Drug-induced leukocytoclastic vasculitis with systemic involvement secondary to nitrofurantoin therapy

INTRODUCTION

Vasculitis may affect a single organ, most commonly, the skin or have systemic involvement. Leukocytoclastic vasculitis (LCV) is vasculitis of small vessels with neutrophilic inflammatory infiltrates which generally present as palpable purpuric lesions.¹ Cutaneous LCV is an isolated cutaneous angiitis without systemic vasculitis or glomerulonephritis as defined in the Chapel Hill conference in 1994. LCV may be primary or secondary to infections, rheumatological diseases and drugs.²

Nitrofurantoin is a first-line antibacterial agent in the treatment of uncomplicated lower urinary tract infection (UTI). Nausea and other gastrointestinal disturbances are its most common side-effects while hepatotoxicity, interstitial nephritis, drug reaction with eosinophilia and systemic symptoms are uncommon.³ We report LCV with systemic involvement as an adverse drug reaction to nitrofurantoin therapy, which may be fatal if not recognized and managed early.

THE CASE

A 61-year-old male presented with history of fever and burning micturition for 1 week. Three days after being started on nitrofurantoin 100 mg twice a day by a local practitioner, the patient developed rash all over the body along with scrotal swelling and pain. While admitted at the local government hospital with these complaints, he developed acute anterolateral wall myocardial infarction (MI) with ventricular tachycardia, which reverted to sinus rhythm following cardioversion. He was then referred to our hospital for further management.

At admission, physical examination revealed livedo reticularis and reticular purpuric plaques with occasional ulceration over both lower limbs, upper limbs and abdomen with extensive scrotal purpura and necrosis (Fig 1). His pulse rate was 110/minute, respiratory rate 26/minute and blood pressure 110/80 mmHg in right arm the supine position. Oxygen saturation was 88% by pulse oximetry while breathing room air. Temperature was 101 °F. Rest of the physical examination was unremarkable. During the course of stay in hospital, his blood pressure remained in the normal range.

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FIG 1.

Clinical photograph showing reticular purpuric plaques with occasional ulceration over bilateral lower limbs

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Suspecting an infective aetiology, he was started on empirical intravenous antibiotics, oxygen supplementation alongwith anticoagulation, antiplatelet drugs, beta-blockers and other supportive therapy. Laboratory investigations revealed neutrophilic leucocytosis (total leucocyte count 15 300 cells/cmm), thrombocytopenia (platelet count 92 000/cmm), acute kidney injury (serum creatinine 2.67 mg/dl) and hepatic dysfunction (serum total bilirubin 2.6 mg/dl and serum conjugated bilirubin 1.4 mg/dl). Of the three samples of urine sent for routine analysis at different times, all showed only trace of albumin and only 1 had 6–8 red blood cells/high-power field. Scrotal ultrasonography revealed epididymo-orchitis. The following day, he developed altered sensorium; computed tomography of the brain showed an infarct in the right fronto-parietal region.

The possibility of LCV with systemic involvement was considered. A punch biopsy of the lesion, confirmed LCV with subepidermal bulla formation (Fig 2). The patient’s history was reviewed again. An adverse drug reaction to nitrofurantoin was suspected as the cause for LCV. Vasculitic work-up was done. The cytoplasmic antineurophil antibody (cANCA) and perinuclear neutrophil antibodies (pANCA) were both negative and therefore myeloperoxidase proteinase 3 was not done. Serum C3 was 79.2 mg/dl (normal range 91–156 mg/dl) and C4 was 23.6 mg/dl (normal range 20–50 mg/dl). Antinuclear antibody (ANA) and ANA profile were also negative.

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FIG 2.

Photomicrograph showing blood vessels with the vessel walls infiltrated by neutrophils and lymphocytes with extravasation of red blood cells (haematoxylin and eosin, ×400)

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He was started on intravenous steroids (dexamethasone 8 mg three times daily) with antibiotic therapy and symptomatic management. The skin lesions subsided gradually and he improved clinically. He was discharged in a stable condition after 2 weeks of in-hospital stay on a tapering dose of oral steroids.

DISCUSSION

Nitrofurantoin is a synthetic antibiotic created from furan, with an added nitro group with a hydantoin side-chain. Nitrofurantoin as the first-line drug for treatment and prophylaxis of uncomplicated UTI and recurrent cystitis especially due to its minimal effect on gut flora. It has relatively few side-effects, with gastrointestinal disturbances being the most frequent. Rarely, severe reactions such as interstitial lung disease patterns, peripheral neuropathy, interstitial nephritis and hepatotoxicity, with or without hepatic necrosis have been reported.^4,5 There have been a few reports of vasculitis with or without systemic involvement as an adverse reaction to nitrofurantoin therapy.² There are two case reports of nitrofurantoin-induced ANCA-associated vasculitis.^3,6 However, LCV due to nitrofurantoin is rare.

LCV is a clinicopathological term. It commonly presents as palpable purpura, urticarial wheals, erythematous plaques, bullous haemorrhages or ulcers. The presence of livedo reticularis (as in our patient), deep skin ulcers and nodules are suggestive of medium size vessel involvement besides small vessels. The incidence of biopsy proven LCV annually is 30 cases/million population.⁷ Up to half the cases of LCV are idiopathic. The most common causes of secondary LCV are chronic infections, drugs, connective tissue disorders and malignancies. Drugs commonly associated with LCV are beta-lactams, erythromycin, clindamycin, vancomycin, sulphonamides, furosemide, beta-blockers, metformin, warfarin, valproic acid, etc.⁸

Evaluation of LCV has two goals; one is to determine the extent of systemic involvement and the other is the determination of aetiology. Biopsy and histopathological examination confirm the diagnosis of LCV. As in our case, the patient may have multi-organ involvement in LCV, especially end-organ damage, respiratory failure, hepatic dysfunction and haematological abnormalities such as leucocytosis and thrombocytopenia. A drug history going back 6 months is advisable while evaluating for the cause of LCV.¹ While polyarteritis nodosa (PAN) was another possible diagnosis; the patient did not have high blood pressure at the time of presentation or during the hospital stay. Skin biopsy findings showed capillaritis with no evidence of involvement of medium size vessels. Hence, PAN was ruled out.

The treatment of LCV depends on two aspects: the cause and the disease severity. If LCV is secondary to an underlying disease or a known drug, treatment involves management of the underlying condition or elimination of the drug. When LCV presents with multi-organ involvement, management generally requires treatment with systemic steroids with or without other immunosuppressive drugs such as rituximab.¹

Our patient had a rare presentation of LCV with systemic involvement as an adverse drug reaction to nitrofurantoin. Early diagnosis with prompt identification and withdrawal of the causative drug alongside steroid therapy is essential for a favourable outcome.