Postgrad Med J 1997; 73: 764- 765 (© The Fellowship of Postgraduate Medicine, 1997 Adverse drug reaction of the month Postgrad Med J: first published as 10.1136/pgmj.73.865.764 on 1 November 1997. Downloaded from Low-grade fever after prosthetic valve insertion and captopril therapy: an iatrogenic cause

MC Bialas, H Varley, HGM Shetty, PA Routledge

A 55-year-old obese woman with previous fever was reported in two of seven individuals hypothyroidism had a myocardial infarction with rash associated with captopril therapy followed by sudden papillary muscle rupture which had been started 1-31 weeks earlier.2 and profound cardiac failure. A Medtronic Fever has also been reported in association mitral valve prosthesis was inserted as an with rash and pericarditis.3 The CSMIMCA emergency but she remained in severe left have received 17 reports of pyrexia in associa- ventricular failure until eventually controlled tion with captopril up until November 1996 on frusemide 100 mg/day, isosorbide mononi- and although fever has sometimes resolved trate 10 mg bid, digoxin 125 jug once daily, with continuing administration,4 it may resolve and captopril 12.5 mg bid. She was also only after captopril is withdrawn.5 In our receiving warfarin because of the prosthetic patient, the persistent pyrexia soon after the valve, thryoxine 150 jug and prednisolone insertion of a prosthetic valve led to a long and 7.5 mg daily for muscular pains (not associated unsuccessful search for infection, and in with other symptoms) diagnosed two years particular infection of the prosthetic valve earlier as possible polymyalgia rheumatica. before an iatrogenic (drug-induced) cause She was making good progress until four was considered. It is likely that only one third months later when she complained of malaise, of cases of pyrexia of unknown origin have an myalgia and arthralgia, of feeling flushed and infective cause and some important drug- she was noted to have a persistent low grade induced causes of fever are shown in box 1, pyrexia (37.5- 38°C), a polymorphonuclear although many more agents are occasionally leucocytosis (white blood cell count 13 000, associated with fever. 80% neutrophils), and an erythrocyte sedi- The rash associated with captopril has been mentation rate of 50 mm/h (previously steady described as pruritic, erythematous, macular or around 35 mm/h). Endocarditis was consid- papular affecting the trunk, face and proximal ered in the differential diagnosis but extensive extremities but psoriasiform, lupus erythema- investigations over a four-week period includ- tosus-like, lichenoid and pemphigus/pemphi- ing repeated blood cultures, virology screen, goid-like eruptions have also been seen.6 The

auto-antibodies, abdominal computed tomo- corticosteroids which our patient was receiving http://pmj.bmj.com/ graphy (CT) scan, transoesophageal echocar- could possibly have suppressed the develop- diography, and white cell scan failed to detect ment of a rash until a late stage since steroids any abnormality and a prolonged course of have been used in the treatment of captopril- antibiotics (including cefuroxime, metronida- induced rash. Arthralgia has been described in zole and flucloxacillin) had no effect on her association with captopril treatment,2'7'8 with symptoms, temperature or leucocytosis. resolution when the drug was discontinued. At four weeks, she developed an erythema Fever, rash and arthralgia are part of a on October 3, 2021 by guest. Protected copyright. multiforme-like rash which persisted when the symptom complex which may also include antibiotics were discontinued and it was myalgia, serositis, vasculitis, positive antinuc- decided that captopril would also be with- lear antibody, raised erythrocyte sedimentation drawn. Within 48 hours, her temperature had rate, eosinophilia, leukocytosis and photosen- fallen to 37°C for the first time in four weeks sitivity seen in association with ACE inhibi- Welsh Adverse Drug and she remained apyrexial, her malaise and tors.9 It appears to be more commonly (but not Reactions Scheme, myalgia disappeared, as did her rash and she University of Wales was discharged home. Unfortunately, her College of Medicine, cardiac failure slowly returned over the next Cardiff, Wales, UK few months and five months later, she was re- Some drugs which may cause fever MC Bialas H Varley admitted and enalapril was instituted at a dose * anticonvulsants (carbamazepine, lamotrigine, HGM Shetty of 10 mg mane and 5 mg nocte. She re- phenytoin) PA Routledge sponded well to addition of this angiotensin- * anti-infectives (isoniazid, minocycline) converting enzyme (ACE) inhibitor without * bisphosphonates (especially intravenous) Correspondence to recurrence of her malaise, myalgia, arthralgia, * ACE inhibitors (captopril) Professor Routledge, * cytokines (aldesleukin) Department of rash, leucocytosis or pyrexia. * cytotoxic Pharmacology, Therapeu- drugs tics and Toxicology, * fibrinolytics (streptokinase, anistreplase) University of Wales Discussion * interferons (a, ,B, y) College of Medicine, * penicillamine Heath Park, Cardiff CF4 Low-grade pyrexia and myalgia with rash in * vaccines 4XN, Wales, UK two patients receiving captopril was first Accepted 1 May 1997 reported nearly 20 years ago.' Subsequently, Box 1 Adverse drug reaction 765

exclusively) reported in association with cap- Learning points topril (which, like penicillamine, contains a sulphydryl group) than with the other ACE * pyrexia ofunknown origin may not always have Postgrad Med J: first published as 10.1136/pgmj.73.865.764 on 1 November 1997. Downloaded from inhibitors. The frequency of the reaction with an infective cause and iatrogenic causes may captopril is unknown but it may well be need to be considered * ACE inhibitors can cause a symptom complex overlooked or not reported to the CSM/ which includes pyrexia, arthralgia, myalgia, MCA. Nevertheless the CSM/MCA had re- rash and raised erythrocyte sedimentation rate ceived 31 reports of arthralgia, 26 of myalgia * these features can occur with one ACE and 19 of erythema multiforme in association inhibitor but not with another and cautious with captopril therapy by 30 December 1996. introduction of an alternative agent can be ACE inhibitor therapy has been a major attempted if clinically indicated advance in the treatment of heart failure and * corticosteroids can mask features of adverse this woman who had profound left ventricular drug reactions and delay their diagnosis failure deteriorated markedly before an ACE inhibitor was re-introduced. Resolution of Box 2 captopril-induced rash after substitution of enalapril has occurred'0 so we decided to effect of these agents. Skin testing has been introduce this drug. The failure of recurrence used to investigate possible hypersensitivity to of symptoms and signs is suggestive of a captopril and was reasonably specific but specific and possibly type B (idiosyncratic) relatively insensitive in patients with cutaneous adverse reaction to captopril rather than a class reactions."I

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