We report a case of severe type IV hypersensitivity reaction to amoxicillin, which occurred in a person with a 12-year history of SLE. The present case illustrates the wide differential diagnosis in a SLE patient who presents with an allergic drug reaction. The attribution of the presenting symptoms to the underlying SLE and/or to the drugs used to treat SLE and coexisting conditions is a major challenge

Couto, M

Duarte, C

Geraldes, A

Inês, L

Malcata, AB

Medeiros, C

CHUC Institutional Repository

Rash, fever and proteinuria after amoxicillin in a SLE patient

Repositório Institucional dos Hospitais da Universidade de Coimbra

ÓRGÃO OF IC IAL DA SOC IEDADE PORTUGUESA DE REUMATOLOGIA - ACTA REUMATOL PORT. 2009;34:526-530526C A S O C L Í N I C OR A S H ,  F E V E R A N D P R O T E I N U R I AA F T E R A M O X I C I L L I N I N A S L E P AT I E N TM. Couto,* C. Duarte,** A. Geraldes,*** Colleen Medeiros,**** L. Inês,***** A. Malcata******quently exposed to drugs, which, “per se” repre-sents a risk factor for DA8 and thus normal controlwould be inappropriate. Pope et al5 studied DA inSLE patients using self-report data from age and sexmatched controls with inflammatory arthritis. Itwas found that, with the exception of skin rash forsulfonamides other DA were not more frequent inSLE. The other possibilities for the reported diffe-rences would be differences in the ethnicity of con-trol groups and the means of ascertaining allergicmanifestations,5 with medical record review1 repor-ting lower frequencies than self-reported.5 Finally,making the attribution of any allergic manifestationmust deal with the fact that drug2,3 may exacerba-te or even induce SLE.9 For instance, sulfonamidesmay cause flares in SLE patients.9 In addition somemanifestations, such as fever, rash and oral ulcers,might be attributed to DA but in fact may be a fea-ture of SLE exacerbation.Case reportA 30-year-old Portuguese female law student pre-sented to our emergency room with a 3-day historyof a progressive maculopapular rash that startedover her legs, odynophagia, minimally productivecough and non-bloody diarrhoea 5-6 times a day.Three days before her admission, she had consul-ted her dentist for dental pain and was given thecombination of amoxicillin 875 mg and clavulanicacid 125 mg bid. She had a history of a rash to pe-nicillin. After taking the second tablet, she develo-ped chills, malaise, myalgia and a rash over lowerextremities.The patient had a 12-year history of SLE mani-fested by malar rash, photosensitivity, oral ulcersand alopecia, leukopenia, polyarthritis and WHOclass IV diffuse membranoproliferative nephritis.When she was seen 2 months before, her SLE disea-se activity measured by SLAM-R was 3 (Table I) withstable doses of prednisone 20 mg qd and azathio-prine 50 mg bid. She was also on captopril 50 mg*Rheumatology Fellow at the Department of Rheumatology,Coimbra University Hospital and Assistant Professor of Physiology, Coimbra University School of Medicine, Coimbra,Portugal**Rheumatology Fellow at the Department of Rheumatology,Coimbra University Hospital, Coimbra, Portugal ***Immuno-Allergology Fellow at the Department of Immunologyand Allergy, Coimbra University Hospital, Coimbra, Portugal**** Clinical Medicine Pharmacist, Boston Medical Centre,Boston, Massachusetts USA*****Consultant Rheumatologist at Department of Rheumatology, Coimbra University Hospital and Assistant Professor of Rheumatology at Health Sciences School ofMedicine, Beira Interior University, Covilhã Portugal******Head of the Department of Rheumatology, Coimbra University Hospital and Assistant Professor of Rheumatology at Coimbra University School of Medicine, Coimbra, PortugalAbstractWe report a case of severe type IV hypersensitivityreaction to amoxicillin, which occurred in a personwith a 12-year history of SLE. The present case il-lustrates the wide differential diagnosis in a SLEpatient who presents with an allergic drug reac-tion. The attribution of the presenting symptoms tothe underlying SLE and/or to the drugs used to tre-at SLE and