key: cord-0854479-j9bx0e9a authors: Ball-Burack, Maya R.; Kosowsky, Joshua M. title: A Case of Leukocytoclastic Vasculitis Following SARS-CoV-2 Vaccination date: 2021-10-23 journal: J Emerg Med DOI: 10.1016/j.jemermed.2021.10.005 sha: 6ab31e5c9def716a374401848b94b7b026ee89d9 doc_id: 854479 cord_uid: j9bx0e9a Background While vaccination against coronavirus SARS-CoV-2 has been proven generally safe, rare but potentially serious adverse reactions do occur. Leukocytoclastic vasculitis (LCV) is a small-vessel vasculitis that has been associated with other immunizations, but, to our knowledge, has not been previously reported in association with vaccines directed against SARS-CoV-2. Case Report We report the case of a 22-year-old man with no known past medical history who presented to the Emergency Department (ED) with two days of migratory arthritis in his ankles and palpable purpura on his bilateral lower extremities, occurring ten days after receiving the Johnson & Johnson SARS-CoV-2 vaccine. The patient's clinical presentation was suggestive of leukocytoclastic vasculitis, and this diagnosis was confirmed on skin biopsy. Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis that is most commonly characterized by palpable purpura on the lower extremities. When occurring in children, in combination with abdominal pain, arthritis, or renal involvement, it is known as IgA vasculitis or Henoch-Schönlein Purpura (HSP). In all its forms, the pathophysiology of LCV involves immune-complex deposition within small vessels as well as activation of the complement system. The etiology of LCV remains somewhat obscure, but, like other vasculitides, a variety of genetic, environmental, and immune factors are thought to play a role. A number of specific inciting factors have been identified, including medications (especially antibiotics, NSAIDs, and diuretics), microbial pathogens (HBV, HCV, HIV, EBV, and streptococci), malignancy, IBD, and connective tissue diseases (SLE, Sjogren Syndrome, RA). Case reports have demonstrated an association between vaccinations such as influenza and the development of LCV, 1, 2,3 and a single case-control study found a correlation between measles-mumps-rubella (MMR) vaccination and an increased risk of HSP in children. 4 In up to 50% of cases, no identifiable cause is found, and the vasculitis is considered idiopathic. Much remains unknown about the effect of infection with SARS-CoV-2 on immune function. Severe cases of COVID-19 have been associated with dysregulation of both the innate and acquired immune system, and, indeed, there have been case reports of IgA vasculitis subtypes following COVID-19 infection. However, to date we know of no previously reported case of LCV following vaccination against the SARS-CoV-2 virus. A 22-year-old, previously healthy male presented to the ED with a chief complaint of ankle swelling and lower extremity rash. He first noticed swelling and pain in his left ankle two days prior. Later that same day, he began to notice a purplish rash on the tops of his feet spreading up toward his shins. The day prior to presentation, the swelling in his left ankle resolved, but his right ankle became swollen and painful. The rash had continued to spread, though it remained confined to his lower legs. He reported no other rash or bruising, no mucosal bleeding, and no fever, myalgias, fatigue, abdominal pain, or hematuria. The patient had received the Johnson & Johnson SARS-CoV-2 vaccine ten days earlier, and this was followed by one day of low-grade fever without associated symptoms. Aside from that, the patient had no recent history of illness other than some isolated rhinorrhea a month prior which was not accompanied by fever, cough, or sore throat. Presentation was in May, outside of typical viral season in this Emergency Department. In addition, presentation was during the COVID-19 pandemic, when masks remained mandated, and rates of influenza and other respiratory viruses were lower than baseline. 11 The patient had no prior history of allergy or autoimmune disease and was taking no prescription or over-the-counter medications. He had no recent travel and no exposure to animals. On examination, the patient appeared to be in no distress, was afebrile at 36.8 degrees centigrade, and was hemodynamically stable with a blood pressure of 129/83 mmHg. He was initially tachycardic at 109/min, but heart rate decreased to 79/min with administration of NSAIDs for pain. He was noted to have scattered, violaceous, palpable purpura over the dorsal surfaces of both feet and the anterior aspects of both lower extremities distal to the knees. The largest lesion was 3cm in diameter, all were non-blanching, and none were tender. His right ankle was swollen, tender, and erythematous with pain upon active and passive range of motion. Figure 1 is a representative photograph of the patient's lower extremities. Laboratory data were notable for 1+ hematuria on urine dip, with 1 RBC/hpf, 1 WBC/hpf and no bacteria in the urine sediment. Serum chemistries were notable for normal renal function, with a BUN of 9 mg/dL and a Cr of 0.88 mg/dL. Complete blood count showed a mild leukocytosis at 10.3 x 10 3 /mL, and normal platelets at 307 x 10 3 /mL. Coagulation studies were within normal limits, with a PT of 14.1 sec and a PTT of 35.5 sec. Dermatology was consulted and recommended a number of secondary laboratory studies as well as biopsy to confirm diagnosis and to investigate possible triggers. They advised brief admission to ensure pain