Ceftriaxone-induced leukocytoclastic vasculitis: a case report and literature review of antibiotic-induced leukocytoclastic vasculitis

Abstract

Leukocytoclastic vasculitis (hypersensitivity vasculitis) is defined as small blood vessel inflammation with skin or other systemic manifestations due to infections, drugs, or neoplastic disease. This clinical case report highlights an association between ceftriaxone and leukocytoclastic vasculitis in a 49-year-old female patient with a history of penicillin allergy, on mirtazapine for anxiety disorder. Articles concerning antibiotic-induced leukocytoclastic vasculitis are also reviewed. The patient reported a symptom of upper respiratory tract infection and fever 5 days previously for which she received ceftriaxone for 2 days before presenting to the emergency department with a pruritic skin rash in the upper and lower extremities and swollen lips for 1 day. The rash was erythematous, maculopapular, itchy, and non-tender, with no mucus membrane involvement. Laboratory investigations revealed leukocytosis (white blood cells, 22.3 × 10⁹/L) that was mainly eosinophilic (18.4%). The patient was administered prednisolone and antihistamine after stopping ceftriaxone empirically. A skin biopsy confirmed the diagnosis of leukocytoclastic vasculitis. Significant clinical improvement was observed after treatment initiation. Upon follow-up, the skin rash was resolved entirely with no scars; however, there was skin-peeling over the lower extremities. Recognition of antibiotic-induced leukocytoclastic vasculitis is crucial as many classes of antibiotics can contribute to this condition. Continuation of the offending drug may lead to life-threatening complications.

Introduction

Leukocytoclastic vasculitis (also known as hypersensitivity vasculitis) is defined as small blood-vessel inflammation, typically presenting with generalized symptoms, such as fever, arthralgia, myalgia, and skin manifestations described as painful purpuric lesions in the lower and upper extremities. ^{1, 2} Leukocytoclastic vasculitis is sometimes associated with other systemic manifestations, for example, involving the renal or gastrointestinal systems. ^{3, 4}

Precipitating factors include infections, drugs, chemicals, and systemic and neoplastic disease, ⁵ with reports of leukocytoclastic vasculitis in patients post coronavirus disease 2019 vaccination, and in those with inflammatory bowel disease. ^{6, 7} When leukocytoclastic vasculitis is suspected, it may be diagnosed after detailed history, physical examination, and laboratory investigations, and confirmed by punch skin biopsy showing neutrophilic infiltration into small venule walls. ^{8 –10}

Most cases of drug-induced leukocytoclastic vasculitis are treated by discontinuation of the offending agent and application of supportive measures. Severe and chronic cases may require systemic steroids. ⁵ Here, the case of a 49-year-old female patient who developed leukocytoclastic vasculitis after receiving ceftriaxone for acute pharyngitis is described, and currently available literature regarding leukocytoclastic vasculitis is discussed.

Case report

A 49-year-old female patient with a history of penicillin allergy and Guillain–Barré syndrome secondary to influenza vaccine, presented to the emergency department of King Abdulla Medical City in September 2019, with a pruritic skin rash in the upper and lower extremities and swollen lips for 1 day. Five days prior to hospital presentation, she reported an upper respiratory infection and fever that was treated with ceftriaxone. After taking 1 g intravenous ceftriaxone, daily for 2 days, she developed a skin rash involving the upper and lower extremities, including the palms and soles. The rash was erythematous, maculopapular, and simultaneously pruritic and burning (Figure 1). Swelling was confined to the lower lip, with no facial puffiness, tongue swelling, hoarseness of voice, difficulty breathing, or change in her mental status. Besides the known history of penicillin allergy, the patient reported an allergy to particular foods that suggested an immunoglobulin (Ig)E-mediated process. There was no reported patient or family history of autoimmune diseases. Systemic review was unremarkable, except for generalized arthralgia and myalgia.

Figure 1.

Representative image of skin lesions in a 49-year-old patient with leukocytoclastic vasculitis. The lesions covered the anterior and lateral aspect of the lower limbs, and showed asymmetrical violaceous discoloration with sharp borders and different sizes, ranging from 1–6 mm.

