American Journal of Emergency Medicine xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Anticytoplasm neutrophil antibodies–positive vasculitis with diffuse alveolar hemorrhage related to a spider bite Abstract Diffuse alveolar hemorrhage is a life-threatening complication of anticytoplasm neutrophil antibodies–associated vasculitis. We report the first case of microscopic polyangiitis with pulmonary-renal syndrome triggered by a spider bite and discuss the potential mechanisms involving neutrophil activation in loxoscelism. This expands the list of autoimmune and toxic reactions related to spider bites, as well as the list of vasculitis triggers. Diffuse alveolar hemorrhage (DAH) is a neutrophil-mediated lifethreatening complication of anticytoplasm neutrophil antibodies (ANCA)–positive vasculitis [1,2]. Insect bites or stings are possible triggers for vasculitis [3]. Although DAH has been rarely seen after Hymenoptera stings [4,5], ANCA-positive vasculitis with pulmonary-renal syndrome has not been reported, to our knowledge, related to spider bites. A 19-year-old rural-living female patient presented to the emergency department in acute respiratory distress syndrome with diffuse arthralgia and myalgia and no fever. Three weeks before, she had been treated by the general practitioner with oxacillin and prednisone for a spider bite that resulted in a limited necrotic rash of the second left toe tip. Clinical examination revealed a discrete purpuric rash with few necrotic elements, mainly on the left toes and dorsum of the foot. The analyses showed inflammation (erythrocyte sedimentation rate, 85 mm/h; C-reactive protein, 10.5 mg/dL) and leukocytosis (12 000 white blood cells per microliter) with left shift (79% neutrophils, 3% eosinophils) and microhematuria (10-15 red blood cells per field). D-Dimers were normal; no schistocytes were found. The hemoglobin value dropped in 2 hours by 2 points (from 11 to 9 mg/dL). Chest radiograph revealed a reverse bat wing appearance, suggestive of DAH (Figure). Bronchoscopy excluded other sources of bleeding. Life support (intubation and ventilation), broad-spectrum antibiotic coverage, methylprednisolone, and then cyclophosphamide pulse were introduced for the suspected vasculitis with pulmonary-renal syndrome. Sputum culture, nose and throat swabs, urine culture, and blood cultures were negative; and procalcitonin was normal. The screening for hepatitis B, C viruses, HIV, TBC, Borrelia, Cytomegalovirus IgM, Mycoplasma IgM, and Leptospirae revealed no positivity. Antimyeloperoxidase antibodies (enzyme-linked immunosorbent assay Innova, 80 IU; reference value, b10 IU) came out positive. The other immunological test results were normal (complement fractions, immunoglobulins including IgE, antiglomerular basement membrane, proteinase-3 antibodies, antinuclear and anticardiolipin antibodies, lupus anticoagulant, rheumatoid factor). A skin punch biopsy revealed leukocytoclastic vasculitis. Therefore, the diagnosis was microscopic polyangiitis.
