Acta Dermatovenerol Croat 2019;27(1):28-32 CLINICAL ARTICLE

Penicillin-induced Cutaneous Necrotizing Eosinophilic with Cryofibrinogenemia

Branislav Lekić1, Mirjana Gajić-Veljić1,2, Branka Bonači-Nikolić2,3, Miloš Nikolić1,2

1University of Belgrade School of Medicine, Belgrade, Serbia; 2Clinic of Dermatovene- reology, Clinical Center of Serbia, Belgrade, Serbia; 3Clinic of Allergy and Immunology, Clinical Center of Serbia, Belgrade, Serbia

Corresponding author: ABSTRACT Cutaneous necrotizing eosinophilic vasculitis Professor Miloš Nikolić, MD, PhD (CNEV) is a rare type of vasculitis. Eosinophilic vasculitis is a necrotizing vasculitis with eosinophilic vascular infiltra- University of Belgrade School of Medicine tion, in which eosinophils mediate vascular damage in the Clinic of Dermatovenereology, Clinical Center of Serbia, disease process. We present a case of an 18-year-old girl Pasterova 2 who developed palpable and hemorrhagic bul- 11000 Belgrade lae over the lower extremities associated with itching, 7 days after the commencement of penicillin therapy. Plasma Serbia cryofibrinogen was positive. Histopathology showed an in- [email protected] filtration of eosinophils within and around the vessel walls and a complete absence of nuclear dust and neutrophils. Oral at 1 mg/kg induced remission in 2 weeks; Received: October 26, 2018 the prednisone dose was tapered and discontinued after Accepted: February 9, 2019 2.5 months. There was no evidence of recurrence after 37 months of follow-up. Our patient represents a rare case of drug/penicillin-induced CNEV associated with cryofibrino- Financial disclosure: Supported by the Ministry of Science genemia, without systemic organ involvement. of the Republic of Serbia, Grant No 175065 KEY WORDS: cutaneous necrotizing eosinophilic vasculitis, drug-induced, penicillin, cryofibrinogenemia

INTRODUCTION Eosinophilic vasculitis is a rare type of vasculitis We present a rare case of drug-induced cutaneous in patients without marked hypereosinophilia or sys- necrotizing eosinophilic vasculitis (CNEV), an unusual temic symptoms, with histological finding of small- form of drug eruption triggered by penicillin, associ- vessel necrotizing vasculitis (1). Eosinophilic vasculitis ated with cryofibrinogenemia, without systemic - or may be an idiopathic or primary process (2) that over- gan involvement. laps with hypereosinophilic syndrome (HES), without specific immunoserological findings (1), or secondary CASE REPORT to connective tissue diseases (CTD) (3), parasitic in- An 18-year-old girl had been treated with intra- fections, or eosinophilic granulomatosis with polyan- muscular penicillin because of tonsillopharyngitis giitis (EGPA) (4). and fever. Purpuric lesions appeared on her legs on

28 ACTA DERMATOVENEROLOGICA CROATICA Lekić et al. Acta Dermatovenerol Croat Penicillin-induced cutaneous necrotizing eosinophilis vasculitis 2019;27(1):28-32

the 7th day of penicillin treatment. Large, tense hem- mg/L), respectively. Complete blood count with dif- orrhagic bullae developed within a few days. The pa- ferential was normal, except eosinophilia of 12.7% tient reported moderate itching during the develop- (absolute eosinophil count 952/mm3). Plasma cryofi- ment of new lesions. There was no fever, joint pain, or brinogen was positive (++). Serum routine biochem- headache. There was no nausea, vomiting, hematuria, istry was normal. Blood tests, C3, C4, im- or urinary symptoms. The patient had no history of al- munoglobulin levels (IgG, IgA, IgM), cryoglobulins, lergic diseases such as asthma or allergic rhinitis. antinuclear , anti-neutrophil cytoplasmic Physical examination showed disseminated pal- antibodies, and anti-streptolysin-O were normal or pable purpura and hemorrhagic bullae, 5 to 20 mm in negative. Serology tests for hepatitis B, C and Ep- diameter, over the legs (Figure 1). Some lesions were stein-Barr virus were negative. Serum protein electro- arranged in a linear pattern (Koebner’s phenom- phoresis was normal, and there was no evidence of enon) (Figure 2). The lower extremities were slightly monoclonal gammopathy. Chest X-ray examination edematous. and abdominal ultrasonography were normal. The Erythrocyte sedimentation rate and C-reactive patient did not have any symptoms or signs of CTD or protein were 26 mm/h and 22 mg/L (normal <5 internal organ involvement. Table 1. Reported cases of primary recurrent cutaneous necrotizing eosinophilic vasculitis Case Age/ Skin lesions Peripheral Immunology Other abnormalities Treatment Sex eosinophilia Chen, 1994 (5) 56/F erythematosus 1.4×109/L normal gingivitis prednisone, papules, purpuric hydroxyurea papules, urticarial plaques, angioedema Chen, 1994 (5) 18/F erythematosus 3.6×109/L IgE 218 μg/L hepatic vein occlusion, prednisone papules, purpuric gingivitis papules, urticarial plaques, angioedema Chen, 1994 (5) 17/M erythematosus 6.2×109/L IgE 59.280 μg/L transient topical papules, purpuric lymphadenopathy with corticosteroid, papules, urticarial hepatosplenomegaly oral antihistamines plaques, angioedema and total alopecia Launay, 2000 (6) 81/F purpura with 3.9×109/L slightly positive no prednisone necrotic lesions ANA Sakuma-Oyama, 27/F palpable purpura, 14.4×109/L ANA 1:320 no prednisone, 2003 (7) urticarial plaques, betamethasone with angioedema suplatast tosilate Tsunemi, 2005 (8) 53/F annular urticarial normal normal no prednisone, plaques betamethasone Tanglertsampan, 53/M papules, nodules, normal normal no prednisone, 2007 (9) and ulcers indomethacin Kiorpelidou, 2011 82/F polycyclic-annular, normal normal chronic periaortitis methylprednisolone, (10) erythematous colchicine plaques and papules