On examination, the patient was conscious, oriented and anxious, but not in distress. Vital signs were as follows: blood pressure, 137/84 mmHg; pulse, 127 beats per min; respiratory rate, 18 breaths per min; body temperature, 37.7 °C; and oxygen saturation, 98% room air. The cardiovascular, respiratory, and gastrointestinal examination was unremarkable. The skin exam revealed erythematous, maculopapular, and non-tender rash that spared the mucus membranes and affected the upper and lower extremities, including the palms and soles.

Initial laboratory investigations revealed leucocytosis (white blood cell count, 22.3 × 10⁹/L) with a predominance of eosinophils (18.4%). Results of renal and liver function tests, and urine analysis, were within normal limits. The chest x-ray was unremarkable, but the electrocardiogram showed sinus tachycardia. The patient was started empirically on an anti-inflammatory dose of prednisolone (0.5 mg/kg, oral, daily) and antihistamine (10 mg oral cetirizine, daily). Results of additional blood workup, including tests for antinuclear antibody, rheumatoid factor, herpes simplex virus, complement levels and tryptase level were within normal limits. Skin biopsy revealed perivascular inflammatory infiltrate composed of neutrophils with frequent eosinophils, and prominent vascular damage evidenced by the presence of endothelial injury and extravasated red blood cells (RBCs), suggestive of leukocytoclastic vasculitis (Figure 2). The skin rash progressed after 3 days to involve the trunk in addition to the extremities, with the development of tense bullae and notable development of palpable purpura, mainly on both ankles and heels, which were swollen. Nevertheless, there remained no facial or mucosal involvement. Prednisolone administration was increased to an immunosuppressive dose (1–2 mg/kg, oral, daily) for 5 days with reduction of 5 mg every 3 days, which led to significant clinical improvement and rash resolution.

Figure 2.

Representative photomicrographs of haematoxylin and eosin-stained skin pinch biopsy sections, showing mild spongiosis with focal vesicle formation and perivascular inflammatory infiltrate in the dermis, composed of neutrophils and frequent eosinophils. Prominent vascular damage is evidenced by the presence of endothelial injury and extravasated red blood cells.

The patient was discharged, and during an outpatient follow-up visit after 1 month, the skin rash was observed to have resolved entirely with no visible scars. However, skin-peeling was observed over the lower extremities.

Ethics approval was not deemed necessary for this case report. Patient data were deidentified and verbal informed consent to publish the case was obtained from the patient. The reporting of this study conforms to CARE guidelines. ¹¹

Discussion

Leukocytoclastic vasculitis is a histopathologic term commonly used for small-vessel vasculitis, also known as hypersensitivity vasculitis. The incidence rate is around 30 cases per million people per year, and it affects both sexes equally. ^{12, 13} Leukocytoclastic vasculitis may occur as a primary disorder or as a secondary condition in association with drugs, infections (particularly upper respiratory tract infections), collagen-vascular diseases, hematologic disorders, or malignancy. ¹⁴ However, in around one-third of patients, the precipitating factors are impossible to ascertain. ¹⁵

Drug-induced leukocytoclastic vasculitis accounts for about 10% of all vasculitis cases. Antibiotics, particularly beta-lactam groups, sulfonamides, and quinolones; cyclosporine; azathioprine; methotrexate; and allopurinol; antithyroid drugs, particularly propylthiouracil; valproic acid; phenytoin; anti-tumour necrosis factor-α agents; and hydralazine are well-known causes of leukocytoclastic vasculitis. ^{15 –19}

Leukocytoclastic vasculitis usually presents as skin lesions in a palpable purpuric form that likely begins 7–21 days after exposure to a particular agent. It mostly involves the lower extremities and less frequently affects the forearm, hand, back, sacral, and gluteal regions. Other less common skin manifestations include vesicles, bullae, nodules, or ulcers. In addition to skin lesions, leukocytoclastic vasculitis may be associated with systemic manifestations, such as abdominal and joint pains, and renal involvement. ²⁰

Detailed history, physical examination and laboratory workup are essential steps in evaluating leukocytoclastic vasculitis, focusing on the presence of underlying cause and systemic involvement. ²¹ The American College of Rheumatology proposed criteria to define leukocytoclastic vasculitis including patient age >16 years; use of a possible drug in temporal relation to symptoms; palpable purpura; maculopapular skin lesions; and biopsy of a skin lesion showing neutrophils around arterioles or venules. At least three of five criteria must be present to diagnose leukocytoclastic vasculitis with a sensitivity of 71% and specificity of 83.9%. ²² The present case scored 5 out of 5, which favours the diagnosis of leukocytoclastic vasculitis.