On immunosuppression and support therapy, she made a complete pulmonary and renal recovery. Chest high-resolution computed tomography after 6-month follow-up found no active alveolitis. Diffuse alveolar hemorrhage is a life-threatening event in microscopic polyangiitis due to alveolocapillary membrane damage from capillary wall fibrinoid necrosis and thrombosis [1]. Neutrophils are the principal effector cells responsible for mediating ANCA-induced acute necrotizing vascular inflammation [1,2]. The pathogenesis of ANCA vasculitis is multifactorial, involving genetic factors such as ANCA expression by neutrophils, antiprotease alleles, and immune response genes polymorphisms, whereas environmental factors are at least adjuvants, if not primary stimuli [2]. Insect bites may produce infectious vasculitis (eg, ricketsial diseases, including Q fever, Lyme disease) or delayed hypersensitivity reactions to venom components. Diffuse alveolar hemorrhage reported after insects sting (mainly Hymenoptera) involved anaphylaxis or previous sensitization [4,5]. Spider bites are generally not dangerous because the amount of venom injected is low and the toxins lack mammal specificity. However, brown spiders (Loxosceles species; brown recluse) and widow spiders (Lactrodectus sp; black widow) may induce systemic reactions [6]. The brown recluse spider bite may result in necrotic arachnidism, a bleb surrounded by ecchymosis, sometimes evolving into pyoderma gangrenosum–like ulcer [6,7]. The “red, white, and blue sign” reflects neutrophil activation with subsequent erythema, ischemi,a and thrombosis, triggered by venom enzymes [5,7,8]. Loxoscelism is a rare systemic reaction occurring 24 to 72 hours after the bite, with lethal potential [6]. Loxosceles species are found worldwide [9]. Reported presentations after spider bites include early necrotizing cutaneous vasculitis [10], protracted arthralgia [11], rhabdomyolysis with renal failure [12], necrotizing fasciitis due to secondary infection [13], and mandibular osteomyelitis [7]. However, spider bites are frequently overemphasized [14]. Diagnosis suspected upon history, like our case, should preferably use insect retention and exclusion of other causes, including Lyme disease [14]. Many alleged brown recluse reactions are due to bacterial infection, usually with methicillin-resistant Staphylococcus aureus [14] and Clostridium perfringens, contained in spider glands [8]. However, S aureus carriage is pathogenetic without evidence of systemic dissemination in granulomatosis with polyangiitis [1]; and a staphylococcal leukocydin is directly linked to the pulmonary hemorrhage [15]. After a brown spider bite, neutrophil degranulation is common [7]. Lysosomal neutrophilic enzymes are largely phylogenetically conserved, having amino acid sequence similarities from prokaryotes to humans [16]. The recluse spider venom enzymatic components include elastase and sphingomyelinase [17]. Elastase is also elevated in the BAL and serum of patients with active vasculitis and is centrally involved in ANCA-induced neutrophilic lung injury [17,18]. Endothelial secretion of
0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Damian L-O, et al, Anticytoplasm neutrophil antibodies–positive vasculitis with diffuse alveolar hemorrhage related to a spider bite, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.06.021
2
L-O. Damian et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Anca Cristea PhD “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj Immunology Laboratory, Emergency Clinical County Hospital Cluj Simona Rednic MD, PhD Rheumatology Department, Emergency Clinical County Hospital Cluj “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj Natalia Hagău MD, PhD “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj Anesthesiology-Intensive Care Department Emergency Clinical County Hospital Cluj http://dx.doi.org/10.1016/j.ajem.2015.06.021 Figure. Chest radiograph showing a reverse bat wing appearance due to alveolar hemorrhage.