Li, 2013 (2) 57/M papules, purpuric 3.4×109/L IgE 658.3 IU/mL no prednisone, plaques, glycyrrhizin necrotic lesions, angioedema Sugiyama, 2013 80/F multiple purpuric 10.080/μL normal no prednisone, patches oral tacrolimus Sawada, 2016 55/F erythemas 781/μL normal Budd-Chiari syndrome balloon angioplasty (11) and for hepatic veins, systemic corticosteroid Riyaz, 2016 (12) 45/F multiple, discrete, normal normal no prednisone and confluent purpuric papules and plaques, angioedema

ACTA DERMATOVENEROLOGICA CROATICA 29 Lekić et al. Acta Dermatovenerol Croat Penicillin-induced cutaneous necrotizing eosinophilis vasculitis 2019;27(1):28-32

The histological finding (purpuric lesion on the eosinophilia (parasite infection/infestation, atopic right lower leg) showed an infiltration of eosinophils and/or allergic diseases, adverse drug reaction, hy- within and around the walls of arterioles and venules poadrenalism, neoplasms, collagen-vascular disease) in the dermal superficial vascular plexus (Figure 3), (13). However, eosinophilic vasculitis in HES is rare: and a complete absence of neutrophils and nuclear only 8 cases have been reported so far (14). EGPA usu- dust. deposits in the vessel walls, luminal oc- ally presents in three phases: the prodromal phase clusions of the vessels (Figure 4), and extravasation of characterized by asthma with or without allergic rhi- red blood cells were also present. Direct immunofluo- nitis; the eosinophilic phase characterized by blood rescence was negative. and tissue eosinophilia; and the vasculitic phase. Eo- The patient was initially treated with oral predni- sinophilic vasculitis has rarely been described in cuta- sone at 1 mg/kg/day with gradual dose tapering over neous vasculitic lesions of EGPA (4). Since our patient 2.5 months. After 9 weeks, the lesions cleared com- had mild eosinophilia and there was no evidence of pletely with residual hyperpigmentation and scar- visceral involvement, she did not fulfill the criteria for ring; cryofibrinogen was negative. The patient has either HES or EGPA. not experienced any recurrence after 37 months of Eosinophilic vasculitis is very rarely associated follow-up. Penicillin avoidance was recommended. with CTDs. This group of patients usually presents with pruritic, erythematous, or purpuric papules with DISCUSSION peripheral blood eosinophilia and hypocomplement- Eosinophilic vasculitis, an idiopathic disease com- emia, and, generally, responds to corticosteroids (3). monly known as recurrent CNEV, is a rare entity first Our patient fulfilled no criteria for CTDs. described in 1994. Recurrent CNEV is clinically char- Based on histology, vasculitis can be classified ac- acterized by recurrent, multiple, pruritic skin lesions cording to the size of vessels affected and the domi- with a chronic/relapsing course and by the absence nant cells mediating the inflammation (neutrophilic, of any features of systemic disease or specific immu- granulomatous, lymphocytic, or eosinophilic) (15). noserological findings. To the best of our knowledge, Histologically, eosinophilic vasculitis is a term for only 12 patients with RCNEV have been described in necrotizing vasculitis with eosinophilic vascular infil- the literature (Table 1) (2,5-12). Patients with recur- tration without leukocytoclasia (5). Eosinophilic leu- rent CNEV usually have peripheral blood eosinophil- kocytoclastic vasculitis presents with palpable pur- ia, but the eosinophil count does not always parallel pura, indistinguishable from classic leukocytoclastic the severity of the disease and some patients expe- vasculitis (LCV). It can be caused by infections, drugs, rience cutaneous eruption without peripheral blood or other triggers, similar to classic LCV. In eosinophilic eosinophilia. Systemic corticosteroids were effective LCV, histopathologically, predominant eosinophils in all cases; however, recurrences were common after are found together with neutrophils, lymphocytes, treatment cessation (2,5). extravasated erythrocytes, nuclear dust, fibrin in and HES encompasses a wide range of clinical mani- around vessel walls, as well as collagen degeneration festations sharing 3 features: 1) peripheral eosino- (16). In our case, necrotizing vasculitis of dermal small philia >1500/mm3 on at least 2 occasions; 2) evidence vessels with prominent infiltration of eosinophils of organ involvement; 3) absence of other causes of without neutrophils and leukocytoclasia strongly supported the diagnosis of CNEV. Clinically, eosino- philic vasculitis is usually accompanied by more or