Biopsy of skin lesions for histopathology and examination under immunofluorescence is the gold standard for confirming a diagnosis. The presence of perivascular inflammatory cell invasion with necrosis of the vessel wall and fibrinoid material deposition is pathognomonic for leukocytoclastic vasculitis. ¹⁷ These findings may change after approximately 2 days, so it is necessary to take a biopsy within 24–48 h from the onset of skin lesions. ^{10, 21}

The precise mechanism of pathogenicity of leukocytoclastic vasculitis is unknown. However, circulating immune complex deposition in the walls of arterioles, capillaries and postcapillary venules is proposed to play a role. ^{23 –25} Immune complex deposition (IgG and IgM) leads to activation of the complement cascade (C3a and C5a), which produces chemotactic factors and vasoactive cytokines. Consequently, neutrophils become activated and migrate to the affected tissue injuring the vessel wall by releasing lysosomal enzymes such as collagenases, elastase and free oxygen radicals. Thus, permeability of the damaged vessel wall increases, causing leakage of RBCs and fluid that generates purpura. ^{3, 4, 10, 25}

The management of cutaneous leukocytoclastic vasculitis depends on the aetiology and severity of disease. Mild cutaneous manifestations are self-limited and may need symptomatic relief with antihistamine and nonsteroidal anti-inflammatory drugs with discontinuation of the offending agent. However, systemic involvement needs steroids alone or in combination with immunosuppressive drugs. ^{10, 20, 26} In general, skin-limited disease has a good prognosis, and the time to recovery is variable, ranging from days to weeks. ^{27, 28} Nonetheless, around 10% of reported cases develop recurrent or chronic involvement. ²⁹

An extensive review of the published literature was performed by searching three databases (PubMed, Scopus, and Google Scholar) for articles published between January 1955 and October 2021. Keywords used in the search were: antibiotic-induced leukocytoclastic vasculitis, antibiotic and leukocytoclastic vasculitis. Case reports and case series with study samples aged >16 years, involving antibacterial drug, that were published in English were included. After removal of duplicates, all articles were fully reviewed by two researchers (AAA and ESB).

A total of 60 published articles were included, comprising a total of 74 cases published between 1955 and 2021 (Table 1). ^{20,26,27,30 –86} Analyses of the reported cases of antibiotic-induced leukocytoclastic vasculitis revealed that it is associated with numerous classes of antibiotic, including penicillin (amoxicillin, amoxicillin-clavulanic acid, oxacillin), cephalosporins (cefazolin, cephalexin, cefuroxime, ceftriaxone, cefotaxime), fluoroquinolone (ciprofloxacin, levofloxacin, ofloxacin), macrolides (azithromycin, clarithromycin), vancomycin, teicoplanin, trimethoprim-sulfamethoxazole, dapsone, linezolid, pristinamycin, tigecycline, isoniazid, streptomycin, rifampin, ethambutol, and pyrazinamide.

Table 1.

Review of published cases reporting antibiotic-induced leukocytoclastic vasculitis.

