antiserums

RabiesRabies TetanusTetanus

Non-protein drugs now most Non-protein drugs now most common causescommon causes

IncidenceIncidence

Directly related to amount and type Directly related to amount and type of foreign serum injectedof foreign serum injected In one study, 10% patients receiving In one study, 10% patients receiving

10ml tetanus antitoxin developed serum 10ml tetanus antitoxin developed serum sickness, whereas, all of those receiving sickness, whereas, all of those receiving 80ml developed serum sickness80ml developed serum sickness

Anti-rabies serum produces higher Anti-rabies serum produces higher incidence (~16%) versus tetanus incidence (~16%) versus tetanus antitoxin (2.5-5%)antitoxin (2.5-5%)

Current Use of Foreign Current Use of Foreign SerumSerum

BotulismBotulism DiphtheriaDiphtheria Tetanus – equine, human antitoxinTetanus – equine, human antitoxin Snake bites (rattlesnakes,copper Snake bites (rattlesnakes,copper

heads,cottonmouth) heads,cottonmouth) Black widow/Latrodectus species Black widow/Latrodectus species ScorpionScorpion Antilymphocyte antibodyAntilymphocyte antibody Digoxin immune FAB (Digibind)Digoxin immune FAB (Digibind)

Other Agents Causing Other Agents Causing Serum SicknessSerum Sickness

AllopurinolAllopurinol Anti-thymocyte globulinAnti-thymocyte globulin Arsenicals derivativesArsenicals derivatives BarbituatesBarbituates BupropionBupropion CaptoprilCaptopril CarbamazepineCarbamazepine CephalosporinsCephalosporins Cholecystographic RCM Cholecystographic RCM CiprofloxinCiprofloxin DextranDextran

FluoxetineFluoxetine FurazolidoneFurazolidone Gold SaltsGold Salts GriseofulvinGriseofulvin HalothaneHalothane HydralazineHydralazine IodidesIodides IndomethacinIndomethacin Infuenza VaccineInfuenza Vaccine ItraconazoleItraconazole MethyldopaMethyldopa

Other Agents Causing Other Agents Causing Serum SicknessSerum Sickness

Mercurial derivativesMercurial derivatives MetronidazoleMetronidazole NSAIDsNSAIDs PenicillaminePenicillamine PenicillinsPenicillins PhenylbutazonePhenylbutazone PhenytoinPhenytoin PiperazinePiperazine ProcainamideProcainamide PropranololPropranolol RifampinRifampin

QuinidineQuinidine StreptokinaseStreptokinase SulindacSulindac SulfonamidesSulfonamides TetracyclineTetracycline ThiouracilsThiouracils

Still more causesStill more causes

Also…Also… Allergen extractsAllergen extracts Blood productsBlood products HormonesHormones VaccinesVaccines Infectious agentsInfectious agents Monoclonal antibodiesMonoclonal antibodies Hymenoptera stingsHymenoptera stings Tick bitesTick bites

What is Going on?What is Going on?

Foreign antigen introducedForeign antigen introduced Antibodies develop and can form Antibodies develop and can form

complexes with the antigencomplexes with the antigen Depending on the size and amount of Depending on the size and amount of

complexes, they may deposit on complexes, they may deposit on vascular wallvascular wall Smaller vessels more commonSmaller vessels more common Leads to vasculitis, nephritis, and arthritisLeads to vasculitis, nephritis, and arthritis

Fixation and activation of complementFixation and activation of complement

What is Going on?What is Going on? Increase in Anaphylatoxins like C3a and Increase in Anaphylatoxins like C3a and

C5aC5a Causes mast cells to degranulateCauses mast cells to degranulate Leads to PMNs influx to area of inflammationLeads to PMNs influx to area of inflammation

Endothelial cells increase expression of Endothelial cells increase expression of adhesion molecules (like ICAM)adhesion molecules (like ICAM)