sphingomyelinase in vessel inflammation amplifies endothelial dysfunction by suppressing nitric oxide release [8,19]. ANCA-associated vasculitis with pulmonary hemorrhage has not been previously described in a spider bite, to our knowledge. Neutrophil activation by venom components was likely the initiating event. We suggest that molecular mimicry between the venom and the neutrophil enzymes could have amplified the neutrophil-induced damage. This report expands the list of life-threatening complications of spider bites and also the list of vasculitis triggers. Conflict of Interests None. Acknowledgements The authors wish to thank Dr Carmen Gota for reviewing the manuscript and Mrs Sally Wood-Lamont for the language and editorial assistance. Laura-Otilia Damian MD, PhD Rheumatology Department, Emergency Clinical County Hospital Cluj Corresponding author. Rheumatology Department Emergency Clinical County Hospital Cluj 2-4 Clinicilor St, 400006 Cluj-Napoca, Romania Tel.: +40 264596912, +40722643760 (Mobile) fax: +40 264431040 E-mail address: [email protected] Cristina Lenuţ MD Emergency County Hospital Alba-Iulia Dan Sebastian Dîrzu MD “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj Anesthesiology-Intensive Care Department Emergency Clinical County Hospital Cluj
References [1] Kallenberg CG. Pathogenesis of ANCA-associated vasculitis, an update. Clin Rev Allergy Immunol 2011;41(2):224–31. http://dx.doi.org/10.1007/is12016-011-8258-y. [2] Jennette JC, Xiao H, Falk RJ. Pathogenesis of vascular inflammation by antineutrophil cytoplasmic antibodies. J Am Soc Nephrol 2006;17(5):1235–42. http:// dx.doi.org/10.1681/JASN.2005101048. [3] Reisman RE. Unusual reactions to insect stings. Curr Opin Allergy Clin Immunol 2005;5(4):355–8. [4] Mukhopadhyay A, Fong KF, Lim TK. Diffuse alveolar haemorrhage: a rare reaction to insect sting. Respirology 2002;7(2):157–9. [5] Lam SM. Acute pulmonary haemorrhage following a honeybee sting: a case report. J Microbiol Immunol Infect 1998;31(2):133–6. [6] Leach J, Bassichis B, Itani K. Brown recluse spider bites to the head: three cases and a review. Ear Nose Throat J 2004;83(7):465–70. [7] Naidu DK, Ghurani R, Salas RE, Mannari RJ, Robson MC, Payne WG. Osteomyelitis of the mandibular symphysis caused by brown recluse spider bite. Eplasty 2008;8:e45 [Published, online 2008 Aug 28]. [8] Upadhyay RK, Ahmad S. A review on spider toxin, a useful source of pharmacological peptides. J Pharm Res 2011;4(4):1169–72. [9] Chaim OM, Trevisan-Silva D, Chaves-Moreira D, Wille ACM, Pereira Ferrer V, Matsubara H, et al. Brown spider (Loxosceles genus) venom toxins: tools for biological purposes. Toxins (Basel) 2011;3(3):309–44. [10] Robb CW, Hayes BB, Boyd AS. Generalized vasculitic exanthem following Loxosceles reclusa envenomation. J Cutan Pathol 2007;34(6):513–4. [11] Richardson-Boedler C. The forensic examiner, fall 08. http://www.theforensicexaminer. com/archive/fall08/7. [12] Hogan CJ, Barbaro KC, Winkel K. Loxoscelism: old obstacles, new directions. Ann Emerg Med 2004;44:608–24. [13] Majeski J. Necrotizing fasciitis developing from a brown recluse spider bite. Am Surg 2001;67(2):188–90. [14] Vetter RS, Bush SP. The diagnosis of brown recluse spider bite is overused for dermonecrotic wounds of uncertain etiology. Ann Emerg Med 2002;39(5):544–6. [15] Lazor R. Alveolar haemorrhage syndromes. Chapter 2. In: Cordier J-F, editor. European respiratory monograph, 54: orphan lung diseases, 54. Eur Resp Mon; 2011. p. 15–31. [16] Hughes AL. Evolutionary diversification of the mammalian defensins. Cel Mol Life Sci 1999;56(1-2):94–103. [17] Seidowsky A, Hoffmann M, Ruben-Duval S, Mesbah R, Masy E, Kyndt X, et al. Elastase ANCA-associated necrotizing crescentic glomerulonephritis: a report of 3 cases. Nephrol Dial Transplant 2007;22(7):2068–71. [18] Hattar K, Oppermann S, Ankele C, Weissmann N, Schermuly RT, Bohle RM, et al. cANCA-induced neutrophil-mediated lung injury: a model of acute Wegener’s granulomatosis. Eur Respir J 2010;36(1):187–95. http://dx.doi.org/10.1183/09031936. 00143308. [19] Kiprianos AP, Morgan MD, Little MA, Harper L, Bacon PA, Young SP. Elevated active secretory sphingomyelinase in antineutrophil cytoplasmic antibody-associated primary systemic vasculitis. Ann Rheum Dis 2012;71(6):1100–2. http://dx.doi.org/10. 1136/annrheumdis-2011-200445.