Antibiotic group		Antibiotic type	Publication	Age	Sex	Duration of antibiotic use	Clinical manifestation		Diagnosis method	Treatment	Resolution
							Cutaneous	Systemic
Penicillin		Amoxicillin	Saenz de Santa Maria Garcia et al., 2016 30	47	Male	5 days	Yes	Renal involvement	Skin biopsy	Discontinue antibioticSystemic steroids	7 days
				73	Male	9 days	Yes	No	Skin biopsy	Systemic steroid	Unknown
		Amoxicillin clavulanic acid	Lunge et al., 2014 31	22	Male	7 days	Yes	No	Skin biopsy	Discontinue antibioticSystemic steroids	1 month
		Oxacillin	Koutkia et al., 2001 32	67	Male	8 days	Yes	Renal and gastrointestinal involvement	Skin biopsy	Discontinue antibioticSystemic steroids	3 weeks
			Chakraborty et al., 2013 20	65	Male	1 day	Yes	No	Skin biopsy	Discontinue antibiotic	6 weeks
			Mericliler et al., 2019 33	32	Female	12 days	Yes	No	Skin biopsy	Discontinue antibiotic	1 month
Cephalosporin		Cefazolin	Ali et al., 2017 34	67	Male	6 weeks	Yes	No	Skin biopsy	Discontinue antibioticSystemic steroids	Unknown
		Cephalexin	Yu et al., 2020 35	67	Male	1 day	Yes	No	Skin biopsy	Systemic steroids	Unknown
		Cefuroxime	Montero et al., 2015 36	66	Female	2 days	Yes	No	Skin biopsy	Discontinue antibioticSystemic steroids	Unknown
			Menon et al., 2019 37	65	Female	3 days	Yes	No	Skin biopsy	Discontinue antibiotic	14 days
		Ceftriaxone	Agrawal et al., 2014 38	17	Female	5 days	Yes	Renal involvement	Skin biopsy	Discontinue antibioticSystemic steroids	5 days
			Raina et al., 2018 39	61	Male	3 days	Yes	No	Skin Biopsy	Discontinue antibiotic	10 days
			Haehn et al., 2019 40	35	Male	14 days	Yes	No	Skin biopsy	Discontinue antibioticSystemic steroids	Unknown
			Current study, 2022	49	Female	2 days	Yes	No	Skin biopsy	Discontinue antibioticSystemic steroids	1 month
		Cefotaxime	Cure et al., 2007 41	51	Male	7 days	Yes	No	Skin biopsy	Discontinue antibiotic	4 days
Glycopeptide		Vancomycin	Marshall et al., 1998 42	54	Male	12 days	Yes	No	Skin biopsy	Discontinue antibiotic	Unknown
				60	Male	17 days	Yes	No	Skin biopsy	Discontinue antibiotic	Unknown
			Sharma et al., 2018 27	83	Male	11 days	Yes	No	Skin Biopsy	Discontinue antibiotic	3 days
			Felix-Getzik et al., 2009 43	76	Female	4 days	Yes	No	Skin biopsy	Discontinue antibiotic	14 days
			Heijnen et al., 2011 44	38	Female	7 days	Yes	No	Skin biopsy	Discontinue antibiotic Systemic steroids	Unknown
			Pongruangporn et al., 2011 45	52	Female	6 days	Yes	No	Skin biopsy	Discontinue antibiotic	18 days
			Pingili et al., 2017 26	79	Male	7 days	Yes	Renal involvement	Skin biopsy	Discontinue antibiotic Systemic steroids	11 days
			Zadroga et al., 2021 46	65	Male	7 days	Yes	No	Skin biopsy	Discontinue antibiotic	3 days
		Teicoplanin	Marshall et al., 1998 42	54	Male	2 days	Yes	No	Skin biopsy	Discontinue antibiotic	Unknown
				60	Male	5 days	Yes	No	Skin biopsy	Systemic steroids	Unknown
			Logan et al., 2005 47	67	Male	17 days	Yes	Renal involvement	Skin biopsy	Discontinue antibioticSystemic steroids	Unknown
			Uchida et al., 2014 48	88	Male	13 days	Yes	No	Skin biopsy	Discontinue antibiotic	7 days
Trimethoprim sulfamethoxazole			LeMaster et al., 2009 49	53	Male	3 days	Yes	No	Skin biopsy	Discontinue antibiotic	2 weeks
Sulfones		Dapsone	Alves-Rodrigues et al., 2005 50	39	Female	23 days	Yes	Renal involvement	Skin biopsy and renal biopsy	Discontinue antibioticSystemic steroids. Cyclophosphamide	2 Months
Macrolides		Azithromycin plus clarithromycin	Park et al., 2008 51	51	Female	3 days	Yes	No	Skin biopsy	Discontinue antibioticTopical steroid	6 days
		Clarithromycin	De Vega et al., 1993 52	68	Male	1 day	Yes	No.	Skin biopsy	Discontinue antibiotic systemic steroids	1 week
			Gavura et al., 1998 53	83	female	6 days	Yes	Gastrointestinal involvement	Skin biopsy	Discontinue antibiotic Systemic steroids	Unknown
		Erythromycin	Block et al., 1993 54	57	Female	5 days	Yes	Renal involvement	Skin biopsy	Unknown	Unknown
Lincosamide		Clindamycin	Yeung et al., 2003 55	65	Female	5 days	Yes	Renal involvement	Skin biopsy	Discontinue antibioticSystemic steroids	7 days
Linezolid			Kim et al., 2009 56	64	Male	9 days	Yes	No	Skin biopsy	Discontinue antibiotic	Died
			Sathyanarayana et al., 2015 57	17	Male	2 days	Yes	No	Clinically	Discontinue antibiotics Systemic steroids	Unknown
			Kruzer et al., 2018 58	55	Male	6 days	Yes	No	Skin biopsy	Discontinue antibiotics Systemic steroids	6 days