control and no acute worsening but did not think it necessary for secondary laboratory data to result prior to discharge, as LCV can most often be managed as an outpatient even on first presentation. Notable laboratory data that resulted post-discharge included a decreased C3 at 61 mg/dL, a negative ANCA, a borderline elevated RF of 16 IU/mL, and an elevated antistreptolysin-O (ASO) antibody titer of 944. CMV IgG was positive, CMV IgM was negative, EBV and HIV antibodies were negative. A SARS-CoV-2 PCR was negative. Biopsy of the lesions showed perivascular and interstitial neutrophilic infiltrate with eosinophils. Immunofluorescence was performed, which demonstrated perivascular deposition of IgA and C3, and IgG. The final pathology report, which resulted one week following discharge, read, in part: "in the context of the immunofluorescence findings, the appearance is most suggestive of leukocytoclastic vasculitis. Clinical correlation is needed to determine the etiology." Patient was followed up in dermatology clinic for biopsy proven LCV, per chart review rash and swelling were noted to be improving. In a patient presenting to the ED with purpura, the differential diagnosis includes conditions ranging from the life-threatening (e.g, meningococcemia, DIC, TTP) to the relatively benign (e.g., ITP). 5 Purpura that are non-palpable are most often associated with pathologies of thrombocytopenia. In a patient with normal platelets and coagulation studies and the presence of other signs and symptoms such as migratory arthritis and microscopic hematuria, the likelihood of vasculitis is high. A variety of small vessel vasculitidies present with dermatologic manifestations including palpable purpura, and associated symptoms can assist in creating a differential. IgA vasculitis, a form of LCV, can present with arthritis and renal disease. Eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis often present with sinusitis and some form of lung involvement and are associated with ANCA positivity. Polyarteritis nodosa, which is typically classified as a medium vessel disease but can cause purpura, often manifests with gastrointestinal symptoms, renal disease, and neuropathy. The classic presentation of LCV is one of palpable purpura appearing on the lower legs, as was seen in this patient. The lesions are typically painless but are sometimes pruritic or mildly painful. Patients with the IgA subtype of LCV classically present with migratory arthralgias or arthritis, or renal involvement with hematuria, as was also seen in this The vaccines developed for SARS-CoV-2 elicit responses from the innate immune system as well as the adaptive immune system (T lymphocytes and B lymphocytes), resulting in the production of both cytokines and antibodies. 6 The Johnson and Johnson vaccine delivers SARS-CoV-2 spike protein genetics on an Ad26 adenovirus vector, which is highly immunogenic. 7 Adenovirus triggers cytokine release, including IL-6, IL-12, and TNF-a, as well as antibody production and T cell activation. 8 An overzealous immunologic response could plausibly result in the formation of aberrant antibody complexes and infiltration of neutrophils in and around small vessel walls. The clinical course of LCV is typically mild and self-resolving, and in the absence of systemic complications (e.g., nephritis), supportive care is generally all that is required. Rest, leg elevation, and compression stockings are often recommended given the tendency for lesions to develop in dependent areas. NSAIDs can be utilized for pain management, and antihistamines for pruritis. 9,10 Glucocorticoids can be utilized if the disease course is prolonged, although data supporting the use of corticosteroids comes only from case reports. In adults with IgA nephritis, glucocorticoids are recommended if there is elevated serum creatinine, proteinuria of more than 1g per day, or biopsy proven kidney involvement. 12 Patients with arthritis generally respond well to NSAID therapy, but glucocorticoid therapy can be effective for persistent pain. Why Should an Emergency Physician Be Aware of This? As a large fraction of the population undergoes vaccination against SARS-CoV-2, ED physicians may see rare adverse reactions potentially associated with immune dysregulation, such as LCV. Though the condition itself is rarely life-threatening, patients with suspected LCV can benefit from prompt recognition, identification of a recent or current trigger, and assessment for and management of associated symptoms. Cutaneous Leukocytoclastic Vasculitis Following Influenza Vaccination in Older Adults: Report of Bullous Purpura in an Octogenarian after Influenza Vaccine Administration A 19-year old man with IgA vasculitis after vaccination A case of leukocytoclastic vasculitis following influenza vaccination Henoch-Schönlein purpura and drug and vaccine use in childhood: a case-control study Purpuric and petechial rashes in adults and children: initial assessment SARS-CoV-2 mRNA Vaccines: Immunological Mechanism and Beyond Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine Adenoviruses as vaccine vectors Management of adults with idiopathic cutaneous small vessel vasculitis IgA Vasculitis (Henoch-Schönlein Purpura): Kidney Manifestations Changes in Influenza and Other Respiratory Virus Activity During the COVID-19 Pandemic -United States Primary cutaneous small vessel vasculitis: approach to diagnosis and treatment Figure 1. Patient's lower extremities This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.