Serum SicknessSerum Sickness

Medicine Morning ReportMedicine Morning Report4/16/20044/16/2004

Oliver Medzihradsky, M.D.Oliver Medzihradsky, M.D.

HistoryHistory

1st described in 1905, as human 1st described in 1905, as human rxnrxn to to equine diphtheria antitoxin equine diphtheria antitoxin (von (von PirquetPirquet and and ShickShick))

88--13 days later: rash, fever, +/13 days later: rash, fever, +/-- facial facial edema, edema, arthralgiaarthralgia, local LAD, , local LAD, albuminuriaalbuminuriaLater, similar seen w/ other horse Later, similar seen w/ other horse antitoxins, antiveninsantitoxins, antiveninsSoon recognized with Soon recognized with NSAIDsNSAIDs, PCN, PCNNow w/ Now w/ monoclonalsmonoclonals, , antithymocyteantithymocyte globglob

DefinitionDefinition

Immune complex (type III) hypersensitivity Immune complex (type III) hypersensitivity reactionreactionRashRash

UrticarialUrticarial, , morbilliformmorbilliform, or , or angioedemaangioedemaArthralgiaArthralgia or Arthritisor ArthritisFeverFeverOnset 5Onset 5--14 days (may be up to 21) after drug 14 days (may be up to 21) after drug or foreign protein exposure (does not require or foreign protein exposure (does not require prior sensitization)prior sensitization)May occur 1May occur 1--3 days later if previous exposure 3 days later if previous exposure

EpidemiologyEpidemiologyDecreasing incidence in U.S. due to:Decreasing incidence in U.S. due to:↑↑ in vaccines in vaccines ----> > ↓↓ need for antitoxins & need for antitoxins & more refined antitoxins (rabies, tetanus)more refined antitoxins (rabies, tetanus)Adult cases: antitoxin/Adult cases: antitoxin/--sera usually responsiblesera usually responsible

5050--85% incidence in recent 85% incidence in recent antithymocyteantithymocyte trialtrialRCT of mouse RCT of mouse MabMab to TNFto TNFαα: 2.3% incidence: 2.3% incidence

In children, more often ATBXIn children, more often ATBX--associated:associated:cefaclorcefaclor >> TMP>> TMP--SMX > SMX > cephalexincephalexin > amoxicillin> amoxicillinAvgAvg incidence 2/100K to 1/10 millionincidence 2/100K to 1/10 million

SxSx are doseare dose-- and antigen typeand antigen type--dependent:dependent:Animal source >>> drugs in terms of riskAnimal source >>> drugs in terms of riskImmunogenicityImmunogenicity of rabies (16%) > tetanus (3of rabies (16%) > tetanus (3--5%)5%)

Etiology Etiology -- 11

Historically, antitoxins & antiveninsHistorically, antitoxins & antiveninstetanus, tetanus, botulinumbotulinum, rabies, snakebites, rabies, snakebites

Now often due to immunogenic Now often due to immunogenic haptenshaptens(often difficult to prove causality)(often difficult to prove causality)Infections with circulating immune complexes Infections with circulating immune complexes

HBV, HCV, HBV, HCV, endocarditis/bacteremiaendocarditis/bacteremia, ?HIV, ?HIVInsect stings: bees, mosquitoes, ticksInsect stings: bees, mosquitoes, ticksPAbs/MAbsPAbs/MAbs from horse/rabbit/mouse serum:from horse/rabbit/mouse serum:

AntithymocyteAntithymocyte globulin, OKT3globulin, OKT3

Etiology Etiology -- 22

MedsMedsATBXATBX: : PCNsPCNs, , cephalosporinscephalosporins, sulfonamides, , sulfonamides, ciprocipro, , tettet, , metronidazolemetronidazole, , rifampinrifampin, streptomycin, , streptomycin, griseofulvgriseofulvAnticonvulsantsAnticonvulsants: : phenytoinphenytoin, , carbamazepinecarbamazepinePsychotropicsPsychotropics: : buproprionbuproprion, , fluoxetinefluoxetine, barbiturates, barbituratesAntiHTNAntiHTN: : propranololpropranolol, , captoprilcaptopril, , hydralazhydralaz, CH4dopa, CH4dopaAntidysrhythmicsAntidysrhythmics: : procainamideprocainamide, , quinidinequinidineAnticancerAnticancer: : mercaptopurinemercaptopurineAntiinflammatoriesAntiinflammatories: gold, : gold, penicillaminepenicillamine, , NSAIDsNSAIDsOtherOther: : allopurinolallopurinol, iodides, , iodides, methimazolemethimazole, , streptokinasestreptokinase