Please cite this article as: Damian L-O, et al, Anticytoplasm neutrophil antibodies–positive vasculitis with diffuse alveolar hemorrhage related to a spider bite, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.06.021
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Anticytoplasm neutrophil antibodies–positive vasculitis with diffuse alveolar hemorrhage related to a spider bite Abstract Diffuse alveolar hemorrhage is a life-threatening complication of anticytoplasm neutrophil antibodies–associated vasculitis. We report the first case of microscopic polyangiitis with pulmonary-renal syndrome triggered by a spider bite and discuss the potential mechanisms involving neutrophil activation in loxoscelism. This expands the list of autoimmune and toxic reactions related to spider bites, as well as the list of vasculitis triggers. Diffuse alveolar hemorrhage (DAH) is a neutrophil-mediated lifethreatening complication of anticytoplasm neutrophil antibodies (ANCA)–positive vasculitis [1,2]. Insect bites or stings are possible triggers for vasculitis [3]. Although DAH has been rarely seen after Hymenoptera stings [4,5], ANCA-positive vasculitis with pulmonary-renal syndrome has not been reported, to our knowledge, related to spider bites. A 19-year-old rural-living female patient presented to the emergency department in acute respiratory distress syndrome with diffuse arthralgia and myalgia and no fever. Three weeks before, she had been treated by the general practitioner with oxacillin and prednisone for a spider bite that resulted in a limited necrotic rash of the second left toe tip. Clinical examination revealed a discrete purpuric rash with few necrotic elements, mainly on the left toes and dorsum of the foot. The analyses showed inflammation (erythrocyte sedimentation rate, 85 mm/h; C-reactive protein, 10.5 mg/dL) and leukocytosis (12 000 white blood cells per microliter) with left shift (79% neutrophils, 3% eosinophils) and microhematuria (10-15 red blood cells per field). D-Dimers were normal; no schistocytes were found. The hemoglobin value dropped in 2 hours by 2 points (from 11 to 9 mg/dL). Chest radiograph revealed a reverse bat wing appearance, suggestive of DAH (Figure). Bronchoscopy excluded other sources of bleeding. Life support (intubation and ventilation), broad-spectrum antibiotic coverage, methylprednisolone, and then cyclophosphamide pulse were introduced for the suspected vasculitis with pulmonary-renal syndrome. Sputum culture, nose and throat swabs, urine culture, and blood cultures were negative; and procalcitonin was normal. The screening for hepatitis B, C viruses, HIV, TBC, Borrelia, Cytomegalovirus IgM, Mycoplasma IgM, and Leptospirae revealed no positivity. Antimyeloperoxidase antibodies (enzyme-linked immunosorbent assay Innova, 80 IU; reference value, b10 IU) came out positive. The other immunological test results were normal (complement fractions, immunoglobulins including IgE, antiglomerular basement membrane, proteinase-3 antibodies, antinuclear and anticardiolipin antibodies, lupus anticoagulant, rheumatoid factor). A skin punch biopsy revealed leukocytoclastic vasculitis. Therefore, the diagnosis was microscopic polyangiitis.