coexisting conditions is a major chal-lenge. Keywords: Systemic Lupus Erythematosus; DrugHypersensitivity; Amoxicillin; Simvastatin; Rhab-domyolysis.IntroductionAllergic drug reactions may be increased in Syste-mic Lupus Erythematosus (SLE) patients. Somestudies show that drug allergies (DA) are similar inSLE and controls,1,2 others suggest that SLE patientshave an increased risk of DA.3-7 One explanation fordiscrepancies between these studies is the choiceof controls and whether they are normal indivi-duals or disease controls. SLE patients are more fre- ÓRGÃO OF IC IAL DA SOC IEDADE PORTUGUESA DE REUMATOLOGIA - ACTA REUMATOL PORT. 2009;34:526-530527M. COUTO E COL.bid, simvastatin 20 mg qd, furosemide 20 mg qdand folic acid 5 mg qd. In the emergency room, her physical examina-tion showed an alert but ill woman, bilateral con-junctival haemorrhages, generalized purpuric rash,and a temperature of 39.5º C. Her pulse was111/min, her blood pressure was 103/70 mm Hg;the rest of her physical examination was normal.Laboratory tests showed high values of serumcreatinine (4.6 mg/L) and C-reactive protein (29.8 mg/dL), hypoalbuminemia (2.9 g/dL), eleva-ted SGOT (311 U/L), SGPT (86 U/L) and CPK (24220 U/L). Her lymphocytes (1.1x103/µl) and pla-telets (57x103/µL) were low (Table II). There was noeosinophilia. Her urine dipstick showed 3+ protei-nuria and hematuria. Her arterial blood gasesshowed pH=7.39 [7.35-7.45]; paO2=118 mm Hg [85-108]; pCO2=21.2 mm Hg [35-45] and HCO3= 12.7 mmol/L [21-29]. The chest X-ray showed dif-fuse bilateral lung interstitial infiltrates. The presumptive diagnoses at emergency roomwere sepsis, drug allergic reaction to the antibio-tic, rhabdomyolysis with secondary acute renal fai-lure and a SLE flare. She received intravenous fluids, paracetamol, bicarbonate, imipenem, a 250mg iv bolus of methylprednisolone followed by oralprednisone 60 mg qd, intramuscular clemastin andsupportive care.After admission to the rheumatology ward,prednisone was tapered from 60 mg qd to 20 mgover 13 days and she was given hydroxyzine 25 mgqd, furosemide 20 mg bid and albumin 1 g tid. Herskin lesions were treated with topical 0.1% betame-thasone. By the third day she became afebrile, wi-thout constitutional symptoms, skin lesions beca-me vesicular and epidermolysis occurred. Antibio-therapy was stopped at the 8th hospital day. Labo-ratory values normalized as she recovered (Figures1 and 2). Sputum was unobtainable and a subse-quent chest film showed clearing of the infiltratespresent at admission.Blood, urine and stool cultures, serology for EBV,CMV, parvovirus B19 and coxsackie were negative.Anti-dsDNA antibody was 34.2 U/ml [<4.2 U/ml],C3 0.78 g/L [0.9-1.8] and C4 0.2 g/L [0.1-0.4]. Shehad a proteinuria of 2.88 g/day, which persistedafter creatinine and CPK normalization. Except forproteinuria, urinalysis did not show abnormaliti-es (Table I); myoglobin, red cell casts and dysmor-phic red blood cells were absent. Her disease acti-vity measured by SLAM-R was 9. A repeat renalbiopsy showed WHO class IV-C diffuse proliphera-tive glomerulonephritis, with diffuse and segmen-Table I. Comparison of laboratorial values at baseline and on admission Baseline values Admission values Reference valuesHgb 11.9 13.0 11.5–16.5 g/dlWBC 3.5 8.4 4–11 x103/µLBlood Lymphocytes 0.7 1.1 1.5-4.95 x103/µLPlatelets 118 57 150–400x103/µLC3 / C4 not available 0.78 / 0.2 0.9–1.8 / 0.1–0.4 g/LAnti-dsDNA not available 34.2 <4.2 U/mlUrine Protein 10 193 0–20 mg/dlLeucocytes 7.4 29.4 1.0–36.0/µLRed blood cells 2.0 28.3 1.0–43.0/µLSLAM-R 3 9 0–81Hgb- haemoglobin;WBC- White blood cells; SLAM-R: SLE Activity Measure-RevisedTable II. Laboratorial values on admissionReference Value valuesCreatinine 4.6 0.6-1 mg/dlCRP 29.8 0-0.82 mg/lAlbumine 2.9 3.5-5 g/dlSGOT 311 5-34 U/LSGPT 86 5-34 U/LCK 24220 29-168 U/LHgb 13.0 11.5-16.5 g/dlLeukocytes 8.4x103 4-11x103/µLLymphocytes 1.1x103 >1.5x103/µLPlatelets 57x103 150-400x103/µLÓRGÃO OF IC IAL DA SOC IEDADE PORTUGUESA DE REUMATOLOGIA - ACTA REUMATOL PORT. 2009;34:526-530528SLE AND ALLERGIC DRUG REACTIONtal