Hypersensitivity Hypersensitivity RxnsRxns

Chronic transplant rejectionContact dermatitis, Hashimoto’sMycobacterial & fungal infex

No Abs: sensitized T cellsIV

Poststrep GN, serum sickness, PAN, SLEHypersensitivity pneumonitisMany more w/ complexes demonstrated

IgG, IgM (IgA) immune complexesIII

Txfusion rxn, ITP, Goodpasture’s

(+/- Graves’, myasthenia)

IgG, IgM complement/phago/NKcytotoxic immune response

II

Local/Atopy (eczema, allergies, asthma)or

Systemic (anaphylaxis)

IgE mast cells, basophilshistamine/LT’s

edema, bronchospasm

I

PathophysiologyPathophysiology

Immune complex process (Type III hypersensitivity)Immune complex process (Type III hypersensitivity)Type of Ag influences Type of Ag influences IgIg type, influencing pathologytype, influencing pathologyTypically Typically IgGIgGOccasionally Occasionally IgMIgM, but more effectively cleared by RES, but more effectively cleared by RESRarely Rarely IgAIgADeposition of immune complexes in vessel walls, Deposition of immune complexes in vessel walls, joints, and renal joints, and renal glomeruliglomeruliActivate complement pathway Activate complement pathway ----> vascular wall injury> vascular wall injury----> PMN influx > PMN influx ----> inflammation w/ tissue injury> inflammation w/ tissue injury

HistopathologyHistopathology

Inflammation of small vessel endotheliumInflammation of small vessel endotheliumSkin > renal, GI, joints > CNSSkin > renal, GI, joints > CNS

LeukocytoclasticLeukocytoclastic vasculitisvasculitisNeutrophilicNeutrophilic (<24 hrs old) or mononuclear infiltration of (<24 hrs old) or mononuclear infiltration of vessel wall & vessel wall & perivascularperivascular regionregionMost prominent in Most prominent in postcapillarypostcapillary venulesvenulesRenal Renal IgGIgG + C3a + C5a deposits along GBM+ C3a + C5a deposits along GBMMononuclear infiltration of Mononuclear infiltration of synoviumsynovium

Little correlation between Little correlation between SxSx and and histologichistologic patternpatternComplexes can be detected: C1q or Complexes can be detected: C1q or RajiRaji cell assaycell assay

Common PresentationsCommon Presentations

Rash (95%): Rash (95%): pruriticpruritic, URTICARIAL, , URTICARIAL, morbilliformmorbilliform, , scarlatiniformscarlatiniform, or , or angioedemaangioedema

May start with May start with prurituspruritus & & erythemaerythema @ injection site@ injection siteFever (~all) (Fever (~all) (usuusu <40C) (precedes rash in 20%)<40C) (precedes rash in 20%)ArthralgiasArthralgias (30(30--60%)60%)MyalgiasMyalgias & Headache (40& Headache (40--60%)60%)Arthritis (10Arthritis (10--50%) (knee, ankle, MCP, wrist) 50%) (knee, ankle, MCP, wrist) (symmetric)(symmetric)Regional Regional lymphadenopathylymphadenopathy (20%)(20%)Facial edema (d/t Facial edema (d/t albuminuriaalbuminuria and/or rash)and/or rash)Duration: 7Duration: 7--30 days, Onset 530 days, Onset 5--21 days post exp21 days post exp

Up to 50% present withUp to 50% present with

Visceral target organ involvementVisceral target organ involvementRare, but may be severe Rare, but may be severe ---- may include:may include:

Renal (Renal (glomerulonephritisglomerulonephritis, acute failure), acute failure)Lymph (generalized LAD, Lymph (generalized LAD, splenomegalysplenomegaly))NeuroNeuro (CN palsy, peripheral/brachial/optic (CN palsy, peripheral/brachial/optic neuritis, GBS, neuritis, GBS, myelitismyelitis, encephalitis), encephalitis)Cardiac (Cardiac (pericarditispericarditis, , myocarditismyocarditis))Pulmonary (Pulmonary (pleuritispleuritis))GI (terminal ileitis)GI (terminal ileitis)