On immunosuppression and support therapy, she made a complete pulmonary and renal recovery. Chest high-resolution computed tomography after 6-month follow-up found no active alveolitis. Diffuse alveolar hemorrhage is a life-threatening event in microscopic polyangiitis due to alveolocapillary membrane damage from capillary wall fibrinoid necrosis and thrombosis [1]. Neutrophils are the principal effector cells responsible for mediating ANCA-induced acute necrotizing vascular inflammation [1,2]. The pathogenesis of ANCA vasculitis is multifactorial, involving genetic factors such as ANCA expression by neutrophils, antiprotease alleles, and immune response genes polymorphisms, whereas environmental factors are at least adjuvants, if not primary stimuli [2]. Insect bites may produce infectious vasculitis (eg, ricketsial diseases, including Q fever, Lyme disease) or delayed hypersensitivity reactions to venom components. Diffuse alveolar hemorrhage reported after insects sting (mainly Hymenoptera) involved anaphylaxis or previous sensitization [4,5]. Spider bites are generally not dangerous because the amount of venom injected is low and the toxins lack mammal specificity. However, brown spiders (Loxosceles species; brown recluse) and widow spiders (Lactrodectus sp; black widow) may induce systemic reactions [6]. The brown recluse spider bite may result in necrotic arachnidism, a bleb surrounded by ecchymosis, sometimes evolving into pyoderma gangrenosum–like ulcer [6,7]. The “red, white, and blue sign” reflects neutrophil activation with subsequent erythema, ischemi,a and thrombosis, triggered by venom enzymes [5,7,8]. Loxoscelism is a rare systemic reaction occurring 24 to 72 hours after the bite, with lethal potential [6]. Loxosceles species are found worldwide [9]. Reported presentations after spider bites include early necrotizing cutaneous vasculitis [10], protracted arthralgia [11], rhabdomyolysis with renal failure [12], necrotizing fasciitis due to secondary infection [13], and mandibular osteomyelitis [7]. However, spider bites are frequently overemphasized [14]. Diagnosis suspected upon history, like our case, should preferably use insect retention and exclusion of other causes, including Lyme disease [14]. Many alleged brown recluse reactions are due to bacterial infection, usually with methicillin-resistant Staphylococcus aureus [14] and Clostridium perfringens, contained in spider glands [8]. However, S aureus carriage is pathogenetic without evidence of systemic dissemination in granulomatosis with polyangiitis [1]; and a staphylococcal leukocydin is directly linked to the pulmonary hemorrhage [15]. After a brown spider bite, neutrophil degranulation is common [7]. Lysosomal neutrophilic enzymes are largely phylogenetically conserved, having amino acid sequence similarities from prokaryotes to humans [16]. The recluse spider venom enzymatic components include elastase and sphingomyelinase [17]. Elastase is also elevated in the BAL and serum of patients with active vasculitis and is centrally involved in ANCA-induced neutrophilic lung injury [17,18]. Endothelial secretion of
0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Damian L-O, et al, Anticytoplasm neutrophil antibodies–positive vasculitis with diffuse alveolar hemorrhage related to a spider bite, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.06.021
2
L-O. Damian et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Anca Cristea PhD “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj Immunology Laboratory, Emergency Clinical County Hospital Cluj Simona Rednic MD, PhD Rheumatology Department, Emergency Clinical County Hospital Cluj “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj Natalia Hagău MD, PhD “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj Anesthesiology-Intensive Care Department Emergency Clinical County Hospital Cluj http://dx.doi.org/10.1016/j.ajem.2015.06.021 Figure. Chest radiograph showing a reverse bat wing appearance due to alveolar hemorrhage.