Proinflammatory cytokines are released Proinflammatory cytokines are released by monocytes and macrophagesby monocytes and macrophages

Proteolytic enzymes are released and Proteolytic enzymes are released and mediate damage (and symptoms)mediate damage (and symptoms)

Mast Cell MediatorsMast Cell Mediators Preformed mediatorsPreformed mediators

HistamineHistamine ProteasesProteases

TryptaseTryptase Acid hydrolasesAcid hydrolases ProteoglycansProteoglycans Cytokines (TNF-Cytokines (TNF-αα, IL-4), IL-4)

Newly formed mediatorsNewly formed mediators ProstaglandinsProstaglandins LeukotrienesLeukotrienes ThromboxanesThromboxanes Platelet activating factorPlatelet activating factor

What is Going on?What is Going on? Increase in Anaphylatoxins like C3a and Increase in Anaphylatoxins like C3a and

C5aC5a Causes mast cells to degranulateCauses mast cells to degranulate Leads to PMNs influx to area of inflammationLeads to PMNs influx to area of inflammation

Endothelial cells increase expression of Endothelial cells increase expression of adhesion molecules (like ICAM)adhesion molecules (like ICAM)

Proinflammatory cytokines are released Proinflammatory cytokines are released by monocytes and macrophagesby monocytes and macrophages

Proteolytic enzymes are released and Proteolytic enzymes are released and mediate damage (and symptoms)mediate damage (and symptoms)

Why Does the Body do Why Does the Body do This?This?

Body’s way of dealing with some insults by Body’s way of dealing with some insults by complexing them before they can elicit their complexing them before they can elicit their damagedamage

These complexes then cleared by RE systemThese complexes then cleared by RE system Serum sickness is a systemic process whose Serum sickness is a systemic process whose

symptoms are determined by where immune symptoms are determined by where immune complexes are depositedcomplexes are deposited There is localized serum sickness reaction called There is localized serum sickness reaction called

Arthus reactionArthus reaction Other human immune-complex diseasesOther human immune-complex diseases

SLE, PAN, PSGNSLE, PAN, PSGN

Why Continued…Why Continued… Larger complexes are cleared more Larger complexes are cleared more

readily, smaller complexes more apt to readily, smaller complexes more apt to depositdeposit

Complexes with cationic charge may bind Complexes with cationic charge may bind negative BM more readilynegative BM more readily

IgG more likely culprit in forming the IgG more likely culprit in forming the complexes that are seen in serum sicknesscomplexes that are seen in serum sickness

Amount and size of complexes based on Amount and size of complexes based on the amount of antigen versus antibody the amount of antigen versus antibody present in system at the time (Zone of present in system at the time (Zone of Equivalence)Equivalence)

• 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

Radio-labeled bovine serum albumin is injected Radio-labeled bovine serum albumin is injected intravenously into normal rabbits at day 0, and intravenously into normal rabbits at day 0, and sequence of immunologic events is followed. At sequence of immunologic events is followed. At

about day 8, immune complexes are formed, about day 8, immune complexes are formed, complement levels fall, and rabbits become ill.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 ofEquivalence

Clinical SymptomsClinical Symptoms

Occur 6-21 days after administration of Occur 6-21 days after administration of foreign antigenforeign antigen Typically 7-14 daysTypically 7-14 days Accelerated symptoms within 2-4 days in Accelerated symptoms within 2-4 days in

patients previously sensitizedpatients previously sensitized Often pain, pruritis, erythema and Often pain, pruritis, erythema and

swelling at injection siteswelling at injection site Most cases resolve in a few days to a Most cases resolve in a few days to a

couple of weekscouple of weeks

Clinical SymptomsClinical Symptoms

FeverFever Mild to significantMild to significant 5-14 days after exposure5-14 days after exposure

LymphadenopathyLymphadenopathy Can be regional (at site) or generalizedCan be regional (at site) or generalized