DiagnosisDiagnosis

History: offending drug or infectionHistory: offending drug or infectionSkin biopsy: Skin biopsy: leukocytoclasticleukocytoclastic vasculitisvasculitis of of venulesvenules/cap’s/cap’sLeukopeniaLeukopenia or slight or slight --cytosiscytosis +/+/-- plasma cells, +/plasma cells, +/-- eo’seo’sLow C3, C4 levels (more with Low C3, C4 levels (more with heterologousheterologous serum than serum than with drugwith drug--induced serum sickness)induced serum sickness)Elevated ESRElevated ESRPolyclonal Polyclonal gammopathygammopathy, transient , transient IgGIgG spikespikeMild Mild proteinuriaproteinuria, micro , micro hematuriahematuria, hyaline casts, hyaline casts+/+/-- cryoglobulinscryoglobulins, often mixed , often mixed IgGIgG--IgMIgM typetype

(may indicate mixed (may indicate mixed cryoglobulinemiacryoglobulinemia due to chronic hepatitis due to chronic hepatitis C infection)C infection)

Differential diagnosisDifferential diagnosis

CryoglobulinemiaCryoglobulinemiaImmediate hypersensitivity reactionImmediate hypersensitivity reactionMononucleosisMononucleosisViral hepatitisViral hepatitisUrticarialUrticarial vasculitisvasculitis with with hypocomplementemiahypocomplementemiaSLESLEInfectious Infectious endocarditisendocarditisAcute rheumatic feverAcute rheumatic feverPoststreptococcalPoststreptococcal glomerulonephritisglomerulonephritis

TreatmentTreatment

Discontinue offending agent Discontinue offending agent Recognize causative infection and treatRecognize causative infection and treatConsider rheum/Consider rheum/immunolimmunol evalevalNSAIDS, antihistamines for NSAIDS, antihistamines for SxSx reliefreliefSteroids if Steroids if significsignific, if , if mutisystemmutisystem SxSx, or if agent , or if agent needs to be continuedneeds to be continued

Review (n=95): 54 no Rx, 26 Review (n=95): 54 no Rx, 26 NSAIDsNSAIDs, 14 steroids, 14 steroidsAt 16 months, 93/95 full recovery, 2 mild renal CRIAt 16 months, 93/95 full recovery, 2 mild renal CRI

Rarely: Rarely: colchicinecolchicine, , dapsonedapsone, , pentoxifyllinepentoxifylline

PrognosisPrognosis

Typically excellentTypically excellentExceptions: progressive GN, CNS injuryExceptions: progressive GN, CNS injuryReconsider Reconsider DxDx if if SxSx persist > 3persist > 3--4 weeks4 weeksAvoid future exposures to agentAvoid future exposures to agent

ReferencesReferences

Abraham et al. 1995. Efficacy and safety of monoclonal antibody Abraham et al. 1995. Efficacy and safety of monoclonal antibody to to human tumor necrosis factor alpha in patients with sepsis syndrohuman tumor necrosis factor alpha in patients with sepsis syndrome. A me. A randomized, controlled, doublerandomized, controlled, double--blind, blind, multicentermulticenter clinical trial. JAMA clinical trial. JAMA 273(12):934273(12):934--41.41.

BieloryBielory et al. 1988. Human serum sickness: a prospective analysis of 35et al. 1988. Human serum sickness: a prospective analysis of 35patients treated with equine antipatients treated with equine anti--thymocytethymocyte globulin for bone marrow globulin for bone marrow failure. Medicine (Baltimore) 67(1):40failure. Medicine (Baltimore) 67(1):40--57.57.

HunderHunder. 2003. Hypersensitivity . 2003. Hypersensitivity vasculitisvasculitis in adults. in adults. UpToDateUpToDate..

NaguwaNaguwa and Nelson. 1985. Human serum sickness. and Nelson. 1985. Human serum sickness. ClinClin Rev Rev AllergAllerg3(1):1173(1):117--26.26.

Platt et al.1988. Serum sicknessPlatt et al.1988. Serum sickness--like reactions to amoxicillin, like reactions to amoxicillin, cefaclorcefaclor, , cephalexincephalexin, and , and trimethoprimtrimethoprim--sulfamethoxazolesulfamethoxazole. J . J InfInf DisDis 158(2):474158(2):474--7.7.