sphingomyelinase in vessel inflammation amplifies endothelial dysfunction by suppressing nitric oxide release [8,19]. ANCA-associated vasculitis with pulmonary hemorrhage has not been previously described in a spider bite, to our knowledge. Neutrophil activation by venom components was likely the initiating event. We suggest that molecular mimicry between the venom and the neutrophil enzymes could have amplified the neutrophil-induced damage. This report expands the list of life-threatening complications of spider bites and also the list of vasculitis triggers. Conflict of Interests None. Acknowledgements The authors wish to thank Dr Carmen Gota for reviewing the manuscript and Mrs Sally Wood-Lamont for the language and editorial assistance. Laura-Otilia Damian MD, PhD Rheumatology Department, Emergency Clinical County Hospital Cluj Corresponding author. Rheumatology Department Emergency Clinical County Hospital Cluj 2-4 Clinicilor St, 400006 Cluj-Napoca, Romania Tel.: +40 264596912, +40722643760 (Mobile) fax: +40 264431040 E-mail address: [email protected] Cristina Lenuţ MD Emergency County Hospital Alba-Iulia Dan Sebastian Dîrzu MD “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj Anesthesiology-Intensive Care Department Emergency Clinical County Hospital Cluj
References [1] Kallenberg CG. Pathogenesis of ANCA-associated vasculitis, an update. Clin Rev Allergy Immunol 2011;41(2):224–31. http://dx.doi.org/10.1007/is12016-011-8258-y. [2] Jennette JC, Xiao H, Falk RJ. Pathogenesis of vascular inflammation by antineutrophil cytoplasmic antibodies. J Am Soc Nephrol 2006;17(5):1235–42. http:// dx.doi.org/10.1681/JASN.2005101048. [3] Reisman RE. Unusual reactions to insect stings. Curr Opin Allergy Clin Immunol 2005;5(4):355–8. [4] Mukhopadhyay A, Fong KF, Lim TK. Diffuse alveolar haemorrhage: a rare reaction to insect sting. Respirology 2002;7(2):157–9. [5] Lam SM. Acute pulmonary haemorrhage following a honeybee sting: a case report. J Microbiol Immunol Infect 1998;31(2):133–6. [6] Leach J, Bassichis B, Itani K. Brown recluse spider bites to the head: three cases and a review. Ear Nose Throat J 2004;83(7):465–70. [7] Naidu DK, Ghurani R, Salas RE, Mannari RJ, Robson MC, Payne WG. Osteomyelitis of the mandibular symphysis caused by brown recluse spider bite. Eplasty 2008;8:e45 [Published, online 2008 Aug 28]. [8] Upadhyay RK, Ahmad S. A review on spider toxin, a useful source of pharmacological peptides. J Pharm Res 2011;4(4):1169–72. [9] Chaim OM, Trevisan-Silva D, Chaves-Moreira D, Wille ACM, Pereira Ferrer V, Matsubara H, et al. Brown spider (Loxosceles genus) venom toxins: tools for biological purposes. Toxins (Basel) 2011;3(3):309–44. [10] Robb CW, Hayes BB, Boyd AS. Generalized vasculitic exanthem following Loxosceles reclusa envenomation. J Cutan Pathol 2007;34(6):513–4. [11] Richardson-Boedler C. The forensic examiner, fall 08. http://www.theforensicexaminer. com/archive/fall08/7. [12] Hogan CJ, Barbaro KC, Winkel K. Loxoscelism: old obstacles, new directions. Ann Emerg Med 2004;44:608–24. [13] Majeski J. Necrotizing fasciitis developing from a brown recluse spider bite. Am Surg 2001;67(2):188–90. [14] Vetter RS, Bush SP. The diagnosis of brown recluse spider bite is overused for dermonecrotic wounds of uncertain etiology. Ann Emerg Med 2002;39(5):544–6. [15] Lazor R. Alveolar haemorrhage syndromes. Chapter 2. In: Cordier J-F, editor. European respiratory monograph, 54: orphan lung diseases, 54. Eur Resp Mon; 2011. p. 15–31. [16] Hughes AL. Evolutionary diversification of the mammalian defensins. Cel Mol Life Sci 1999;56(1-2):94–103. [17] Seidowsky A, Hoffmann M, Ruben-Duval S, Mesbah R, Masy E, Kyndt X, et al. Elastase ANCA-associated necrotizing crescentic glomerulonephritis: a report of 3 cases. Nephrol Dial Transplant 2007;22(7):2068–71. [18] Hattar K, Oppermann S, Ankele C, Weissmann N, Schermuly RT, Bohle RM, et al. cANCA-induced neutrophil-mediated lung injury: a model of acute Wegener’s granulomatosis. Eur Respir J 2010;36(1):187–95. http://dx.doi.org/10.1183/09031936. 00143308. [19] Kiprianos AP, Morgan MD, Little MA, Harper L, Bacon PA, Young SP. Elevated active secretory sphingomyelinase in antineutrophil cytoplasmic antibody-associated primary systemic vasculitis. Ann Rheum Dis 2012;71(6):1100–2. http://dx.doi.org/10. 1136/annrheumdis-2011-200445.
Please cite this article as: Damian L-O, et al, Anticytoplasm neutrophil antibodies–positive vasculitis with diffuse alveolar hemorrhage related to a spider bite, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.06.021