			Menon et al., 2019 37	65	Female	3 days	Yes	No	Skin biopsy	Discontinue antibiotic	14 days
Streptogramin		Pristinamycin	Ladhari et al., 2017 59	60	Male	3 days	Yes	No	Skin biopsy	Discontinue antibioticsSystemic steroids	5 days
Tetracycline		Tigecycline	Bhairavarasu et al., 2015 60	21	Male	2 days	Yes	No	Skin biopsy	Discontinue antibioticSystemic steroids Colchicine	4 days
Fluroquinolones		Ciprofloxacin	Stubbings et al., 1992 61	79	Female	10 days	Yes	No	Clinically	Unknown	4 weeks
				71	Female	4 days	Yes	No	Skin biopsy	Discontinue antibiotic	7 days
			Block et al., 1993 54	57	Female	5 days	Yes	No	Skin biopsy	Unknown	Unknown
			Beuselinck et al., 1994 62	18	Female	4 days	Yes	No	Skin biopsy	Discontinue antibiotic	6 days
			Shih et al., 1995 63	80	Male	2 weeks	Yes	Renal involvement	Renal biopsy	Discontinue antibioticSystemic steroidsCyclophosphamide	2 weeks
				81	Male	2 weeks	Yes	Renal involvement	Renal biopsy	Systemic steroidsCyclophosphamide	3 weeks
			Lieu et al., 1997 64	76	Male	4 days	Yes	No.	Clinically	Discontinue antibiotic	1 week
			Reano et al., 1997 65	61	Female	90 min	Yes	No	Oral challenge testSkin biopsy	Discontinue antibiotic	1 week
			Yeung et al., 2003 55	65	Female	5 days	Yes	Renal involvement	Skin biopsy	Discontinue antibioticSystemic steroid	7 days
			Storsley et al., 2007 66	50	Male	10 days	Yes	Renal involvement	Renal biopsy	Discontinue antibioticSystemic steroids	1 month
			Maunz et al., 2009 67	68	Male	7 days	Yes	No.	Clinical	Discontinue antibiotic	Unknown
				74	Male	8 days	Yes	No	Clinically	Discontinue antibiotic	1 week
			Van den Berg et al., 2010 68	82	Female	4 days	Yes	No	Clinically	Discontinue antibiotics	2 weeks
				71	Male	6 days	Yes	No	Clinically	Discontinue antibiotics	3 days
			Morgado et al., 2016 69	71	Male	4 days	Yes	Gastrointestinal involvement	Skin biopsyEndoscopy	Discontinue antibioticsSystemic steroid	11 days
		Levofloxacin	Famularo et al., 2002 70	73	Male	3 days	Yes	Renal involvement	Clinical	Discontinue antibioticSystemic steroids	4 weeks
			Zaigraykin et al., 2006 71	80	Female	5 days	Yes	Renal involvement	Clinically	Discontinue antibioticSystemic steroid	5 days
			Maunz et al., 2009 67	65	Male	3 days	Yes	No	Skin biopsy	Discontinue antibiotic	Unknown.
			Blyth et al., 2012 72	64	Male	5 days	Yes	No	Skin biopsy	Discontinue antibioticSystemic steroids	1 month
			Aoud et al., 2015 73	63	Male	3 days	Yes	No	Skin biopsy	Discontinue antibiotic	2 weeks
		Ofloxacin	Huminer et al., 1989 74	67	Male	1 day	Yes	Renal involvement	Skin biopsy	Discontinue antibioticSystemic steroid	Unknown
			Pace et al., 1989 75	75	Male	Unknown	Yes	Gastrointestinal involvement	Skin biopsy	Unknown	Died
			Ceyhan et al., 1995 76	75	Male	3 days	Yes	Gastrointestinal involvement	Skin biopsyEndoscopy	Discontinue antibiotic. Systemic steroidsCyclophosphamide	1 week
			Pipek et al., 1996 77	81	Female	1 day	Yes	Gastrointestinal involvement	Skin biopsy	Discontinue antibiotic	1 week
Anti-TB		Isoniazid and Streptomycin	Edge et al., 1955 78	34	Female	7 days	Yes	No	Necropsy	Discontinue antibioticSystemic steroidsCorticotrophin	Died
		Rifampin	Iredale et al., 1989 79	79	Male	Unknown.	Yes	Renal involvement	Clinical	Discontinue antibioticSystemic steroid	Unknown.
		Isoniazid, rifampicin, and ethambutol	Chan et al., 1990 80	64	Male	5 months	Yes	Renal involvement	Skin biopsy	Discontinue antibiotics	Unknown
		Isoniazid, rifampicin, pyrazinamide and ethambutol		41	Male	4 months	Yes	Renal involvement	Skin biopsy	Discontinue antibiotics	Died
		Rifampin	Munoz et al., 2008 81	76	Male	1 week	Yes	Renal involvement	Skin biopsy	Discontinue antibiotic	2 weeks
		Pyrazinamide and rifampin	Kim et al., 2010 82	38	Male	1.5 months	Yes	No	Skin BiopsyOral challenge test	Discontinue antibioticSystemic steroid	3 days
		Isoniazid and rifampin	Chanprapaph et al., 2013 83	62	Male	2 weeks	Yes	No	Skin biopsy	Discontinue antibiotics	1 week
		Isoniazid	Bondalapati et al., 2014 84	64	Male	4 days	Yes	No	Skin biopsyOral challenge test	Discontinue antibiotic	1 week
		Pyrazinamide	Shim et al., 2015 85	56	Male	4 weeks	Yes	Gastrointestinal involvement	Skin biopsyEndoscopy	Discontinue antibioticSystemic steroids	Unknown
		Isoniazid, rifampicin, pyrazinamide and ethambutol	Shim et al., 2017 86	72	Male	2 weeks	Yes	Gastrointestinal involvement	Skin biopsyEndoscopy	Discontinue antibioticSystemic steroid	Unknown