ArthralgiasArthralgias More common in large joints like kneesMore common in large joints like knees Metacarpal and TMJ also seenMetacarpal and TMJ also seen Pain often out of proportionPain often out of proportion

Clinical SymptomsClinical Symptoms

Arthritis less commonArthritis less common Some patients may feel chest pain or Some patients may feel chest pain or

shortness of breathshortness of breath Edema may occur (especially face Edema may occur (especially face

and neck)and neck) Some patients may have visceral Some patients may have visceral

involvement such as hepatomegalyinvolvement such as hepatomegaly

Cutaneous EruptionsCutaneous Eruptions Present in 95%Present in 95% Urticaria - mediated by IgE and/or Urticaria - mediated by IgE and/or

complementcomplement Morbilliform eruptionMorbilliform eruption Maculopapular exanthemMaculopapular exanthem Erythema multiformeErythema multiforme PurpuraPurpura Angioedema, especially of face and neckAngioedema, 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 EruptionsCutaneous Eruptions

Characteristic serpiginous Characteristic serpiginous erythematous, purpuric eruption at erythematous, purpuric eruption at the junction of palmar and plantar the junction of palmar and plantar skin and the dorsum of the hands skin and the dorsum of the hands and feetand feet

Reported in 75% of patients Reported in 75% of patients receiving antithymocyte globulin in receiving antithymocyte globulin in one studyone study

Serpiginous Erythematous Serpiginous Erythematous (purpuric eruption at the (purpuric eruption at the junction of palmar and junction of palmar and

plantar skin)plantar skin)

Other ManifestationsOther Manifestations

Generalized vasculitisGeneralized vasculitis Peripheral neuritisPeripheral neuritis

Brachial Plexus most commonBrachial Plexus most common Guillain-Barre rareGuillain-Barre rare

GlomerulonephritisGlomerulonephritis

LabsLabs

May see proteinuria or hematuriaMay see proteinuria or hematuria May see a leukocytosis or May see a leukocytosis or

leukopenialeukopenia May have eosinophiliaMay have eosinophilia May have elevated ESRMay have elevated ESR Decreased complement (C3 and C4), Decreased complement (C3 and C4),

increased C3aincreased C3a

The Complement The Complement PathwaysPathways

Kuby, 336

Lectin pathway

DiagnosisDiagnosis

Typical symptom complex in a Typical symptom complex in a patient given foreign protein or drug patient given foreign protein or drug within the appropriate time intervalwithin the appropriate time interval

Symptoms have not lasted longer Symptoms have not lasted longer than one monththan one month

No single laboratory test is No single laboratory test is confirmatoryconfirmatory

TreatmentTreatment

Stop offending agent -should lead to Stop offending agent -should lead to resolution of the signs and diagnosis resolution of the signs and diagnosis within a period of days to a few within a period of days to a few weeks weeks

Symptoms are usually mild and Symptoms are usually mild and spontaneously resolve in a few days spontaneously resolve in a few days or weeks with symptomatic therapyor weeks with symptomatic therapy

Antihistamines and NSAID’s relieve Antihistamines and NSAID’s relieve the pruritis and painthe pruritis and pain

Treatment of Severe Treatment of Severe Serum SicknessSerum Sickness

CorticosteroidsCorticosteroids Administered and tapered over 10-14 Administered and tapered over 10-14

daysdays Shorter courses are associated with Shorter courses are associated with

relapsesrelapses Relapses are more difficult to alleviateRelapses are more difficult to alleviate

ProphylaxisProphylaxis

Incidence of serum sickness may be Incidence of serum sickness may be reduced by pretreatment with reduced by pretreatment with antihistaminesantihistamines Negates the effect of vasoactive aminesNegates the effect of vasoactive amines Decreases vascular permeabilityDecreases vascular permeability Reduces passive deposition of immune Reduces passive deposition of immune

complexescomplexes