sclerosis without active lesions (Figures 3 and4). Intradermal skin tests confirmed type IV hyper-sensitivity to amoxicillin, ampicilin and dicloxa-cillin.The patient was discharged at the 28th hospitalday treated with prednisolone 10 mg qid, furosemi-de 40 mg bid, enalapril 5 mg qid and azathioprine50 mg bid. After discharge, the Nephrologist decidedto change azathioprine for mycophenolate mofetil1 g bid, stopped after one year due to lack of bene-fit. She continues her follow-up at the Rheumato-logy and Nephrology Outpatient Clinics. She main-tains mild chronic renal insufficiency with a SLAM-R score of 3 (low disease activity) at last visit.DiscussionIn this patient several diagnoses had to be consi-dered. These were in order of likelihood: 1) amoxi-cillin hypersensitivity; 2) sepsis; 3) rhabdomyolysisfrom simvastatin precipitated by amoxicillin he-patotoxicity; 4) sepsis causing a lupus flare; 5) amo-xicillin- induced lupus flare or 6) some combina-tion of the above.Drug allergy (DA) to amoxicillin was the mostprobable precipitating event considering the pati-ent’s previous history, the temporal sequence ofevents and because allergic reactions to β-lactamicdrugs are common. Our patient presented a typeIV hypersensitivity reaction, which can occur fromone hour to several days after re-exposure to thedrug, more commonly 48-72 hours after.10 This re-action differs from an immediate hypersensitivityreaction, which generally appears within 12 minu-tes and no longer than one hour of an antigen chal-lenge with urticaria with or without angioedema oranaphilaxis.1 There is evidence that the longer theinterval between drug intake and appearance ofthe reaction the less the probability of being IgEmediated. The patient had no family or personalhistory of atopy, which has been associated with anincreased risk of DA.2 The onset of maculopapularlesions occurring after the re-exposure to antibio-tics is typical of Type IV hypersensitivity reactions.3As the mechanism is not IgE-mediated, measuringIgE specific to amoxicillin would not help confirmthe diagnosis. The use of skin testing, such as in-011 3 5 9 262435060.00050.00040.00030.00020.00010.00070.000Creatinine (U/ml)CRP (mg/dl)Hospital dayCreatinine and CPK evolution over timeCreatinineCPKFigure 1. Evolution of creatinine and CPK over time02001 3 5 9 264006008001.00002530201510535SGOT and SGTP(U/ml)CRP (mg/dl)Hospital dayCRP, SGOT and SGTP over timeSGOTSGTPCRPFigure 2. Evolution of creatinine and CPK over time ÓRGÃO OF IC IAL DA SOC IEDADE PORTUGUESA DE REUMATOLOGIA - ACTA REUMATOL PORT. 2009;34:526-530529M. COUTO E COL.tradermal or patch testing is somewhat controver-sial and some contend that is particularly not help-ful in autoimmune diseases like SLE.3Oral challenge test with amoxicillin is the diag-nostic gold standard test,4 but in this patient it wascontraindicated because she had a severe eventand testing was potentially dangerous or even fa-tal. In this case, the positive intradermal test toamoxicillin helped to confirm the diagnosis. The other major differential was sepsis from herdental infection. High fever, hypotension and ele-vated CRP made sepsis diagnosis very likely andthus the decision to treat her immediately with an-tibiotic. Knowledge of a previous allergy to Benzylpenicillin could have prevented this hospitalizati-on; penicillin, amoxicillin and, to a lesser extentcephalosporins share extensive cross-reactivity.5One might also question the use of imipenem du-ring her hospitalization as it is a β-lactamic and itscross-reactivity is not fully known.6,7 Rhabdo-myolysis is uncommon in amoxicillin DA, but is aknown and rare adverse effect of simvastatin andthought to be dose-related. Hepatotoxicity hasbeen described in amoxicillin and liver injury couldinterfere with the metabolism of simvastatin re-sulting in higher drug levels leading to muscle ne-crosis. Acute renal failure develops in 30-40% ofpatients with rhabdomyolysis. Suggested mecha-nisms include precipitation of myoglobin and uricacid crystals within renal tubules, decreased