Based on the present review, the most common antibacterial drug-type to cause leukocytoclastic vasculitis was the fluoroquinolone group, particularly ciprofloxacin. The minimum duration for developing symptoms was 1 day and the maximum duration was 5 months. Patient age ranged between 17 and 88 years and twice as many male than female patients were affected, which contradicts a previous study suggesting no predominance between the sexes. ²⁶

All cases presented with non-blanching purpuric rash in all extremities, and the trunk and face without affecting the mucous membrane. However, 26 cases showed systemic manifestations along with skin lesions; 18 of which involved the kidney in the form of acute kidney injury, seven involved gastrointestinal systems and presented with diarrhoea and hematemesis, and one case had both gastrointestinal and renal involvement.

The patient in the present case was a 49-year-old female who presented with localized symptoms in the form of a non-blanching purpuric rash that started in both extremities and progressed to involve the trunk. There was no systemic involvement, and the rash was preceded by ceftriaxone intravenous injection that was administered for upper respiratory tract infection 2 days prior to presentation for rash. The majority of cases included in the review (64 out of 74 cases) were diagnosed by skin biopsy and a few were diagnosed by clinical examination, kidney biopsy, endoscopy, or oral challenge test. The present case was diagnosed by skin biopsy that showed a typical finding for cutaneous vasculitis.

The reviewed cases were treated either by discontinuation of the offending antibiotic alone or with the addition of systemic steroids. Cyclophosphamide was administered in four cases, all of which had systemic involvement (renal and gastrointestinal). Most of the cases were observed to have complete skin manifestation resolution and normalized kidney function, except four deceased cases. The duration of resolution varied from 3 days to 2 months. In the present case, ceftriaxone discontinuation and systemic steroid administration resulted in complete recovery in 1 month.

In conclusion, medications are one of the important precipitating factors of leukocytoclastic vasculitis and some, such as antibiotics, are used in daily practice. Thus, recognition of this reaction is important as it may lead to fatal consequences, and discontinuation of the offending drug is a major part of the management.

To the best of our knowledge, this is the first reported case of ceftriaxone-induced leukocytoclastic vasculitis in the Middle East, and the first published review of articles concerning antibiotic-induced leukocytoclastic vasculitis.