Figure 1. Palpable purpura and hemorrhagic bullae on both lower extremities (with marked skin discoloration caused by eosin). Figure 2. Koebner’s phenomenon.

30 ACTA DERMATOVENEROLOGICA CROATICA Lekić et al. Acta Dermatovenerol Croat Penicillin-induced cutaneous necrotizing eosinophilis vasculitis 2019;27(1):28-32

Figure 3. Histopathological findings: infiltration of eosino- Figure 4. Histopathological findings: infiltration of eosino- phils and a few lymphocytes and histiocytes around and phils and a few lymphocytes and histiocytes around the within the vessel walls, luminal occlusions of the vessels vessel walls, luminal occlusions of the vessels, complete (hematoxylin and eosin, ×200). absence of neutrophils and nuclear dust (hematoxylin and eosin, ×400). less severe itch, while “classical” LCV is usually not CONCLUSION pruritic (2,5). CNEV is a rare or underreported disease, while Drug-induced LCV can also feature prominent penicillin- or other drug-induced CNEV has never blood eosinophilia and a high degree of tissue eosin- been reported before. Furthermore, the association ophilia (17). In the classical drug-induced LCV limited of cryofibrinogenemia and CNEV has not been re- to the skin, just the discontinuation of causative drug, ported so far. New cases should be investigated to bed rest, and topical corticosteroid therapy may be elucidate all the pathogenic processes active in this sufficient. Only severe cases may necessitate systemic peculiar disease. corticosteroid therapy (18). On the other hand, sys- temic corticosteroids should be the first-line therapy References: in eosinophilic vasculitis for at least two reasons: a) 1. Nakajima H, Nakamura T. Thrombotic eosinophilic to reduce blood and tissue eosinophilia, preventing vasculitis. Clin Exp Dermatol. 2009;34:e69-71. eosinophil-mediated tissue damage; b) to prevent a 2. Li W, Cao W, Song H, Ciu Y, Lu X, Zhang F. Recurrent potentially life-threatening prothrombotic state (19). cutaneous necrotizing eosinophilic vasculitis: a Cryofibrinogenemia may be essential or second- case report and review of the literature. Diagn ary to underlying disorders (malignancies, drugs, Pathol. 2013;8:185. infection, vasculitis, CTDs, or associated with cryo- 3. Chen KR, Su WP, Pittelkow MR, Conn DL, George globulinemia) (20). In eosinophilic vasculitis, micro- T, Leiferman KM. Eosinophilic vasculitis in con- thrombi are possibly induced by high levels of major nective tissue disease. J Am Acad Dermatol. basic protein released by numerous eosinophils. Ma- 1996;35:173-82. jor basic protein has direct toxic effects on microvas- 4. Ishibashi M, Kawahara Y, Chen KR. Spectrum of cular endothelial cells, exposing collagen and thus cutaneous vasculitis in eosinophilic granulomato- causing clot formation (21). We did not detect cryofi- sis with polyangiitis (Churg-Strauss): a case series. brinogen deposition on serial sections of the biopsy Am J Dermatopathol. 2015;37:214-21. performed on an early lesion, but we cannot exclude 5. Chen KR, Pittelkow MR, Su D, Gleich J, Newman W, the possibility of later deposition of cryofibrinogen in Leiferman KM. Recurrent cutaneous necrotizing previously damaged blood vessels subsequently pro- eosinophilic vasculitis. A novel eosinophil-media- ducing more severe necrosis resulting in blister for- ted syndrome. Arch Dermatol. 1994;130:1159-66. mation. It has been shown that cryofibrinogenemia 6. Launay D, Delaporte E, Gillot JM, Janin A, Hachulla may severely complicate (infection, sepsis) the course E. An unusual cause of vascular purpura: recurrent of underlying disease (20). Unfortunately, in many cutaneous eosinophilic necrotizing vasculitis. centers, cryofibrinogen is not always sought for. Acta Derm Venereol. 2000;80:394-5.

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