glo-merular perfusion, and the nephrotoxic effect offerrihemate (formed upon dissociation of myoglo-bin in the acidic environment of the renal pa-renchyma).8Infection2,7 and drugs,9 including antibiotics cantrigger a systemic lupus flare or the patient couldhave had a lupus flare not related to these. The pre-sence of chills, neutrophilia, leucocytosis arethought to be markers of infection rather thanSLE11 and our patient had these features. The pati-ent had SLE class IV diffuse glomerulonephritissince ten years before. On this admission, presen-ce of fever, hypocomplementemia, lymphopenia,thrombocytopenia, elevated anti-dsDNA and al-most nephrotic-range proteinuria (compared toher baseline) favours a lupus flare. A non-renal lu-pus flare is likely to have occurred. The reversal ofacute renal failure could relate to improvement ofthe drug reaction but a lupus nephritis flare couldalso have improved with the increase in steroidtherapy. However, the argument for a lupus nephri-tis flare is weak, since the renal biopsy showed noevidence of active lesions. Furthermore, the trialwith mycophenolate mofetil produced no impro-vement, as expected from the biopsy.   In conclusion, the most likely causal pathway forthe most severe manifestations was a type IV hyper-sensitivity reaction due to amoxicillin causing he-patotoxicity leading to increased simvastatin pre-cipitating rhabdomyolysis and acute renal failure.Also, a non-renal lupus flare and possibly an infec-tion likely occurred in this complex clinical case.Correspondence to:Maura Couto Department of Rheumatology, Coimbra University Hospital,Coimbra, PortugalE-mail: maura_couto@yahoo.comFigure 3. Two hyaline glomeruli with global sclerosis;chronic interstitial nephritis with fibrosis (PAS staining;magnification: 20x)Figure 4. Two hyaline glomeruli and peritubular sclerosiswith epithelial atrophy (Masson tricromic staining;magnification: 20x) ÓRGÃO OF IC IAL DA SOC IEDADE PORTUGUESA DE REUMATOLOGIA - ACTA REUMATOL PORT. 2009;34:526-530530SLE AND ALLERGIC DRUG REACTIONAcknowledgmentsWe are extremely grateful to Dr Matthew Liang for hisinsightful comments that much contributed for thecase discussion.References1. Adkinson NF Jr, Yunginger JW, Busse WW, BochnerBS, Holgate ST, Simons FER. Drug Allergy. In Middle-ton`s Allergy, principles and practice. New York: Mos-by Co, 2003: 1679-1694.2. Pope J. Frequency of adverse drug reactions in pa-tients with sytemic lupus erythematosus. J Rheum2003; 30: 480-484.3. Brockow K, Romano A, Blanca M, Ring J, Pichler W,Demoly P. General considerations for skin test proce-dures in the diagnosis of drug hypersensitivity. Al-lergy 2002; 57: 45-51.4. Aberer W, Bircher A, Romano A et al. Drug provoca-tion testing in the diagnosis of drug hypersensitivityreactions: general considerations. Allergy 2003; 58:854-863.5. Zandman-Goddard G, Shoenfeld Y. Infections andSLE. Autoimmunity 2005; 38: 473-485.6. Gomez MB, Torres MJ, Mayorga C, Demoly P,DeWeck A. Immediate allergic reactions to betalac-tams: facts and controversies. Curr Opin Allergy ClinImmunol 2004; 4:261-266.7. Kishiyama JL, Adelman DC. The cross-reactivity andimmunology of beta-lactam antibiotics. Drug Saf1994; 10:318-327.8. Craig S. Rhabdomyolysis.  eMedicine: Specialties:Emergency Medicine. Updated in 2008.9. Rubin RL. Drug-induced lupus. In Wallace, D J.;Hahn, BH. Dubois' Lupus Erythematosus. Baltimore:Lippincott Williams & Wilkins, 2007: 874-875.10. Pichler WJ. Drug Hypersensitivity reactions: Classifi-cation and relationship to T-Cell activation. In DrugHypersensitivity. Basel: Karger, 2007: 168-189.11. Stahl NI, Klippel JH, Decker JL. Fever in systemic lu-pus erythematosus. Am J Med 1979; 67:935-940.V Jornadas de Reumatologia e Medicina Familiar do AlgarveAlgarve, Portugal30 a 31 de Outubro de 20094th European Workshop on Immune Mediated Inflammatory DiseasesCascais, Portugal18 a 20 de Novembro de 2009 

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Rash, fever and proteinuria after amoxicillin in a SLE patient

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